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Volume 67
Part 4
Pages 271-281
April 2011
Received 1 September 2010
Accepted 22 November 2010
iMOSFLM: a new graphical interface for diffraction-image processing with MOSFLM
aMRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, England
Correspondence e-mail: andrew@mrc-lmb.cam.ac.uk
iMOSFLM is a graphical user interface to the diffraction data-integration program MOSFLM. It is designed to simplify data processing by dividing the process into a series of steps, which are normally carried out sequentially. Each step has its own display pane, allowing control over parameters that influence that step and providing graphical feedback to the user. Suitable values for integration parameters are set automatically, but additional menus provide a detailed level of control for experienced users. The image display and the interfaces to the different tasks (indexing, strategy calculation, cell refinement, integration and history) are described. The most important parameters for each step and the best way of assessing success or failure are discussed.
1. Introduction
MOSFLM (Leslie, 2006) is a program to process diffraction data collected using the oscillation method (Arndt & Wonacott, 1977). A graphical user interface (GUI) for the program was developed in the 1990s based on a set of X11 routines provided by J. W. Campbell (Campbell, 1995). While this interface offered a high degree of functionality, the overall graphical quality was limited and the restrictions of the routines available made efficient and intuitive design difficult. A new Tcl/Tk-based GUI, iMOSFLM, has recently been developed to address these issues.
There are a variety of reasons why a graphical interface is valuable when processing diffraction data, and GUIs are a feature of many processing packages including HKL-2000 (Otwinowski & Minor, 1997), SAINT (Bruker Analytical X-ray Systems, Madison, USA), d*TREK (Pflugrath, 1999) and XGEN (Howard, 2000). The ability to inspect the diffraction images, especially with the predicted diffraction pattern overlaid, is invaluable in identifying potential problems that might occur during subsequent processing. These arise for a wide variety of reasons, including poor spot shape, very high crystal mosaicity, multiple lattices, anisotropic diffraction, the presence of diffraction spots or rings owing to ice formation, shadows from backstops or experimental equipment, errors in the direct-beam position and zingers (bright pixels resulting from cosmic rays or radioactive decay events in the fibre-optic taper). Being able to continuously monitor the refined detector and crystal parameters as processing proceeds provides a means of assessing the stability of the refinement and identifying if and when problems occur.
The new interface was designed to provide an intuitive route to data processing, so that inexperienced users are guided in a logical fashion through the stages of data processing and alerted to potential problems. At the same time it was felt important to provide the full functionality of the MOSFLM program (available via a very large number of keywords in the command-line version) for more experienced users, but in an unobtrusive fashion. The overall structure of the GUI and a more detailed description of the individual tasks and their graphical output are given below.
2. Overall structure of the iMOSFLM GUI
iMOSFLM acts as a `front end' to the MOSFLM program itself. iMOSFLM generates the MOSFLM commands for particular tasks, based on user input, and then passes these commands to MOSFLM, which carries out all the computation. The results of these tasks are then passed back to iMOSFLM for display, either on completion of the task (e.g. spot-finding, auto-indexing, strategy calculations) or while the task is still in progress (e.g. cell refinement and integration). iMOSFLM and MOSFLM are run as separate processes, with the MOSFLM process being started by iMOSFLM. This means that iMOSFLM always retains all the parameters relevant to a particular task, so that if MOSFLM encounters an error that causes it to fail, iMOSFLM can restart MOSFLM and the user can attempt to recover from the failure.
2.1. The iMOSFLM panes
Each iMOSFLM task has its own pane where relevant parameters can be set and the results are displayed. The available tasks (Images, Indexing, Strategy, Cell Refinement, Integration and History) are listed on the vertical icon bar on the left-hand side of the GUI (Fig. 1) and can be selected by the user, but a particular icon will only become active (i.e. user-selectable) once any necessary preceding actions have been carried out. For example, indexing can only be selected once images have been added to the session using the Add Images button in the Images pane. This displays a file browser and selecting any image file will add all images that have the same filename template. Images with different filename templates can also be added but will be assigned to different sectors. The start and end oscillation angles of each image are listed and once an image has been processed the missetting angles (changes in crystal orientation relative to the initial orientation) are added. The cell, space group, mosaicity and mosaic block size are also listed in the Images pane (and are user-editable).
Figure 1
An overview of the iMOSFLM GUI. The Integration pane is shown and the icons for the various tasks are displayed in the vertical icon bar on the left-hand side of the window. Refined detector and crystal parameters are displayed graphically in the central upper and middle windows, respectively. Intensity statistics are displayed in the lower central and lower right-hand windows. The average spot profile for spots in the central region of the detector is shown in the upper right panel and the standard profiles for different regions of the detector are shown in the central right panel.
2.2. The Image Display window
As soon as one or more images have been added to the session, the first image will be displayed in the Image Display window (Fig. 2). Buttons in the tool bar control display of the direct-beam position, spots found (for indexing), predicted reflections, masked areas (e.g. the backstop shadow), spot search region and resolution limits, while other icons control zooming and panning, a selection tool, manual addition of spots, the definition of masked regions, the definition of the centre of a circle and the erasure of either masks or manually added spots. Additional icons control image zoom (about the current centre), image size and image contrast. Any image can be selected for display from a drop-down list. A useful feature of the zoom window is that the zoomed region is always preserved when changing from one image to another. The View option in the menu bar allows the size of the image display to be changed, while the Tools option allows a reflection with particular indices to be located. The selection tool displays the resolution at any point in the image (when the Ctrl key is depressed) and when over a predicted reflection also displays the Miller indices. It can be used to make `drag-and-drop' adjustments to the spot-search areas, resolution limits, direct-beam position and masked areas.
Figure 2
The iMOSFLM Image Display window. The functions of the buttons in the tool bar are explained in the main text.
2.3. Drop-down menus
The Session and View menus are always accessible via the menu bar. The Session drop-down menu allows the user to start a new session, save the current session or load a previously saved session. A new session is started each time iMOSFLM is run or when selected by the drop-down menu. Saving a session stores all the information about the current state of the interface, including the images that have been read, the current values of all refineable parameters and processing options and the graphical information for all steps carried out during the session. The View menu allows access to the various settings dialogues that allow experimental and detector parameters to be defined (under Experiment Settings) and a large number of parameters and options influencing the processing stages to be set (under Processing Options). Some of these will be described in later sections.
3. The Indexing pane
On selecting the Indexing task, iMOSFLM issues commands to find spots on two images: the first image in the series and the image that is as close as possible to a 90° rotation away from the first. Found spots are displayed both in the Image Display window and in a representation of the images in the Indexing pane (Fig. 3). Spots above the current threshold for use in indexing are shown as red crosses; those below the threshold are shown in yellow. Typically, indexing works best with a few hundred spots (in total). Additional images can be included in the indexing by entering the image numbers into the Images field or by selecting them from a drop-down list of all images. The images to be used in indexing, the number of spots found and the number of spots above the threshold are displayed. Individual images can be deselected by clicking the Use box, but can subsequently be included without repeating the spot search by selection from the drop-down list of all images. Auto-indexing, which is carried out by clicking the Index button, uses an FFT-based auto-indexing algorithm to determine the crystal lattice (Steller et al., 1997; Powell, 1999). If successful, auto-indexing produces a list of possible solutions sorted on penalty. Typically, there will be a group of solutions with low penalty followed by a series of solutions with much higher penalty values (unless the crystal is triclinic, in which case there may only be a single solution with low penalty). MOSFLM selects a solution based on a simple analysis of the penalty and the metric symmetry. The preferred solution is highlighted and the prediction is displayed on the image display. At this stage, only information about the lattice shape is available (based on observed spot positions) and therefore the assignment of symmetry (above triclinic) is an assumption that needs to be tested after images have been integrated.
Figure 3
The iMOSFLM Indexing pane. Parameters that influence spot finding and indexing are shown in the tool bar. Details of the images used for indexing and the number of spots found and used are presented as a table and graphically. The list of possible indexing solutions is shown, with the preferred solution highlighted.
If the appropriate option is set in the Processing Options dialogue, the indexing and mosaicity-estimation processes will be carried out automatically after spot finding without the requirement to click the Index button.
3.1. Spot-finding parameters
Parameters that control spot finding are listed in the Spot finding tab of the Processing Options dialogue. The search area is set by default to be between circles of radii corresponding to 5 and 95% of the radius of the inscribed circle centred on the direct-beam position, but this can be adjusted graphically with the spot-finding button on the Image display or by setting the values explicitly. The default threshold value for a pixel to be considered part of a spot is set to 5.0 above the background (where is determined by counting statistics) and a variety of rejection criteria are applied to distinguish true Bragg spots from noise features in the image. These include a minimum number of pixels, minimum and maximum sizes (mm), a minimum r.m.s. variation of pixel values within the spot, a maximum anisotropy in spot dimensions, a minimum spot separation and a maximum peak separation within spots. The default values have been optimized for images collected on synchrotron beamlines, where the spots tend to be smaller than for images collected on a laboratory source. For the latter, if the spots are large and diffuse then better results can be obtained by decreasing the threshold (e.g. to 2.0), increasing the minimum number of pixels to 20-30, reducing the r.m.s. spot variation to 1.0 and setting the minimum spot separation to values around 1.5 mm (although this is best set to the actual size of the diffraction spots in the image).
Two algorithms are available for determining the local X-ray background. The simpler one assumes that the background is circularly symmetric about the direct-beam position and determines the background in a radial stripe 50 pixels wide. The orientation of this stripe is at 90° to the direction of the rotation axis in order to avoid any shadow arising from a solid backstop support (on the assumption that these are normally aligned parallel to the rotation axis), but this can be changed by `drag and drop' in the Image display or via the Spot finding tab. For tiled detectors, this stripe is automatically offset to avoid using pixels in the gaps between tiles for the initial estimate of the radial background. The second and generally preferred algorithm uses a local background calculation, which by default finds the background in boxes of size 50 × 50 pixels. In some cases, the local background method results in spurious spots being located close to sharp shadows in the image (e.g. owing to the backstop support). These are normally below the threshold for use in auto-indexing and can be ignored, but reducing the size of the local background region (e.g. to 20 × 20 pixels) will often eliminate these spurious spots. Even when the local background method is being used, an initial radial stripe background is determined to set parameters associated with the background determination, so it is important that this stripe (which can be displayed on the image with the spot-finding search area button) does not lie over a large shadow on the detector.
The inclusion of spots arising from crystalline ice can easily result in the failure of auto-indexing. To avoid this problem, spots within narrow resolution shells centred on the principal reflections of hexagonal crystalline ice are automatically excluded. In addition, if the diffraction is very weak the resolution limit for spot finding is automatically reduced to 4.5 Å in order to avoid including any noise features that might occur at higher resolution (e.g. owing to zingers) and the minimum spot size is also decreased. If there are only a few true Bragg spots present, the inclusion of only a small number of noise spots can lead to failure of the indexing. Finally, the intensity threshold for spots to be included in the auto-indexing is automatically set to 5, 10 or 20 depending on the strength of the diffraction (on the last image processed), which also decreases the chance of indexing failure. All of these options can be overridden in the Processing Options dialogue.
3.2. Indexing parameters
Only two user-definable parameters influence the indexing algorithm. These are the threshold for spots to be included in indexing (as mentioned in §3.1) and the maximum cell edge. The default value for the latter is set to the real-space distance corresponding to the closest two spots to be used in indexing, but this can be too high if spurious spots are above the indexing threshold or if a second lattice is present.
3.3. Judging the success of the indexing
The most reliable way of assessing whether the chosen solution is correct is by inspecting the resulting prediction, preferably on all the images used in indexing and, if available, also on some images not used in indexing. The predicted reflections should agree with the observed Bragg spots both in position and in terms of the general appearance of the lunes (the typically crescent-shaped or sometimes approximately circular regions of spots on the image, each of which contains reflections from a different plane in reciprocal space). Note that unless the mosaicity has been estimated (see §3.7) not all observed spots are predicted. Different solutions in the indexing results table can be selected to check the corresponding predictions. A correct solution will normally have a penalty lower than 20, provided that the values for the experimental parameters (direct-beam position, distance and wavelength) are correct. Another useful indicator is the positional residual, denoted (x,y) in the table, which is the r.m.s. difference between the observed and calculated spot positions. Typical values are 0.1-0.2 mm for synchrotron images and 0.2-0.3 mm for images collected using a laboratory source (where the spots are larger). However, if the spots are split or very irregular in shape this value can be as high as 1-1.5 mm for the correct solution and therefore it is not possible to define a cutoff value that is applicable in all cases. Errors in the experimental parameters may also produce larger values. The positional residual can be a useful indicator of the presence of pseudosymmetry. If, for example, the symmetry is monoclinic but with a angle close to 90°, the automatically chosen solution will probably be the (pseudo) orthorhombic one. If close inspection reveals that there is a monoclinic solution with a positional residual that is more than 0.1 mm less than that for the orthorhombic solution, it is very probable that the monoclinic solution is correct. Choosing the correct solution is important when selecting a data-collection strategy, but the only way to be confident of the correct Laue group is to collect and integrate images corresponding to a small rotation (e.g. 3-10°) and then to run POINTLESS (Evans, 2011; see §6.7).
3.4. Common causes of indexing failure
3.4.1. Errors in direct-beam coordinates
The most common cause of indexing failure is having incorrect values for the direct-beam coordinates (these are read from the image-file header). The direct-beam position is indicated in the Image display (as a green cross) and so it is immediately obvious if this is seriously in error (e.g. not within the backstop shadow). The beam position can be adjusted manually (using the selection tool to drag and drop) and in favourable cases (small backstop shadow, clear lune definition) it can easily be positioned close enough to the correct position to allow indexing. If ice rings are present a tool is available in the Image display to determine the centre of the ring (and hence the direct-beam position) by circle-fitting a small number of points on a ring (this assumes that the face of the detector is normal to the X-ray beam, i.e. there is no 2 offset). The accuracy required for the beam coordinates depends on the cell dimensions, with larger unit cells requiring more accurate coordinates. To avoid mis-indexing, the coordinates need to be known to an accuracy corresponding to less than one half of the spot separation for the longest cell axis. For cell axes longer than about 250 Å it can be very difficult to detect from the results of the indexing if the pattern is mis-indexed by one index along the long axis. However, integration of even a small rotation range and subsequent symmetry detection with POINTLESS will immediately detect this error, as even Friedel pairs will give poor agreement. As an alternative to manually defining the direct-beam position a two-dimensional grid search can be carried out where, by default, the beam coordinates will be varied by ±1.0 mm in 0.5 mm steps (these parameters can be changed in the Processing Options dialogue) and the indexing carried out for each new position. The positional residual and consistency between the refined beam coordinates can be used to select the most probable correct beam position. This procedure works best if at least two images (preferably widely separated in rotation angle) are used.
3.4.2. Problem cases
It is not uncommon for images to show evidence of multiple lattices or for the second image used for indexing to show the results of severe radiation damage. In such cases, selecting a single (less problematic) image can result in successful indexing, while inclusion of both images fails. In the case of multiple lattices, it may only be necessary to increase the intensity threshold for spots to be included in the indexing, with values of up to 100 sometimes being necessary. The same approach works well for crystals with very high mosaicity (no distinct lunes visible). In marginal cases, usually those with very weak diffraction resulting in very few spots above the threshold, varying the threshold slightly from the default value can make the difference between failure and success. The use of more than two images can also be helpful in difficult cases, ideally with the additional images well separated in rotation angle from those already being used. All of these modifications to the default behaviour are readily achieved via the Indexing pane.
Another possible cause of indexing failure, especially if the diffraction is strong and there is no evidence of other problems, is that the direction of spindle rotation is opposite to that conventionally used. This is the case on a number of synchrotron beamlines. In this case, indexing should be successful when only a single image is used, but if the next image in the series is inspected the prediction will not match the observed spots. This can be dealt with checking a box in the Detectors tab of the Experiment Settings dialogue and repeating the spot search for all images used in indexing to ensure that the correct values are assigned.
3.5. Other indexing issues
Caution is required if only a single image is used for indexing since for low-symmetry space groups it is possible to find an indexing solution that will correctly predict one image but will not correctly predict images that differ significantly in . This is why iMOSFLM always uses two images by default.
When inspecting the predicted pattern, it is also important to check if pseudo-centring or lattice repeats have resulted in a particular class of reflections being systematically weak. If only strong reflections are used in the indexing, the resulting unit cell will be too small to predict the weak reflections and the indexing should be repeated with a reduced intensity threshold.
3.6. Choice of space group
If the correct space group is known, it can be selected from a drop-down menu. If it is not known, the lowest symmetry should be assumed until the data have been integrated and the symmetry assessed with POINTLESS (see §6.7). The selection of the space group will only affect the strategy calculation and will have no effect whatever on cell refinement or data integration.
3.7. Mosaicity estimation
An initial estimate of the crystal mosaicity is obtained (Rossmann, 1979) by integrating the (first) image with different values for the mosaic spread and selecting the value for which the total intensity of all predicted spots reaches a plateau value (Fig. 4a). If the unit cell is large, the total intensity will drop for large values of the mosaic spread as some reflections become flagged as overlapped and are not integrated (Fig. 4b). The mosaicity is refined during cell refinement and data integration, so the accuracy of this initial estimate is not critical.
Figure 4
Mosaicity estimation. The total intensity for all predicted spots is plotted as a function of the mosaic spread. (a) In most cases the total intensity will reach a plateau at the correct value for the mosaic spread. (b) With large unit cells (or large oscillation angles) the total intensity can drop rather than plateau because spatially overlapping spots are not integrated.
3.7.1. The mosaic block size
If the mosaic block size of the crystal is very small (less than a few micrometres) this has the effect of changing the apparent crystal mosaicity as a function of resolution (Nave, 1998; Juers et al., 2007). In practice, this can give rise to an apparent mosaic spread of one or two degrees at low resolution compared with a much smaller value at high resolution. This can be modelled by reducing the mosaic block size (default value 100 µm) so that the predictions match the observed pattern at both low and high resolution (Fig. 5). This is performed manually by entering different values for the mosaic block size in the Image pane, but is best performed after cell refinement (see §5) when the cell, mosaic spread and crystal missetting angles have been optimized.
Figure 5
The effect of the mosaic block size on the predicted diffraction pattern. Reducing the mosaic block size effectively increases the apparent mosaic spread at low resolution with little or no effect at high resolution. (a) 100 µm mosaic block size. (b) 2 µm mosaic block size.
4. The Strategy pane
Once an indexing solution has been found it is possible to access the Strategy pane (Fig. 6), which allows the calculation of an optimal geometrical data-collection strategy based on the Laue group and the crystal orientation defined in the indexing stage. On selecting the strategy task, values will be displayed for the completeness of the overall data and the anomalous data. These figures assume that the entire range between the first and last images has been collected, which is not the case if only two initial screening images (normally separated by a 90° rotation) have been taken in order to characterize the crystal. In these cases, the Auto-complete button should be used to calculate the best data-collection strategy. The default mode (Auto) will work out the start and end that will give a complete data set. Options are available to include data already collected from the same crystal in the same orientation or to optimize the completeness of anomalous data. In many space groups it is possible to collect data with high completeness (>95%) using a total rotation that is significantly less than that strictly required for that Laue group, especially if the crystal is oriented so that none of the principal axes are aligned with the rotation axis. For example, in an orthorhombic space group a 60° rotation in two 30° segments is generally sufficient for 95% overall completeness (although the completeness will be less than this at low resolution). The option is therefore provided to collect the data in up to three distinct segments with a total rotation of between 30 and 90°. Various statistics on completeness and multiplicity as a function of resolution and total rotation angle are presented in graphical form. An interactive graphical representation of the suggested rotation segment(s) is displayed in the lower left area of the pane (Fig. 6) and by clicking it is possible to adjust the start and end values and recalculate the statistics.
Figure 6
The iMOSFLM Strategy pane. Details are given in the main text.
Another button (Check for overlaps) will calculate the maximum oscillation angle per image that will avoid spatial overlaps, based on the current values for the resolution, minimum spot separation and crystal mosaicity, as a function of for the suggested rotation range. Alternatively, the percentage of overlapped reflections can be calculated for different values of the oscillation angle. In both cases, the results are displayed graphically as histograms in the lower right area of the pane.
5. The Cell Refinement pane
The cell parameters determined from the auto-indexing step are based on spot positions and are limited in accuracy as they are highly correlated with the crystal-to-detector distance, which is not refined by default as, except for very high-resolution data, this distance is not well determined. The Cell Refinement task (Fig. 7) allows the refinement of cell parameters, crystal orientation and mosaicity based on a post-refinement procedure (Rossmann et al., 1979; Winkler et al., 1979; Leslie, 2006) that provides more accurate values provided that the resolution of the data is better than 3.5 Å. The procedure involves integrating a small number of segments of data (two by default, but three or more may give better results for triclinic or monoclinic symmetries). The optimal number of images in each segment, which depends on the oscillation angle and the mosaic spread, is calculated automatically. Two segments separated by 90° in (or as close to 90° as possible) are chosen provided that the images are available. The distribution of the total intensity of partially recorded reflections across the images on which they lie, together with a model for the rocking curve, are used for the refinement. During integration of the images, the refined detector and crystal parameters are displayed graphically, together with the average spot profile for spots in the centre of the detector (Fig. 7). Any of these graphs can be expanded to fill the pane by using the mouse scroll wheel or a combination of shift and left mouse button. These graphs are useful in detecting any problems with the integration and will be described in more detail in §6.1. The detector parameters and crystal orientation are refined for every image, but the cell parameters are only refined following integration of all of the images. If there is a large shift in the cell parameters, all images are re-integrated and cell refinement is repeated, and this whole process is repeated to convergence (or a maximum of five times). On completion, the initial and final cell parameters and their estimated uncertainties are reported. The estimated uncertainties should normally be less than 0.1 Å in cell edges and 0.1° for cell angles. Graphs are produced of r.m.s. error in spot positions (referred to as r.m.s.d. below), the refined crystal-to-detector distance and the refined YSCALE parameter (a relative scale factor in the Y direction of the detector), both for each image and separately for each cycle of refinement. Indicators of a successful refinement are a decrease in the r.m.s.d. values, YSCALE values close to unity for all images (except for R-AXIS IV and HTC image-plate detectors, for which the correct value is 0.995) and consistent detector distances for all images.
Figure 7
The iMOSFLM Cell Refinement pane. In this example the refined direct-beam coordinates are plotted in the upper central graph, the refined crystal missetting angles and mosaic spread are plotted in the lower central graph and the r.m.s. residual is plotted in the lower right graph, all as a function of image number. The average spot profile for spots in the central region of the detector is displayed in the upper right panel. The initial and refined cell parameters and an estimate of their standard uncertainties are given in the table.
In situations where the data are too weak or the resolution is too low for successful post-refinement, the cell parameters obtained from the auto-indexing should be used, and in these cases including three or four images (widely separated in ) may improve the accuracy of the cell parameters.
6. The Integration pane
Although it is possible to integrate the data directly after auto-indexing, it is generally recommended that the cell parameters are refined first (as described in §5). This can provide a significant improvement in data quality, especially if the crystal-to-detector distance (read from the header of the image file) is significantly in error. A possible exception is in cases where the true Laue group is uncertain, for example a monoclinic space group with a angle close to 90°. In such cases integration of 5-10° of data with the cell derived from auto-indexing, followed by symmetry assessment with POINTLESS (Evans, 2011), will allow determination of the true symmetry, which in turn will determine which cell parameters are to be refined.
The Integration pane (Fig. 1) allows control of data integration and in addition symmetry detection (POINTLESS) and preliminary scaling (SCALA; Evans, 2006). By default, the image display is not updated during integration as this adds a significant time overhead, but the option to turn image updating on or off during integration is accessible via a button on the tool bar. The results of the integration are written to a multi-record CCP4 MTZ file, which is assigned a filename based on the image filenames, but this can be reset if required. Other icons in the toolbar allow the rejection of all reflections lying in narrow resolution shells corresponding to crystalline ice and a `wait' function that can be used to integrate images that have not yet been collected when processing is started. This latter option is useful when processing data that are being collected on a synchrotron beamline, as it allows processing of the entire data set to start before data collection is complete.
Data integration proceeds in blocks of images, with typically 5-10 images in a block. The detector parameters are refined for each image and the pixel values for the measurement boxes for all predicted spots are written to a scratch file. The standard profiles are formed using all the images in the block and each image is then integrated in turn. Normally, the results of integration are written to a single MTZ file that cannot be used (e.g. to run scaling on intermediate results) until processing is complete. The option is available in the Processing Options dialogue to write a separate MTZ file for every block of images. These files can be used to run either POINTLESS or SCALA before the integration has finished and there is an option to run POINTLESS automatically after integration of each block of images.
6.1. Refined detector parameters
The refined detector parameters are plotted as integration proceeds. Any combination of parameters can be plotted simultaneously, although for simplicity only two different vertical scales are allowed. There is also the option to fix any of the refineable parameters at the input value, which can improve the processing of very weak diffraction data. These graphs will highlight any instability in the refinement. Typically, beam coordinates should not vary by more than 0.1 mm, detector tilt and twist should not vary by more than 0.2°, the distance should be stable to within 0.5 mm and the YSCALE value should equal 1.000 (except as noted in §5) for all images. In addition, the r.m.s. residual (the r.m.s. difference between observed and predicted spot positions) should remain approximately constant, especially for spots in the central region of the detector, unless there is noticeable change in spot shape. Typical values are 0.03-0.06 mm for synchrotron data, where the spots are usually relatively small.
If the crystal unit-cell parameters change significantly during the data collection as a result of radiation damage, the crystal-to-detector distance will decrease monotonically and the YSCALE parameter may also change. In addition, if the cell parameters are not accurate, the YSCALE and detector distance parameters will vary in a systematic way in an attempt to achieve the best fit of the predicted and observed spot positions. Inaccurate cell parameters may also result in large variations in the detector tilt and twist. This can, for example, occur when an orthorhombic solution has been chosen for a crystal that is actually monoclinic but with a angle close to 90°. Systematic changes in the detector tilt and twist are excellent indicators of inaccurate cell parameters or other problems with the integration.
6.2. Refined crystal parameters
The crystal missetting angles [(x), (y), (z)] are refined independently for every image (or, for fine-sliced data, for groups of images). It is not unusual to see changes of a few tenths of a degree in these angles for a complete data set. This can either reflect genuine small changes in orientation or can be a consequence of the rotation axis not being exactly orthogonal to the X-ray beam (which is an implicit assumption), which results in apparent changes in missetting angles that repeat with a periodicity of 360°. Providing that the change in orientation between successive images is less than approximately one-tenth of the crystal mosaicity, these changes in orientation will have no effect on data quality. The cell parameters are normally fixed during integration because for technical reasons there are not sufficient data available to define the values of all of the cell parameters accurately. The crystal mosaicity is refined during integration, as the mosaicity can be anisotropic and can increase as a result of radiation damage. The mosaicity refinement can be unstable, refining towards a value close to zero if there are errors in either the cell dimensions or the crystal orientation. For this reason, during the first cycle of cell refinement (see §5) the mosaicity is only refined after all the images have been integrated. If the mosaicity refinement is unstable it is advisable to fix it at the estimated value and integrate a small number of images. This will update the crystal orientation and if these images are then re-integrated the refinement is often stable and the mosaicity need no longer be fixed.
6.3. Intensity and other statistics
The mean value of the ratio of the intensity to its standard uncertainty [I/(I)] is plotted separately for all reflections and for reflections in the highest resolution bin as a function of image number for both fully and partially recorded reflections (Fig. 1, lower left graph). These plots indicate if the overall strength of diffraction is changing with time, for example owing to radiation damage or owing to crystal miscentring in the beam. The number of spatially overlapped reflections, overloaded reflections and reflections flagged as `bad spots' are also plotted against image number. For a crystal with a very long axis (or axes) it may be necessary to reduce the minimum spot-separation values (calculated automatically based on spot sizes) in order to avoid large numbers of reflections being flagged as spatially overlapped at low resolution. These parameters can be changed via the Processing Options dialogue.
6.4. Central spot profile
The average spot profile for reflections in the centre of the detector is plotted for every image processed (Fig. 1), with the boundary between the peak and the background regions of the measurement box plotted as a blue outline. Problems in detector-parameter refinement often result in a deterioration in the appearance of this average spot profile. The MOSFLM program automatically determines the measurement box parameters, which define both the overall size of the box and the position of the peak-background boundary. Additional control over the peak-background definition, making the peak region either smaller or larger, can be achieved by varying the profile tolerance parameters in the Processing Options dialogue. For very closely spaced spots the profile tolerance values can be increased, decreasing the size of the peak, which can result in more stable refinement of the detector parameters and improved spot profiles. The minimum allowed spot separation is calculated based on the size of the peak region of the average spot profile and is updated for every block of images.
6.5. The standard profiles
The standard profiles for different regions of the detector are displayed for each block of images processed. The peak-background boundary is plotted as described for the central spot profile. The appearance of the standard profiles gives a very good indication of the quality of diffraction. Ideally, all the standard profiles are of a regular shape and will not show evidence of spot splitting or contamination with ice spots or other non-Bragg diffraction. When the diffraction is too weak to allow the formation of a well defined standard profile, an averaged profile is calculated by including spots from adjacent regions of the detector. The averaged profiles are indicated by a red border and the original (unaveraged) profile can be viewed by clicking on the relevant profile. Parameters controlling the profile averaging can be altered via the Processing Options dialogue.
6.6. Resolution-dependent statistics
The mean I/(I) values in different resolution ranges are plotted as a histogram for each image, with separate plots for fully recorded and partially recorded reflections. This plot can provide an estimate of the resolution limit of the data as the resolution at which the mean I/(I) drops to below 2.0, but the final resolution limit will depend on the multiplicity of the data and the presence of radiation damage, so this is only an approximate indicator.
6.7. Checking the symmetry with POINTLESS: QuickSymm
Once a series of images has been integrated, the QuickSymm button in the tool bar launches a run of the program POINTLESS (Evans, 2011) to detect Laue and space-group symmetry. The results are displayed in a web browser in graphical form, as a summary and as a full logfile using the CCP4 Baubles utility (Briggs & Cowtan, 2007). POINTLESS typically gives reliable results for the Laue group based on only a few degrees of data and so if the space group is unknown it is useful to run POINTLESS on a few images prior to cell refinement or integration of the full data set. It is only necessary to know the correct Laue group (not the space group) to optimize the data integration.
6.8. Performing preliminary scaling with SCALA: QuickScale
The QuickScale button will first run POINTLESS to determine the correct Laue group and then run SCALA (Evans, 2011) to scale the data in the Laue group determined by POINTLESS. There is no control over the input to SCALA, which is run with the default options. The results are also displayed in a web browser using Baubles. Although it may be necessary to fine-tune the SCALA options to obtain the best final scaling, this approach provides a very rapid and useful indicator of the data quality.
6.9. Processing data non-interactively
Although there are many advantages to processing data interactively, there is a significant time penalty. For straightforward data sets it is often most efficient to index and refine the cell interactively and possibly integrate a few images to ensure that there are no problems, but to carry out the integration step non-interactively as a background job. The Process button in the tool bar allows submission of a batch job via the drop-down button options. Selecting Batch will display a MOSFLM script for the processing job in a new window. This script can be run directly on the host machine or submitted to a remote host on the network. Experienced users can edit the script before submission or even copy and paste it into an existing generic data-processing command script. This results in faster processing, but has the disadvantage that at present it is not possible to generate the iMOSFLM graphical output from batch jobs. However, many of the graphs displayed in iMOSFLM can also be viewed by running the CCP4 program LOGGRAPH on the summary file produced by MOSFLM.
6.10. Warning messages
A summary of the warning messages produced by MOSFLM is produced in a pop-up box that can be viewed by clicking on the Warnings icon at the bottom right corner of any iMOSFLM pane. The level of importance of the warning is indicated and further details can be obtained by double clicking on the warning or by examining the MOSFLM logfile.
7. The History pane
The History pane shows a tree structure of all operations carried out during the present session. Using the Reload option, it is possible to display the graphical output of an earlier cell refinement or integration run in the session. This pane also allows access to the MOSFLM logfile that contains detailed output of every step of the processing. The logfile is also written to a date-stamped file with the generic name MOSFLM_yyyymmdd_hhmmss.lp.
8. Technical description
iMOSFLM and MOSFLM run as separate processes and communication between the two is via TCP/IP sockets. iMOSFLM passes instructions to MOSFLM in the form of standard MOSFLM keywords, while the information passed back to iMOSFLM for storage and display is defined in extensible markup language (XML).
iMOSFLM is written is object-oriented Tcl/Tk and makes use of a number of extensions to the core language. Several of the widgets used are built on code provided by the Iwidgets package. The image display and the customized buttons make use of parts of the tkImg extension (for displaying the diffraction image rendered in JPEG format and the buttons either as PNG or GIFs). The results from processing and the current state of the GUI are stored in an internal tree structure using the TreeCtrl package. All the XML produced by MOSFLM and received through the socket by iMOSFLM is parsed using the tDom package.
iMOSFLM can be run using any version of Tcl/Tk from version 8.4, although some minor versions have particular bugs that militate against their use. For example, Tk version 8.4.13 has an error in the image-display routines that make it unusably slow. Tcl/Tk 8.5 can be used, but the extensions discussed above are not included in most distributions and thus would need to be installed separately.
9. Conclusions
The iMOSFLM interface provides an intuitive easy-to-use approach to processing diffraction data. The software is undergoing active development to improve overall performance, to allow processing of images containing multiple lattices, to provide improvements to the strategy calculations where data are collected from multiple crystals and to add new task panes to allow more control over running POINTLESS and SCALA and displaying the results from these programs. The ability to launch multiple parallel background jobs to process entire data sets very rapidly and display the results graphically is also being investigated. The software is distributed with the CCP4 package (Winn et al., 2011) and the latest versions are available from http://www.mrc-lmb.cam.ac.uk/harry both as source code and as precompiled executables for Windows, Mac OSX and Linux platforms.
Acknowledgements
The authors wish to thank Phil Evans, Frank von Delft and many other users for valuable advice and feedback. The work on iMOSFLM is supported by CCP4 and that on MOSFLM by BBSRC Grant BB/F020384/1.
References
Arndt, U. W. & Wonacott, A. J. (1977). Editors. The Rotation Method in Crystallography. Amsterdam: North-Holland.
Briggs, P. & Cowtan, K. (2007). CCP4 Newsl. 47, contribution 7.
Campbell, J. W. (1995). J. Appl. Cryst. 28, 236-242.
Evans, P. (2006). Acta Cryst. D62, 72-82.
Evans, P. R. (2011). Acta Cryst. D67, 282-292.
Howard, A. J. (2000). In Crystallographic Computing 7: Macromolecular Crystallographic Data, edited by P. E. Bourne & K. D. Watenpaugh. Oxford University Press.
Juers, D. H., Lovelace, J., Bellamy, H. D., Snell, E. H., Matthews, B. W. & Borgstahl, G. E. O. (2007). Acta Cryst. D63, 1139-1153.
Leslie, A. G. W. (2006). Acta Cryst. D62, 48-57.
Nave, C. (1998). Acta Cryst. D54, 848-853.
Otwinowski, Z. & Minor, W. (1997). Methods Enzymol. 276, 307-326.
Pflugrath, J. W. (1999). Acta Cryst. D55, 1718-1725.
Powell, H. R. (1999). Acta Cryst. D55, 1690-1695.
Rossmann, M. G. (1979). J. Appl. Cryst. 12, 225-238.
Rossmann, M. G., Leslie, A. G. W., Abdel-Meguid, S. S. & Tsukihara, T. (1979). J. Appl. Cryst. 12, 570-581.
Steller, I., Bolotovsky, R. & Rossmann, M. G. (1997). J. Appl. Cryst. 30, 1036-1040.
Winkler, F. K., Schutt, C. E. & Harrison, S. C. (1979). Acta Cryst. A35, 901-911.
Winn, M. D. et al. (2011). Acta Cryst. D67, 235-243.
Acta Cryst (2011). D67, 271-281 [ doi:10.1107/S0907444910048675 ]
This is an open-access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.
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login ask-a-question questions unanswered tags faq
I'm looking for software that will help me keep my notes from phone calls organized. I work as a sales manager and spend a large part of every day on the phone with my salespeople. In the course of our conversations, they'll often drop an unfamiliar name or tidbit of information - a new grant, say, or a dynamic colleague we might want to work with. I note these things down in my notebook, but sometimes struggle to retrieve later when it's appropriate.
Is there some kind of software for the PC that can take these fragments of information and aggregate them and make them searchable, like Gmail does with email? That way when I'm looking for a new sales person in Ohio, I can instantly call up the recommendation my colleague gave me two years ago.
asked Jan 06 '12 at 13:52
mooandrew
1
My STRONG recommendation is Evernote. It is easily searchable both by tags (that you determine) or simply by querying your total database of text. Evernote is also a great repository for audio notes (and there are services available that transcribe said notes and post them in text form), photos and web-clippings. I use it every day, and I add to the ways it proves valuable almost daily.
http://www.evernote.com
Bruce Bradford
link
answered Jan 09 '12 at 11:39
Bruce Bradford
31
Evernote is my favorite for taking notes. It syncs across all your computers and phones, and does it quietly in the background. There is a a Web clipping app for Firefox and Chrome that takes a snapshot of the webpage and saves it as a note. Notes can have multiple tags, and store in multiple notebooks. Notes can be shared via Facebook, Twitter, and email. Add-on apps make the program even more useful, by personalizing the functionality. And the basic version is free!
http://www.evernote.com
-Doug Barnard
link
answered Jan 09 '12 at 11:43
dbarnard
16
Evernote is my fave. Chrome browser plug-ins, Clip to Evernote and Clearly are great. You can throw anything at it and sort it. Great with the newer range of small, document scanners to file various cards, recpts, invoices, etc. and voice & photo note captures. Since I use a desk top at work, and one at home, and transport a combination of smart phone, iPad, and/or laptop, Evernote keeps them all in synch and updated. Filing system is plenty robust and search function works great. Basic version got me hooked, now I use it for so many things that I had to get into the purchase territory. Have not regretted it.
link
answered Jan 09 '12 at 12:31
Iowill
16
Agreed. Evernote. Indispensable. Especially when used with Dropbox to store documents.
link
answered Jan 09 '12 at 12:44
Bob Morris
1
Add that Evernote can be made to recognize text in images -- so if you snap a photo of a receipt, or a business card, or a page of a book with a passage you'd like to reference later, you can search for text in those images, with fair success, ever if you never got around to tagging, labeling, and sorting such images.
In other words, you'll end up using Evernote for purposes beyond the specific one you now have in mind.
link
answered Jan 09 '12 at 17:10
Spandrel
1
edited Jan 09 '12 at 17:10
If you need only text Simplenote can't be beat. Evernote is awesome but there's additional baggage that comes with it's flexibility in managing PDFs, images, and so on.
Simplenote has a web client, can sync with desktop apps (for example Notational Velocity on the Mac, ResophNotes on Win, there are others), has native iOS clients for iPhone/iPad. The interface is pared down to the minimum. The search is instantaneous, blindingly fast.
I love it.
http://simplenoteapp.com/
link
answered Jan 10 '12 at 01:31
miguelmarcos
1
edited Jan 10 '12 at 01:31
Thanks all for the recommendations! I'll look into both Simplenote and Evernote. Much Appreciated!
link
answered Jan 13 '12 at 06:51
mooandrew
1
I'm going to go against the grain here a little bit. I love Microsoft's OneNote. It has a slew of impressive features and greatly facilitates note-taking and organization. I also like how I can "print to OneNote" and "copy to OneNote" and it automatically provides citations for that. As a technical consultant and 3+ projects at a time (plus internals and personal projects), I love it.
link
answered Jan 14 '12 at 10:05
Derek Murawsky
226
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Australian Bureau of Statistics
Celebrating the International Year of Statistics 2013
ABS Home > Statistics > By Release Date
5204.0 - Australian System of National Accounts, 2004-05
Previous ISSUE Released at 11:30 AM (CANBERRA TIME) 07/11/2005
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ABOUT THIS RELEASE
Previously: Australian National Accounts: National Income and Expenditure (ISSN: 0067-1983)
Previously: Australian National Accounts: National Income, Expenditure and Product (ISSN: 1322-5006)
Detailed presentation of annual national accounts data. Includes: main aggregates and productivity measures; sectoral accounts for households, financial and non-financial corporations, general government and the rest of the world; estimates of product, operating surplus, compensation of employees and other aggregates dissected by industry; tables of capital formation and capital stock; national balance sheets; flow of funds tables. Includes both current price and chain volume measures.
For state details see 5220.0. Includes data from 5221.0, 5234.0 and 5241.0 as from the 1997-98 issue.
© Commonwealth of Australia 2013
Unless otherwise noted, content on this website is licensed under a Creative Commons Attribution 2.5 Australia Licence together with any terms, conditions and exclusions as set out in the website Copyright notice. For permission to do anything beyond the scope of this licence and copyright terms contact us.
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Australian Bureau of Statistics
Celebrating the International Year of Statistics 2013
ABS Home > Statistics > By Release Date
8752.1 - Building Activity, New South Wales, Dec 2000
Previous ISSUE Released at 11:30 AM (CANBERRA TIME) 02/05/2001
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• About this Release
ABOUT THIS RELEASE
Presents number of dwelling units and value of residential buildings (new houses and new other residential); value of alterations and additions to residential buildings and value of non-residential building by class of building (e.g. hotels, offices, etc.), for private and public sectors; stage of construction (commenced, under construction, completed); value of work done during the reference period, and value of work yet to be done. Seasonally adjusted series show number of dwelling units commenced and completed and value of work done. Also includes value of work commenced and work done in chain volume measures, with the reference year being the year prior to the latest complete financial year.
© Commonwealth of Australia 2013
Unless otherwise noted, content on this website is licensed under a Creative Commons Attribution 2.5 Australia Licence together with any terms, conditions and exclusions as set out in the website Copyright notice. For permission to do anything beyond the scope of this licence and copyright terms contact us.
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Australian Bureau of Statistics
Celebrating the International Year of Statistics 2013
ABS Home > Statistics > By Release Date
6220.0 - Persons Not in the Labour Force, Australia, Sep 2008 Quality Declaration
Previous ISSUE Released at 11:30 AM (CANBERRA TIME) 27/03/2009
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NOTES
ABOUT THIS PUBLICATION
This publication presents information about people aged 15 years and over who are not in the labour force: that is, neither employed nor unemployed. The data measure the potential supply of labour not reflected in employment and unemployment statistics, and measure the characteristics of that potential supply.
Statistics in this publication were obtained from the Persons Not in the Labour Force Survey, conducted throughout Australia in September 2008 as a supplement to the Australian Bureau of Statistics (ABS) monthly Labour Force Survey (LFS).
Information collected in the survey includes details about whether people not in the labour force wanted to work, reasons why they were not actively looking for work, or were not available for work, and their main activity while not in the labour force.
Many people not in the labour force could be considered to have some attachment to the labour force. For example, they may want a job, but for a variety of reasons are not actively looking for work even though they are available to start a job. There is an expectation that many of these people could move into the labour force in the short term, or could do so if labour market conditions changed.
CHANGES IN THIS ISSUE
From September 2008, a change has been made to the category 'Home duties or caring for children' for the data item 'Main activity when not in the labour force'. The category has been split into 'Home duties' and 'Caring for children'. For more information about the data item 'Main activity when not in the labour force' see paragraphs 25-26 of the Explanatory Notes.
NOTES ABOUT THE ESTIMATES
Sample reductions in the Labour Force Survey, (see Information Paper: Labour Force Survey Sample Design, Nov 2007 (Second edition) (cat. no. 6269.0)), resulted in the Persons Not in the Labour Force Survey sample being approximately one-third smaller than the sample size in September 2007.
ROUNDING
As estimates have been rounded, discrepancies may occur between sums of the component items and totals.
INQUIRIES
For further information about these and related statistics, contact the National Information and Referral Service on 1300 135 070 or Labour Market Section on Canberra (02) 6252 7206.
© Commonwealth of Australia 2013
Unless otherwise noted, content on this website is licensed under a Creative Commons Attribution 2.5 Australia Licence together with any terms, conditions and exclusions as set out in the website Copyright notice. For permission to do anything beyond the scope of this licence and copyright terms contact us.
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Australian Bureau of Statistics
Celebrating the International Year of Statistics 2013
ABS Home > Statistics > By Release Date
5206.0 - Australian National Accounts: National Income, Expenditure and Product, Jun 2005
Previous ISSUE Released at 11:30 AM (CANBERRA TIME) 07/09/2005
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Feature Article 2: Hours Worked Estimates in the Quarterly National Accounts
ABSTRACT
In March quarter 2005, the ABS suspended publication of seasonally adjusted hours worked estimates to assess the quality of the time series. Investigation has revealed some issues with the application of holiday correction factors that are applied to the hours worked series prior to normal seasonal adjustment. These factors have been re-estimated and the seasonally adjusted hours worked series and the associated seasonally adjusted GDP per hour worked series have been reintroduced for the June quarter 2005 National Accounts publication.
The aim of holiday correction is to estimate and remove holiday impacts prior to seasonal factor estimation. The extent of the impact of a particular holiday will depend on how different persons are affected by that holiday. For example, there may be different reactions to specific holidays in different states, in metropolitan/ex-metropolitan areas and in different industries. For some holidays the effect may not be consistent from year to year due to factors such as the different dates of public holidays in different states. Estimated holiday correction factors were found to be statistically significant for the following holidays: (i) Easter, (ii) the start date of the Labour Force Survey in January; (iii) Queen's Birthday; (iv) Australia Day; and (v) school holidays in particular months.
The chart below shows a comparison over the last five years of published quarterly movements in the seasonally adjusted estimates. The seasonally adjusted movements are very similar but show increasing divergence during 2004. For example, the estimated December 2004 percentage movement has now been published as 0.7%, compared to an initially published estimate of 0.1%. These differences reflect the updated holiday corrections applied in the seasonal adjustment of hours worked estimates and the revision of seasonally adjusted estimates as additional original estimates have become available.
Hours worked estimates, Seasonally adjusted - As published Dec-04 and Jun-05
Click here for the full feature article 'Issues with Seasonal Adjustment of Hours Worked'.
© Commonwealth of Australia 2013
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Australian Bureau of Statistics
Celebrating the International Year of Statistics 2013
ABS Home > Statistics > By Catalogue Number
4841.0 - Facts at your Fingertips: Health, 2011
Latest ISSUE Released at 11:30 AM (CANBERRA TIME) 03/11/2011 First Issue
First Release
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Software
rnaSeqMap: a Bioconductor package for RNA sequencing data exploration
Anna Leśniewska1,2 and Michał J Okoniewski2*
Author Affiliations
1 Poznan University of Technology, Institute of Computer Science, ul.Piotrowo 2, 60-965 Poznan, Poland
2 Functional Genomics Center UNI ETH Zurich, Winterthurerstrasse 190, CH-8057, Switzerland
For all author emails, please log on.
BMC Bioinformatics 2011, 12:200 doi:10.1186/1471-2105-12-200
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2105/12/200
Received:7 October 2010
Accepted:25 May 2011
Published:25 May 2011
© 2011 Leśniewska and Okoniewski; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background
The throughput of commercially available sequencers has recently significantly increased. It has reached the point where measuring the RNA expression by the depth of coverage has become feasible even for largest genomes. The development of software tools is constantly following the progress of biological hardware. In particular, as RNA sequencing software can be regarded genome browsers, exon junction tools and statistical tools operating on counts of reads in predefined regions. The library rnaSeqMap, freely available via Bioconductor, is an RNA sequencing software which is independent of any biological hardware platform. It is based upon standard Bioconductor infrastructure for sequencing data and includes several novel features focused on deeper understanding of coverage expression profiles and discovery of novel transcription regions.
Results
rnaSeqMap is a toolbox for analyses that may be performed with the use of gene annotations or alternatively, in an unsupervised mode, on any genomic region to find novel or non-standard transcripts. The data back-end may be a MySQL database or a set of files in standard BAM format. The processing in R can be run on a machine without any particular hardware requirements, and scales linearly with the number of genomic loci and number of samples analyzed. The main features of rnaSeqMap include coverage operations, discovering irreducible regions of high expression, significance search and splicing analyses with nucleotide granularity.
Conclusions
This software may be used for a range of applications related to RNA sequencing by building customized analysis pipelines. The applicability and precision is expected to increase in parallel with the progress of the genome coverage in sequencers.
Background
Massive parallel sequencing of short oligo reads has already found multiple applications in molecular biology. One of the promising novel ones is RNA sequencing, used to determine abundance of transcripts in the sample [1] - which is a more general description of gene expression profiling. The throughput of commercially available sequencers has reached the level where the depth of coverage is sufficient to measure the differences in RNA expression for the larger genomes. For example - in a typical run of ABI SOLID v4, there are 800 million reads (50 bp each). Assuming that half of these may be mapped to the known human genes, it gives 20 Gbp of coverage, which allows for more than 10 times coverage of all the Ensembl human genes. In practice, the distribution of reads coverage over the genes is very skewed.
A recent study [2] also shows good correlation of transcription measurements between RNA sequencing and microarrays even in the cases with limited number of replicate samples.
As has already happened with other technologies in molecular biology, the software development is trying to catch up with the improvements in the hardware [3]. A number of recent significant developments in the area of read mapping software [4] allow the building up of tools for both managing short reads data and for secondary analysis adapted to particular biological applications. In the first group there are ShortReads package [5], Genominator package or several commercial tools.
In the case of RNA sequencing the current approaches in secondary analysis tools are focused on three categories: genome browsers for displaying the reads over the genome [6,7], statistical tools to find significantly expressed genes and tools for predicting the transcript structure with coverage and exon junctions, such as the Tophat-Cufflinks pipeline [8,9], Scripture [10] or MapSplice [11].
The group of statistical software packages introduces the use of negative binomial distribution [12,13] of counts within genes to find the significant ones. This has solid statistical foundations and usually relies on the databases of annotations to determine the loci where the reads are counted. However, the microarrays have already demonstrated that aggregating gene expression values on the gene level or averaging of the expression of gene fragments, is often very useful but may lead to spurious results in case of non-typical transcripts [14,15].
Many of the tools may be used in a parallel computing environment, which enables publicly available cloud computing (e.g. by EBI services [16] or with Myrna [17]). However, the assumption of the rnaSeqMap library is the minimization of the computing resources needed and platform independence for the secondary analysis. Although the pipelines created with rnaSeqMap may be parallelized to multiple cores with standard R or MySQL mechanisms, they are supposed to run efficiently on a single, standalone machine. Using the pre-defined annotation of genes, transcripts and exonic regions is not taking full advantage of the predictive qualities of RNA sequencing data. The annotations can be assumed to be the real expression area boundaries, whereas the expression does not often follow the patterns frozen in the annotation databases [18].
The new Bioconductor library, rnaSeqMap, tries to overcome these limitations. This is achieved by describing the expressed regions not only by counts, but also by determining the boundaries with nucleotide precision. It may enable the exploration of RNA sequencing data using pre-defined annotations, but also complementarily in a purely exploratory way - by adjusting the findings to the expressed areas. rnaSeqMap can not only merely use the annotations, but may also confirm them, modify them or create novel ones. Managing such a massive amount of RNA sequencing data is another difficult issue. The operational memory is too small to keep the whole datasets, so it is necessary to use special mechanisms to select fragments of the data and annotations from the storage and process them. rnaSeqMap solves this issue by keeping the sequencing reads and the annotations in the same relational database.
The assumption of rnaSeqMap is to use the existing tools in the areas where they evolved into useful solutions. Its main goal is to serve as a complementary "middleware" to create analytical and discovery pipelines. Thus, it relies on pre-processed mapping of the reads to a reference genome and well known database of annotations in the back-end and on existing software for finding significantly expressed genes in the front-end. rnaSeqMap was designed to be independent of any sequencing platform, mapping software and statistical add-ons. By running it with real experimental data it was shown to be efficient at both tasks. In particular, the tests and data presented in the paper come from sequencing with an ABI SOLiD machine and mapping the colorspace reads using Bioscope.
Implementation
Design paradigms
rnaSeqMap has been designed according to a set of principles that turned out to be useful and efficient in exonmap - the Affymetrix exon array analysis software in Bioconcuctor and its continuation, xmapcore [15,19,20]. Those paradigms are:
• working with the genome coordinates of expression areas
• using database back-end for annotations and mapped reads
• top-down analysis - starting from a global search and getting into interesting details
• visualization of the genome by fragments
• alternative splicing analysis
• searching for the expression in potentially non-coding or non-annotated areas
rnaSeqMap uses reads mapped to the genome, characterized by a set of genome coordinates: chromosome, start, end and strand of the mapping. The option of using data from unstranded protocols is available. In this paper all the results are from a protocol with strand information. Using such minimal information about reads gives the opportunity to freely tune parameters such as mismatches or multiple targeting in the mapper software. Scripts that may be found in the installation version of rnaSeqMap are examples of how the SAM files may be trimmed to this basic set of attributes.
Back-end modes of feeding the R objects with data
rnaSeqMap supports three modes of getting the read data: directly from BAM files (binary representation of sequencer reads), from a table in the MySQL database (where the data may be processed together with annotations) and from tables in text files.
Reading and processing of BAM files uses current Bioconductor infrastructure for processing sequencing reads: RSamtools, IRanges and GenomicRanges libraries. In case of the database back-end it is expected to follow the xmapcore database format, extended by tables for sequencing reads, junction reads and samples, with appropriate stored procedures included in the SQL scripts attached to the rnaSeqMap package.
Data processing
In rnaSeqMap the global part of the analysis finds genomic and intergenic regions and then processes the coverage function (number of reads mapped per nucleotide) iteratively for subsequent regions. This approach allows the analyses to use a limited amount of operational memory, with nucleotide-level granularity of the findings.
The regions found as a result of the analyses and their qualities (coverage, fold change, splicing index) may be visualized using their genome coordinates - also in the areas not annotated previously to any gene or exon.
Figure 1 presents the technical schema of the processing in the rnaSeqMap. Data generated by a sequencer are mapped to the genome annotated in the xmapcore database. The reads can be extracted from BAM files with samtools or from SAM files by an AWK script. Then the reads are imported into the MySQL seq_read table, while the bio_sample table includes the experimental setup and details of the samples. Stored procedures are used to uniformly query the extended xmapcore database and provide the data into rnaSeqMap wrappers in the R environment. The wrappers are used for building and processing objects of the classes SeqRead and NucleotideDistr. From the NulcleotideDistr object it is possible to generate distributions, summaries, visualizations or further input for higher-level statistical libraries.
Figure 1. Schema of data processing. The flow of RNA sequencing data processing in the xmapcore database and the rnaSeqMap library.
Technologies
rnaSeqMap may use MySQL database as a back-end, because Ensembl and, derived from it xmapcore, use this format. From version 5.1 onwards, MySQL engine has the partitioning mechanism which is used to partition reads in the seq_read table into sub-tables by chromosome - which speeds up searches by an order of magnitude in the case of larger genomes with multiple chromosomes.
The library has been written in R (version 2.11 or higher) and makes use, among other things, the following Bioconductor libraries: IRanges during the processing, supporting input object creation for edgeR [13] and DESeq [12]. The critical algorithms for processing nucleotide distributions were written in C for performance reasons.
Distinctive features of rnaSeqMap
Many of the functionalities presented above are novel not only in Bioconductor. Some combinations of features are also currently unique. Such issues as the application of the same database for annotation and reads, platform and mapping independence or genome visualizations have been described above. Here we describe some other features in detail.
Region mining algorithm
The algorithm for finding genomic regions with the mean coverage above a defined level μ is an adaptation of Aumann and Lindell algorithm for mining quantitative association rules [21]. This algorithm uses two sliding windows that run across the genome, adding the coverage value of a nucleotide in every step and joining the windows under specific conditions. This results in a property of the discovered regions called irreducibility. Biological meaning and utility of the algorithm is discussed in the further sections.
Classes SeqReads and NucleotideDistr
To encapsulate the sequencing data in a given region, rnaSeqMap has two classes. SeqReads keeps the raw read data and may be filled in from a database or directly from a file. From an object of the class SeqReads, an object of NucleotideDistr (an S4 class) is constructed. In the data slot, it holds the distribution of the coverage function for all the nucleotides in the studied region. Then the NucleotideDistr object may be a subject to various transformations of the coverage.
Building blocks for analysis pipelines
The building blocks of the analytic infrastructure in rnaSeqMap may be grouped in the following categories:
• database access procedures, which are in fact wrappers for MySQL stored procedures - similarly as in xmapcore
• classes for encapsulating the sequencing reads and distributions
• functions for normalization of the coverage distributions (eg. lowess [22]), summarizing them, calculating fold change and splicing index on the nucleotide level
• Aumann-Lindell two-sliding-window algorithm implementation
• functions for finding genomic and intergenic regions in given fragments of chromosomes - to iterate the searches over them
• connectors to statistical libraries - DESeq and edgeR
• visualization - genome plots and histograms
Those building blocks may be used to construct processing pipelines that iterate over fragments of chromosome, genes or intergenic spaces (see Figure 2).
Figure 2. An example of rnaSeqMap analysis pipeline. The figure depicts data containers (circles) and processes (squares) that form the processing flow of the analysis. It iterates over chromosomes. The chromosomes are dissected into gene regions and intergenic spaces. The read counts in genes and significant novel regions of expression are then made available to the statistical analysis packages.
Nucleotide-level splicing index
The idea of the splicing index comes from the paper [23] and in rnaSeqMap was adapted to the sequencing data defined for every nucleotide, where the coverage may differ by many orders of magnitude. The nulcleotide-level splicing index is defined as follows:
where E1n and E2n are the coverage values for a given nucleotide, while G1n and G2n are the counts of reads in the region or gene.
Such an approach enables visualization of the splicing index on a genome plot and exploring its significant regions using the Aumann-Lindell algorithm. The example of the splicing index plot is presented on the Figure 3.
Figure 3. An example of splicing index plot. Two coverage functions on the same genome region transformed into a splicing index. The first plot presents the distribution in two samples, the second, the calculated splicing index. The third plot includes the irreducible regions of expression for both coverage functions.
Discovery mode
The genome regions and their analysis may be categorized in the following way:
• gene regions, with boundaries defined according to annotations, searched for expression within the limits
• extended gene regions - to check possible expression up- or downstream from a gene and extend its boundaries
• intergenic regions - searched with the Aumann-Lindell algorithm for novel expression places
The analysis by the two latter categories may lead to discovery of novel expression regions on the genome, which may be verified with databases of ESTs and other genomic sources of evidence. This type of analysis is independent from the genomic annotation scheme.
Providing input data to the statistical packages
Significance analysis packages for RNA sequencing such as DESeq or edgeR require the count data in defined regions (most often in genes) as an input, then they perform analysis using binomial distributions. rnaSeqMap may generate such tables from the reads data in the database, the regions may be defined as gene boundaries or just regions that happen to be found significantly expressed in the discovery mode. In this way RNA sequencing can perform significance analysis that goes beyond microarray-style predefined regions checking.
Results and Discussion
To evaluate the predictive performance of the software on a real sequencing dataset, we randomly selected a single strand of a human chromosome (ch 15, forward) and searched for expressed regions in 6 samples. It turned out to have 1330 genes. The number of irreducible regions of expression in genes is summarized in the Table 1. Traces of expression of coverage higher than 5 are found in ca 70% of genes, while consistent expression over 6 samples with irreducible regions can be found in ca 10% of genes.
Table 1. The number of genes containing irreducible regions in at least × out of 6 samples on the forward strand of human chromosome 15.
A particular point which may be the subject of wet-lab verification is whether the irreducible regions found by the Aumann-Lindell algorithm are indeed exons. The algorithm normally needs tuning with the parameters μ (threshold for the coverage level) and minsup, which is here the length of a region. They have to be set according to the overall coverage in the experiment and knowledge of biological factors - such as expected exon length and the characteristics of the concentration-coverage curve. Some of this tuning may be automated by multiple runs of the algorithm across the regions with different parameters. In rnaSeqMap, the function regionBasedCoverage() is an example of such a procedure. It searches for irreducible regions for several values of μ and sets the coverage value to the maximal of them. The resulting coverage function with discrete values may be more 'human readable' and this also removes peaks of over-amplified reads and less significant local minima.
The issue of time and memory efficiency of the analyses is also important. rnaSeqMap avoids memory overloads by providing the tools to slice the genome coverage into manageable fragments, still big enough to represent even longest genes measured in many samples - and encapsulating them into objects with well-defined analytical methods. The database MySQL back-end is an engine that may be run on a single standard computer and contain a database from a complete RNA sequencing experiment, in the case of BAM files the limitation is the disc capacity.
Time of analysis is comparable to other operations in sequencing, such as preparing the libraries or mapping the reads to the reference genome. The result of a scalability tests is depicted in Additional files 1 and 2 and shows that the processing time scales linearly with the number of genomic loci and number of processed biological samples. For example, for 5 BAM files of 1.5 Gb (25 M reads) each, the processing time was less than a second per gene on a standalone machine. The proof of linear complexity of the region mining algorithm can be found in [21]
Additional file 1. Scalability of processing experiment. Execution time (in seconds) of the basic operations creating SeqReads and NucleotideDistibution object, processing the coverage) for 1 to 2000 random genes and 1 to 5 BAM les, 1.5 GB (25.1 M reads) each, system time. The time is linearly scaling with the number of genes and files.
Format: PNG Size: 18KB Download file
Additional file 2. Scalability of processing experiment. Execution time (in seconds) of the basic operations creating SeqReads and NucleotideDistibution object, processing the coverage) for 1 to 2000 random genes and 1 to 5 BAM les, 1.5 GB (25.1 M reads) each, elapsed time. The time is linearly scaling with the number of genes and files.
Format: PNG Size: 16KB Download file
Properties and tuning the region mining algorithm
The definition of an irreducible rule in [21] follows the intuitive understanding of the expressed region in rnaSeqMap: the coverage may fall below μ in a fragment of an exon due to some artifacts (GC content etc), but the region itself may still have a consistent expression representation and clearly marked boundaries (see Figure 4).
Figure 4. Irreducible regions of coverage found by Aumann-Lindell algorithm. The coverage function on the genomic region (upper plot) analysed with the Aumann-Lindell algorithm finds two irreducible regions of expression (lower plot). In the first region, the coverage happens occasionally to drop below μ = 11, but it keeps the property of irreducibility.
According to the definition in [21], an irreducible region is one that may be split anywhere into two sub-regions with the mean value of the analyzed variable (here: coverage) remaining above the predefined μ level in both. In addition, it may be proven that irreducible regions always start and end with a value above μ [24]. Thus the Aumann-Lindell algorithm is expected to precisely find expressed regions which may be understood as exons in the biological meaning.
The advantages of searching for novel expression regions with Aumann-Lindell algorithms are depicted in the Figure 5 and can be summarized as follows:
Figure 5. Irreducible regions. An example of irreducible regions found on simple numeric data. a) shows a part of the region, where the local coverage falls below μ, b) points out that region constraints can be used to skip the local peaks. Minsup stands here for minmal region width.
• Skipping small, local drops of the coverage value, as the coverage in the region may drop locally, not violating its irreducibility
• Not overestimating the artefactual peaks, because the window algorithm does not consider them for the whole region. If the peaks are separate ones they do not fulfill the minimum support (width) condition
• Defining the boundaries of the region only for expression which is high enough, as they have to start with at least μ value
To tune the outcome of the algorithm several strategies may be used. Simple ones rely on a single μ level, that may be understood as a 'detection threshold' for the expression - often 5 is used as a threshord value for coverage. More sophisticated strategies choose μ as a given fraction of local minima or maxima of coverage, or apply a search with several levels μ of iteratively and choosing the highest as a value of coverage (regionBasedCoverage function).
Region mining with Aumann-Lindell rules is based upon the magnitude and irreducibility of the coverage function, while Cuffinks [9] relies mainly on exon junctions mapping. As a result the susceptibility to different types of artifacts have been observed, although the two approaches often agree in the case of well pronounced exon expression (see Additional files 3 and 4).
Additional file 3. An example of Cufflinks-rnaSeq comparison. Example of comparison of regions found by Cufflinks (Tophat mapping) and rnaSeqMap (Bioscope mapping)
Format: PNG Size: 34KB Download file
Additional file 4. An example of Cufflinks-rnaSeq comparison. Example of comparison of regions found by Cu inks (Tophat mapping) and rnaSeqMap (Bioscope mapping)
Format: PNG Size: 32KB Download file
The lowess algorithm (locally weighted scatterplot smoothing) [22], widely used for adjusting the bias of microarrays, is used in rnaSeqMap to minimize the influence of artifacts (peaks, non-expressed small gaps) of the coverage. Applying lowess is recommended before region mining to stabilize the outcome. The effect of lowess and region mining together is shown on Additional files 5 and 6. Using lowess smoothing as a preprocessing step may possibly influence the precision of the region boundaries.
Additional file 5. An example of coverage plot smoothed by lowess. An example of lowess use to smoothen artifacts of sequencing coverage. The original RNA-seq coverage (upper section), after lowess with f = 0.1 (middle section) and after region mining (lower section).
Format: PNG Size: 48KB Download file
Additional file 6. An example of coverage plot smoothed by lowess. An example of lowess use to smoothen artifacts of sequencing coverage. The original RNA-seq coverage (upper section), after lowess with f = 0.1 (middle section) and after region mining (lower section).
Format: PNG Size: 51KB Download file
Conclusions
Overall, the analyses performed by rnaSeqMap belong more to data mining than to statistics - as the library does searches for interesting local phenomena, without pre-assumptions, starting from a global overview and dissecting it into significant slices of expressed transcriptome. Such an approach is necessary, knowing that the existing annotations are just an approximated and constantly evolving snapshot of the real biological phenomena of transcription and alternative splicing. Although it is not a classic data mining (i.e. OLAP style), the novel features of rnaSeqMap make it different from classic genome browser and statistical tools using curated genome annotation, and is complementary to them.
The analyses performed with rnaSeq map will become gradually more precise, with the increased coverage of the RNA sequencing. This is expected, because this particular technology is currently a cutting-edge of biomolecular techniques. Thus, the applicability and utility of such an exploratory approach is expected to grow. According to [25] the RNA sequencing data are over-dispersed. There are also still a number of artifacts coming most likely from sample preparation and amplification protocols, and the closer look at the data with rnaSeqMap confirms this point of view.
Availability and Requirements
• Project name: rnaSeqMap
• Project home page: http://www.bioconductor.org/packages/release/bioc/html/rnaSeqMap.html webcite
• Operating systems: Windows, MacOS, Unix
• Programming language: R, C, SQL
• Other requirements: R v2.12 or higher, Bioconductor libraries v2.8 or higher, MySQL v5.1 or higher in case of using the database
• License: GPL-2
The rnaSeqMap library is available in Bioconductor from version 2.7. The MySQL database and processing may be run on any standard operating system platform. Hardware requirements do not go beyond standard desktop computers, however the amount of RAM memory limits the size of the processed objects so the size of genome fragments analyzed, and the speed of the hard drive are the main limiting factors for database operations and input BAM files.
Authors' contributions
AL has prepared the implementation of rnaSeqMap, developed the algorithms, heuristics and the adaptation of xmapcore database, performed the quantitative experiments and helped to draft the manuscript. MO conceived the idea of the software, participated in the implementation of rnaSeqMap and drafted the manuscript. Both authors read and approved the final manuscript.
Acknowledgements
The authors would like to thank Marzanna Künzli, Remy Brugmann, Hubert Rehrauer, Sirisha Aluri and Martin Ryan for all the valuable discussions and help with testing the package, and Prof. Beat Schäfer, Marco Wachtel and Lucia Bautista Borrego for providing and discussing with us the experimental data. The work was supporthed by Sciex-NMS.ch grant No. 09.025.
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Research article
Mammalian cells lack checkpoints for tetraploidy, aberrant centrosome number, and cytokinesis failure
Connie Wong1 and Tim Stearns1,2*
Author Affiliations
1 Department of Biological Sciences, Stanford University, Stanford, CA 94305, USA
2 Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
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BMC Cell Biology 2005, 6:6 doi:10.1186/1471-2121-6-6
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2121/6/6
Received:26 September 2004
Accepted:15 February 2005
Published:15 February 2005
© 2005 Wong and Stearns; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background
Mammalian cells have been reported to have a p53-dependent tetraploidy checkpoint that blocks cell cycle progression in G1 in response to failure of cell division. In most cases where the tetraploidy checkpoint has been observed cell division was perturbed by anti-cytoskeleton drug treatments. However, other evidence argues against the existence of a tetraploidy checkpoint. Cells that have failed to divide differ from normal cells in having two nuclei, two centrosomes, a decreased surface to volume ratio, and having undergone an abortive cytokinesis. We tested each of these to determine which, if any, cause a G1 cell cycle arrest.
Results
Primary human diploid fibroblasts with intact cell cycle checkpoints were used in all experiments. Synchronized cells exhibited G1 arrest in response to division failure caused by treatment with either cytochalasin or the myosin II inhibitor blebbistatin. The role of tetraploidy, aberrant centrosome number, and increased cell size were tested by cell/cell and cell/cytoplast fusion experiments; none of these conditions resulted in G1 arrest. Instead we found that various drug treatments of the cells resulted in cellular damage, which was the likely cause of the arrest. When cytokinesis was blocked in the absence of damage-inducing drug treatments no G1 arrest was observed.
Conclusions
We show that neither tetraploidy, aberrant centrosome number, cell size, nor failure of cytokinesis lead to G1 arrest, suggesting that there is no tetraploidy checkpoint. Rather, certain standard synchronization treatments cause damage that is the likely cause of G1 arrest. Since tetraploid cells can cycle when created with minimal manipulation, previous reports of a tetraploidy checkpoint can probably be explained by side effects of the drug treatments used to observe them.
Background
Cell cycle checkpoints preserve genome integrity by monitoring the fidelity of DNA replication and segregation. In mammalian somatic cells, the best-characterized checkpoints are the DNA damage/replication checkpoints and the mitotic spindle checkpoint. The DNA damage/replication checkpoints result in cell cycle arrest if DNA is not fully replicated, or is damaged [1]. The mitotic spindle checkpoint results in cell cycle arrest prior to anaphase if the spindle is not properly assembled [2].
There is also evidence that defects in events relating to cell division itself can result in cell cycle arrest. Lanni and Jacks [3] and Casenghi et al.[4] found that mammalian cells that had adapted to microtubule depolymerization and exited mitosis without undergoing cytokinesis arrested in G1 of the subsequent cell cycle. Kurimura and Hirano [5] and Andreassen et al. [6] reported that inhibition of cytokinesis with the actin-depolymerizing drug cytochalasin resulted in a similar arrest in G1 of the subsequent cell cycle. These treatments resulted in cells that were tetraploid, and Andreassen et al. [6] proposed that the cell cycle arrest was triggered by ploidy, terming this effect a "tetraploidy checkpoint".
Other evidence suggests that mammalian cells are not sensitive to tetraploidy. Rao and Johnson used cell fusion to study the regulation of DNA synthesis and mitosis by fusing cells at different cell cycle stages [7,8]. Binucleate tetraploid cells resulting from fusion between cells in different cell cycle stages were able to progress through the cell cycle. Uetake and Sluder ([9], reviewed in [10]) reported that inhibition of cytokinesis with a low dose of cytochalasin also allowed cell cycle progression. Most strikingly, there are rare cases of human infants born with fully tetraploid karyotypes [11]. Although these individuals have severe defects, their existence argues against tetraploidy as a trigger for cell cycle arrest.
Here we investigate whether tetraploidy or other cellular defects in binucleate cells lead to cell cycle arrest. We show that neither tetraploidy, aberrant centrosome number, cell size, nor failure of cytokinesis lead to G1 arrest, suggesting that there is no tetraploidy checkpoint. Rather, certain standard synchronization treatments cause DNA damage that is the likely cause of G1 arrest.
Results and discussion
Immortalized cell lines often have altered checkpoints, therefore we used early passage primary cells to investigate the tetraploidy checkpoint. All experiments were performed with human diploid fibroblasts (HDF) from infant foreskin and used prior to passage 10. We had previously developed methods for synchronizing these cells [12], and tested them here for the presence of normal checkpoint mechanisms. First, the levels of p53 were determined by western blotting and found to be similar to other p53+/+ cell lines (not shown). Second, we tested for a functional DNA damage response. G1 phase HDF cells were released from serum starvation and irradiated with ultraviolet (UV) light. The cells were then assayed for entry into S phase by 5-bromodeoxyuridine (BrdU) incorporation. The HDF cells exhibited a normal DNA damage response; at a low dose of UV, cells were delayed by about 12 h for entry into S phase, and at a higher dose most cells did not enter S phase even 36 h after irradiation (Figure 1A). Third, we tested for a functional spindle checkpoint. Exponentially-growing HDF cells were treated with nocodazole for 12 h to depolymerize microtubules, and assayed by light microscopy. Nocodazole treatment caused a 6-fold increase in the mitotic index, indicating that the cells had a functional spindle checkpoint.
Figure 1. Cell cycle responses of human diploid fibroblast (HDF) cells. (A) Response to DNA damage. HDF cells were exposed to 0, 10 or 20 J/m2 ultraviolet light and entry into S phase was assayed by BrdU incorporation. For each bar n ≥ 300 cells. (B) Recovery from nocodazole arrest. HDF cells were arrested in mitosis by double thymidine block followed by nocodazole (left) and released for 30 min. (center and right). DNA, blue; α-tubulin, green; γ-tubulin, red. (C) Example of binucleate cells created by cytochalasin-induced cytokinesis failure. DNA, blue. (D) Cell cycle progression of HDF cells in response to cytokinesis failure induced with 2 μM cytochalasin. Cells were assayed for BrdU incorporation at the indicated times after removal of cytochalasin. "control" cells were not treated with cytochalasin; "cytochalasin (mononucleate)" cells were treated, but completed cytokinesis, and "cytochalasin (binucleate)" cells were treated and failed to divide in cytokinesis. For each bar n ≥ 300 cells. (E) Cell cycle progression of HDF cells in response to cytokinesis failure induced with 12.5 μM blebbistatin. Cells were assayed for BrdU incorporation at the indicated times after removal of blebbistatin. "control" cells were not treated with blebbistatin; "blebbistatin (mononucleate)" cells were treated, but completed cytokinesis, and "blebbistatin (binucleate)" cells were treated and failed to divide in cytokinesis. For each bar n ≥ 300 cells. (F) Cell cycle progression in response to the presence of extra centrosomes. Image shows the product of fusion between a G1 cell and a G1 cytoplast. 24 h after fusion this cell has four centrosomes, indicating that it has undergone centrosome duplication, and has incorporated BrdU, indicating that it has entered S phase. DNA, blue; BrdU, green; pericentrin, red. Punctate blue staining is due to cell surface marker used to identify fusion products [12]. Scale bars represent 10 μm.
We first tested HDF cells for the previously described G1 arrest following cytochalasin-induced failure of cytokinesis [6]. Cells were synchronized in mitosis by double thymidine arrest followed by nocodazole treatment (Figure 1B), then released for 30 min, after which most cells had a bipolar spindle. Cells were then allowed to proceed into interphase in medium containing BrdU, +/- 2 μM cytochalasin. By 10 h after the addition of cytochalasin, both control and cytochalasin-treated cells had exited mitosis; approximately 30% of the cytochalasin-treated cells had two nuclei (binucleate) (Figure 1C) and the remainder had a single nucleus (mononucleate), presumably having completed cytokinesis successfully. Thus there were two types of control cells in these experiments: cells that had not experienced the drug, and cells that had experienced the drug, but remained mononucleate. The cultures were washed at this point to remove drug and allowed to proceed in the cell cycle.
At 6 h after the removal of cytochalasin, 50% of the untreated control cells had entered S phase, whereas only about 10% of either the mononucleate or binucleate cytochalasin-treated cells had entered S phase (Figure 1D); these numbers changed only slightly by 12 h. However, at 24 h after cytochalasin removal, 75% of the control cells and 44% of the mononucleate cytochalasin-treated cells had entered S phase, whereas only 11% of the cytochalasin-treated binucleate cells had entered S phase. Similar results were obtained with 5 μM and 10 μM cytochalasin (not shown). Thus, binucleate HDF cells resulting from cytochalasin-induced failure of cytokinesis did arrest in G1, as previously described for other cells [6].
A potential problem with cytochalasin treatment is that depolymerization of the actin cytoskeleton is likely to have effects other than blocking cytokinesis. Indeed, we found that even at 2 μM, cytochalasin had a strong cytotoxic effect, delaying cell cycle progression significantly, with slow recovery after release (data not shown and [13]). To determine whether the effect was specific to cytochalasin, the above experiment was repeated using two other drugs that inhibit cytokinesis: blebbistatin and aurora kinase inhibitor-1 (AKI-1). Blebbistatin is an inhibitor of non-muscle myosin II, the motor protein that provides the force for furrow ingression during cytokinesis [14]. AKI-1 inhibits the aurora family of kinases, which play important roles in mitosis and cytokinesis [15].
HDF cells were synchronized in mitosis by double thymidine block followed by nocodazole treatment, then released into medium containing BrdU, +/- 12.5 μM blebbistatin. By 10 h after the addition of blebbistatin, most cells had exited mitosis; in the presence of blebbistatin approximately 30% of the cells were binucleate and the remaining cells were mononucleate, presumably completing cytokinesis successfully. Blebbistatin was removed, and cells were assayed for S phase entry over time.
At 6 h after the removal of blebbistatin, 44% of the untreated control cells and 53% of the mononucleate blebbistatin-treated cells had entered S phase, whereas only 18% of the binucleate blebbistatin-treated cells had entered S phase (Figure 1E). By 24 h the fraction of both untreated and blebbistatin-treated mononucleate cells that had entered S phase rose to about 70%, whereas the fraction of binucleate cells that had entered S phase remained at about 20% (Figure 1E). Similar results were obtained with 25 μM and 50 μM blebbistatin, as well as with 5 μM AKI-1 (not shown). This indicates that synchronized mitotic cells that failed cytokinesis became arrested in G1 regardless of the specific inhibitor used.
Cells that have failed to divide after mitosis differ from normal cells in that they have two nuclei, two centrosomes, and a decreased surface area to volume ratio. We tested each of these defects individually for an effect on G1 arrest. To test the role of centrosome number, serum-starved G0 cells were fused with enucleated G0 cytoplasts to create cells with two centrosomes, but only one diploid nucleus (Figure 1F). The cell-cytoplast fusions were released from G0 into BrdU-containing medium and allowed to proceed through the cell cycle. The fused cells were compared to cells in the population that had experienced the fusion treatment but had not fused. At 24 h after fusion, 66+/-15% of cytoplast-cell fusions with an extra centrosome had entered S phase, and 63+/-11% of unfused control cells had entered S phase. Therefore the presence of an extra centrosome at G1 does not delay S phase entry and is not responsible for the G1 arrest in binucleate cells resulting from cytochalasin-induced failure of cytokinesis.
To test the role of tetraploidy, serum-starved HDF cells were fused to create binucleate cells. Creating binucleate cells by fusion avoided disruption of the actin cytoskeleton, allowing us to examine the effect of ploidy alone. The binucleate cells resulting from fusion were both tetraploid and had two centrosomes; we showed above that centrosome number was not a factor in the G1 arrest. As above, unfused cells in the population served as an internal control. At 24 h after fusion, 72+/-2% of the unfused cells and 75+/-1% of the fused, binucleate, cells had entered S phase. Therefore, tetraploidy does not cause the observed G1 arrest resulting from cytochalasin-induced failure of cytokinesis.
Cells that fail to divide at cytokinesis are larger than normal cells. Larger cells have a decreased surface area to volume ratio, which might affect the response to perturbation of the cytoskeleton. Thus, the apparent sensitivity to cytokinesis failure might derive directly from a difference in size. To test this, we created large binucleate cells by fusing serum-starved G0 cells to each other. The fusion products were released into growth medium for 3 h to allow for reattachment to the culture substrate. We then added 25 μM blebbistatin, 5 μM cytochalasin, or 5 μM AKI-1 to cells for 10 h, followed by release into BrdU-containing medium. Figure 2 shows that mononucleate and binucleate cells in the control and drug-treated populations entered S phase with similar kinetics. Note that in the cells treated with cytochalasin there was a significant delay in S phase entry, consistent with the cytotoxicity of cytochalasin that we and others have described [13]. These results demonstrate that binucleate cells are not more sensitive to cytokinesis inhibitors due to their increased size.
Figure 2. Cytokinesis inhibitors do not block the G1 to S phase progression of binucleate HDF cells. Serum-starved G0 cells were fused and released into medium containing BrdU and (A) no drug, (B) 25 μM blebbistatin, (C) 5 μM AKI-1, or (D) 5 μM cytochalasin. Some cells remain unfused after the fusion treatment, and were used as mononucleate controls. Time points were taken to assay for S phase entry.
If cells were sensitive to failure of cytokinesis, one might expect that the sensitivity would be expressed as a delay in exit from mitosis, a time when a cytokinetic defect could be corrected. This would be similar to the known DNA damage, DNA replication and spindle assembly checkpoints [16]. We tested in two ways whether mammalian cells delay the exit from mitosis in response to cytokinesis failure. First, HDF cells were imaged by time-lapse microscopy as they progressed through mitosis in the presence or absence of blebbistatin. Cells were synchronized in mitosis by nocodazole treatment, then released for 30 min, when 25 μM blebbistatin was added. Control cells (n = 5) exhibited cytokinetic constrictions beginning about 60 min after release from nocodazole. These cells flattened and began to spread, signaling the end of mitosis, about 85 min after release (Figure 3A). Blebbistatin-treated cells (n = 9) did not undergo observable cytokinesis, as expected, but did flatten and spread about 110 min after release from nocodazole (Figure 3A). We also tested for a delay in mitotic exit by staining with MPM-2, and antibody specific for mitotic phosphoepitopes [17]. Cells that were MPM-2 positive and had condensed DNA were considered to be in mitosis (Figure 3B). After release from nocodazole arrest, the fraction of mitotic cells declined in both the control and blebbistatin-treated populations with only a slight delay apparent in the blebbistatin-treated cells (Figure 3C). Both assays showed that blebbistatin treatment resulted in only a brief delay in the exit from mitosis, suggesting that failure of cytokinesis does not trigger a checkpoint-like arrest.
Figure 3. Cytokinesis failure does not significantly delay the exit frommitosis. (A) Images from time-lapse series of HDF cells at the indicated times after release from nocodazole-mediated mitotic arrest. "Control" cells were not treated with blebbistatin; "Blebbistatin" cells were treated with blebbistatin beginning at 30 min after release from nocodazole. (B) MPM-2 immunofluorescence as a marker for mitotic exit. Fluorescence image of a mitotic cell with condensed DNA and intense MPM-2 staining (top) and a cytokinetic cell with decondensed DNA and diminished MPM-2 staining (bottom). DNA, blue; MPM-2, green. Scale bar represents 10 μm. (C) Mitotic index of control and blebbistatin-treated cells after mitotic release. "Control" cells were not treated with blebbistatin; "Blebbistatin" cells were treated with blebbistatin beginning at 30 min after release from nocodazole. Mitotic index was determined by MPM-2 staining and DNA morphology, as in (B). For each point n = 100 cells.
Since we had ruled out most of the cellular defects associated with division failure as being the cause of the G1 arrest, we attempted to further characterize the arrest. Andreassen et al. [6] reported that p53 is important in the G1 arrest caused by cytokinesis failure. To test the role of the p53 pathway, we repeated the blebbistatin experiment above with wt, p53 -/-, and p21 -/- mouse embryonic fibroblast (MEF) cells. Wt MEF cells behaved similarly to the HDF cells, arresting in G1 in response to cytokinesis failure (Figure 4A). However, in p53 -/- and p21 -/- MEF cells both binucleate and mononucleate cells entered S phase with the same kinetics (Figure 4A). Thus, the p53-p21 pathway is required for the G1 arrest of binucleate cells.
Figure 4. Cells arrested in G1 by cytokinesis failure enter p53- and p21-dependent premature senescence. (A) p53 pathway dependence of the G1 arrest following cytokinesis failure. Wt, p53-/- and p21-/- mouse embryo fibroblasts were synchronized and treated with blebbistatin and assayed as in Figure 1E. For each bar n ≥ 200 cells. (B) G1 arrested binucleate cells entered premature senescence as assayed by senescence-associated β-galactosidase activity (SA-β-gal). The dark stain in the binucleate cell shown is the reaction product of Xgal cleavage. Scale bar represents 10 μm. (C) Time course of appearance of senescent cells. Mononucleate and binucleate cells were assayed for SA-β-gal at the indicated days after blebbistatin removal. For each point n = 60–100 cells.
p53-p21-dependent G1 arrest often results in either apoptosis or senescence [18,19]. To determine the fate of the G1-arrested products of a failed cytokinesis, binucleate HDF cells were prepared using blebbistatin as described above. Blebbistatin was then removed and the cells were assayed by microscopy. The binucleate cells persisted in the population over the course of more than two weeks, consistent with these cells being permanently arrested in the cell cycle. The binucleate cells did not undergo apoptosis, as assayed by morphology and staining with annexin V, an early marker of apoptosis (not shown). However, the binucleate cells did develop several hallmarks of senescence, including becoming flattened and enlarged, and accumulating senescence-associated β-galactosidase activity (Figure 4B). As the criteria for defining cellular senescence are not firmly established [20], we will refer to this phenotype as "senescent-like". At 4 days after blebbistatin removal approximately 35% of binucleate cells and 10% of mononucleate cells were senescent-like; by 12 days virtually all of the binucleate cells, but only 10% of mononucleate cells, were senescent-like (Figure 4C).
We have shown that failure of division of synchronized cells results in a p53-dependent arrest, but that the arrest is not due to ploidy, centrosome number, or cell size, and that the arrest is not preceded by a delay in mitotic exit, suggesting that it is not a classical checkpoint. The characteristics of the arrest are similar to those of the G1 arrest caused by the DNA damage checkpoint in HDF cells, which respond to irreparable DNA damage by entering senescence, instead of apoptosis [21]. These similarities led us to test whether the binucleate G1 arrest might actually be due to DNA damage suffered during the treatment. Cells were synchronized in mitosis by the double thymidine – nocodazole regimen described above and treated with 25 μM blebbistatin. The binucleate cells were released from blebbistatin for 1 h, 3 days, and 8 days respectively, then stained for γ-H2AX, a marker of DNA damage [22]. As a positive control for DNA damage, asynchronous cells were treated with 1 mM hydrogen peroxide for 30 min, allowed to recover in medium for 1 h, and stained for γ-H2AX.
In the untreated control cells, only 3.4% of cells contained γ-H2AX foci, whereas in the hydrogen peroxide treated cells, 33% of cells contained γ-H2AX foci (Figure 5A). Remarkably, at 1 h after release of synchronized cells from blebbistatin, 52% of the binucleate cells contained γ-H2AX foci in one or both nuclei (Figure 5A), suggesting the presence of DNA damage. However, we found that 32% of the mononucleate cells that successfully completed cytokinesis after blebbistatin treatment also contained γ-H2AX foci. This suggested that the observed DNA damage might not be the result of division failure per se, and therefore might have occurred prior to the addition of blebbistatin, possibly during cell synchronization. At 3 days after release from blebbistatin, 30% of the binucleate cells and 11% of the mononucleate cells contained visible γ-H2AX foci. At 8 days after release from blebbistatin, 29% of the binucleate cells and only 6% of the mononucleate cells contained γ-H2AX foci. Most of the binucleate cells also displayed senescent-like phenotypes at 8 days after the removal of blebbistatin (Figure 5B).
Figure 5. Binucleate cells contain nuclear γ-H2AX foci. (A) Binucleate cells were prepared by synchronization and treatment with 25 μM blebbistatin as described above, then stained for the DNA damage marker γ-H2AX. Untreated control cells (top) did not contain any visible γ-H2AX foci, whereas binucleate cells, after released from blebbistatin for 1 h, (bottom) contained γ-H2AX foci that were similar to those of cells treated with H2O2 (middle). Scale bar represents 2.5 μm. (B) Culture was continued for 8 days after release from blebbistatin. Most mononucleate cells lacked γ-H2AX foci (top), whereas approximately 30% of binucleate cells still contained nuclear γ-H2AX foci (bottom). The binucleate cells were also flattened and enlarged, consistent with a senescent-like arrest. Scale bar represents 10 μm.
The binucleate cells that persisted in culture were arrested in G1, as they did not incorporate BrdU after the previous round of mitosis, and they did not proceed to the next round of mitosis, as evidenced by the preservation of the binucleate phenotype. The presence and persistence of nuclear γ-H2AX foci in the G1-arrested binucleate cells suggested that DNA damage might be the cause of the arrest. However, not all the arrested binuclear cells contained visible γ-H2AX foci, indicating that γ-H2AX-associated DNA damage might not be the only cause of the arrest. The percentage of binucleate cells with nuclear γ-H2AX decreased from 52% to 29% over 8 days of culturing, possibly indicating that some cells were able to correct the DNA damage after being arrested in G1 for several days. In contrast, the percentage of mononucleate cells that displayed γ-H2AX foci decreased dramatically over 8 days of culturing, however this was likely due to proliferation of normal mononucleate cells in the culture rather than a difference in response of the mononucleate and binucleate cells to the treatment.
The presence of γ-H2AX foci in the mononucleate cells that successfully completed cytokinesis after blebbistatin treatment suggested that the DNA damage might have been the result of the synchronization treatments, prior to the addition of blebbistatin. Therefore, we tested whether any of the cell synchronization treatments alone had an effect on cell cycle progression. Asynchronous cells were treated with double thymidine block, nocodazole, or blebbistatin individually, following the same protocols used above in multiple treatments. Cells were released from drug and S phase entry was assayed at time points. Figure 6A shows that none of the drug treatments resulted in a substantial failure of cell cycle progression after release. Most importantly, we found that most of the binucleate cells that resulted from cytokinesis failure with blebbistatin treatment alone were able to enter S phase normally after release. This result indicates that there is no cytokinesis checkpoint, in accord with the results of Uetake and Sluder [9].
Figure 6. The combination of double thymidine block and nocodazole treatment causes DNA damage in HDF cells (A) Asynchronous HDF cells were treated with either double thymidine, nocodazole, or blebbistatin individually, then released into BrdU-containing growth media and assayed for S phase entry. For each bar n ≥ 200 cells. (B) Cells were subjected to the treatments in the order double thymidine, nocodazole, blebbistatin. Samples of cells were taken after release from each drug, and S phase entry was assayed. For each bar n ≥ 200 cells. (C) Cells were treated with double thymidine block followed by nocodazole, then stained for γ-H2AX. Scale bar represents 2.5 μm.
Since none of the single drug treatments resulted in a cell cycle arrest, we reasoned that some combination of the treatments must be responsible. To determine which combination of treatments caused a G1 arrest, cells were subjected to the treatments in the order double thymidine, nocodazole, blebbistatin. Samples of cells were taken after release from each drug, and S phase entry was assayed (Figure 6B). Although neither double thymidine nor nocodazole arrest and release alone resulted in a G1 arrest, the combination of them did; only about 45% of such cells progressed into S phase. The addition of blebbistatin to the treatment did not cause a further reduction in the fraction of cells entering S phase; about 64% of the mononucleate cells progressed into S phase. However, only about 22% of the binucleate cells that failed cytokinesis after blebbistatin treatment progressed into S phase. This indicated that the G1 arrest in our experiments is due to the double thymidine block, followed by nocodazole treatment, and that binucleate cells are more susceptible to this effect.
To determine whether the thymidine – nocodazole combination caused the DNA damage we observed, cells were treated with both drugs as above and stained for γ-H2AX. At 3 h after release from the drug treatments, about 33% of cells had γ-H2AX foci (Figure 6C). Thus the thymidine – nocodazole synchronization treatment caused the DNA damage that resulted in cells becoming arrested in G1. Given these results we suggest a simple model for the increased susceptibility of binucleate cells: those cells that failed cytokinesis are more likely to become arrested in G1 because they contain two nuclei, and thus have twice the chance of inheriting DNA damage compared with cells that successfully divided.
Conclusions
We have shown that tetraploidy, aberrant centrosome number, increased cell size, and failure of cytokinesis do not lead to G1 arrest in primary human diploid fibroblasts. Rather, we found that the observed G1 arrest in cells that have failed to divide is likely due to cellular damage caused by standard synchronization treatments. We note that all published observations of a G1 arrest in response to division failure involved extensive manipulation of mammalian cells in culture. It seems likely that these manipulations resulted in DNA damage, or in other damage, that resulted in a G1 arrest, but was not directly associated with division failure. For example, Uetake and Sluder [9] found that supplementing the culture substrate with fibronectin allowed binucleate cells formed by cytochalasin treatment to progress through the cell cycle, suggesting that cell adhesion was defective in the drug-treated cells. Given that binucleate cells clearly can cycle when formed with minimal manipulation, it is likely that all previous reports of a tetraploidy checkpoint can be explained by side effects of the drug treatments used to observe them.
Methods
Cell methods
Human diploid fibroblasts (HDFs) were from infant foreskin. Wt, p53 -/- and p21 -/- mouse embryo fibroblasts (MEFs) were the kind gift of Laura Attardi (Stanford, CA). HDFs and MEFs were cultured in DMEM (Gibco) with 10% fetal bovine serum. HDFs were used prior to passage 10 and MEFs were used prior to passage 5. HDFs were synchronized in G0 by serum starvation [12] and S phase by double thymidine block [23], as described. In the cell fusion experiments, serum-starved G0 cells, or cytoplasts derived from those cells by centrifugation, were fused with serum-starved G0 cells, as described [12]. Immunocytochemistry was as described [12]. Live cell imaging was with a Nikon Diaphot microscope equipped with an environmental chamber allowing incubation at 37°. Images were collected with a CCD camera (Photometrics) and processed with Openlab (Improvision) and Photoshop (Adobe) software. Senescence-associated β-galactosidase activity (SA-β-gal) was assayed as described [24].
Assay for S phase entry by BrdU incorporation
Cells were incubated with 20 μM BrdU (Sigma) for indicated times and fixed in -20°C methanol for at least 10 min. Fixed cells were treated with DNase I (Boehringer Mannheim) and exonuclease III (New England Biolabs) to expose the BrdU epitope prior to incubation with anti-BrdU antibodies, as described [12]. Nuclei were visualized by staining 4',6-diamidino-2-phenylindole (DAPI). Cells were observed with a Zeiss Axioskop microscope with a Zeiss Plan-Neofluar 100/1.3 objective, and images were collected with a cooled-CCD camera (Hamamatsu) controlled by Openlab software.
Assay for DNA damage by γ-H2AX staining
Cells were fixed with 2% paraformaldehyde at room temperature for 10 min, washed 3× with PBS, then permeabilized with-20°C methanol for 5 min and stained with 27 ng/ml γ-H2AX antibody (Trevigen, MD). Only cells with multiple, clearly labeled foci were counted as being γ-H2AX positive.
Drug-induced cytokinesis failure
Cells synchronized in S phase by double thymidine block were released from the block for 6 h to allow completion of S phase. Nocodazole (100 ng/ml) (US Biological) was then added for 6 h to arrest the cells in mitosis. Cells were released from the mitotic arrest for 30 min, during which time most cells formed a bipolar mitotic spindle (Fig 1B). At 30 min after release from mitotic arrest, 20 μM BrdU was added to the medium, together with the indicated concentration of cytochalasin B (Sigma) or (s)-(-)-blebbistatin (Toronto Research Chemicals). Cells were incubated in this medium for 10 h to inhibit cytokinesis, then changed to growth medium containing 20 μM BrdU but no cytokinesis inhibitor, and assayed for S phase entry at the indicated times.
Authors' contributions
CW participated in the design of the study and carried out the experiments. TS conceived of the study and participated in its design.
Acknowledgements
We thank Laura Attardi for insightful discussion about cellular senescence, Aaron Straight for an initial gift of blebbistatin, and Tarun Kapoor for aurora kinase inhibitor. This work was supported by NIGMS grant GM52022 to T.S.
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Study protocol
Preventing mood and anxiety disorders in youth: a multi-centre RCT in the high risk offspring of depressed and anxious patients
Maaike H Nauta1*, Helma Festen1, Catrien G Reichart2, Willem A Nolen3, A D Stant4, Claudi LH Bockting1, Nic JA van der Wee5, Aartjan Beekman6, Theo AH Doreleijers7, Catharina A Hartman3, Peter J de Jong1 and Sybolt O de Vries3,8
Author affiliations
1 Department of Clinical Psychology, University of Groningen, Grote Kruisstraat 2/1, 9712 TS, Groningen, The Netherlands
2 Curium/Leiden University Medical Center, Endegeesterstraatweg 27, 2342 AK, Oegstgeest, The Netherlands
3 Department of Psychiatry/Interdisciplinary Center of Pathology of Emotion, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands
4 Department of Epidemiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands
5 Department of Psychiatry and Leiden Institute for Brain and Cognition, Leiden University Medical Center, Albinusfreef 2, 2333 ZA, Leiden, The Netherlands
6 Department of Psychiatry and EMGO institute, VU University Medical Center/GGZ inGeest, A.J. Ernststraat 1187, 1081 HL, Amsterdam, The Netherlands
7 de Bascule/Academic Medical Center Amsterdam, p/a Postbus 303, 1115 ZG, Duivendrecht, the Netherlands
8 Mental Health Care Friesland (GGz Friesland), Borniastraat 34B, 8934 AD, Leeuwarden, The Netherlands
For all author emails, please log on.
Citation and License
BMC Psychiatry 2012, 12:31 doi:10.1186/1471-244X-12-31
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-244X/12/31
Received:30 January 2012
Accepted:17 April 2012
Published:17 April 2012
© 2012 Nauta et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background
Anxiety and mood disorders are highly prevalent and pose a huge burden on patients. Their offspring is at increased risk of developing these disorders as well, indicating a clear need for prevention of psychopathology in this group. Given high comorbidity and non-specificity of intergenerational transmission of disorders, prevention programs should target both anxiety and depression. Further, while the indication for preventive interventions is often elevated symptoms, offspring with other high risk profiles may also benefit from resilience-based prevention programs.
Method/design
The current STERK-study (Screening and Training: Enhancing Resilience in Kids) is a randomized controlled clinical trial combining selected and indicated prevention: it is targeted at both high risk individuals without symptoms and at those with subsyndromal symptoms. Individuals without symptoms meet two of three criteria of the High Risk Index (HRI; female gender, both parents affected, history of a parental suicide (attempt). This index was developed in an earlier study and corresponds with elevated risk in offspring of depressed patients. Children aged 8–17 years (n = 204) with subthreshold symptoms or meeting the criteria on the HRI are randomised to one of two treatment conditions, namely (a) 10 weekly individual child CBT sessions and 2 parent sessions or (b) minimal information. Assessments are held at pre-test, post-test and at 12 and 24 months follow-up. Primary outcome is the time to onset of a mood or anxiety disorder in the offspring. Secondary outcome measures include number of days with depression or anxiety, child and parent symptom levels, quality of life, and cost-effectiveness. Based on models of aetiology of mood and anxiety disorders as well as mechanisms of change during interventions, we selected potential mediators and moderators of treatment outcome, namely coping, parent–child interaction, self-associations, optimism/pessimism, temperament, and emotion processing.
Discussion
The current intervention trial aims to significantly reduce the risk of intergenerational transmission of mood and anxiety disorders with a short and well targeted intervention that is directed at strengthening the resilience in potentially vulnerable children. We plan to evaluate the effectiveness and cost-effectiveness of such an intervention and to identify mechanisms of change.
Trial registration
NTR2888
Keywords:
Prevention; Offspring; Anxiety; Depression; Randomised controlled trial; Cost effectiveness
Background
Anxiety disorders are highly prevalent among children and adolescents with estimates of 11.6% year prevalence in adolescents alone [1], and depression is highly prevalent among adolescents, with estimates of 3.8% year prevalence [1]. Anxiety and mood disorders in childhood and adolescence not only have a high impact on present functioning [2,3], but are also associated with long-term negative consequences [4,5]. In the Netherlands alone, estimations are that as many as 37.400 adolescents (3.8%) suffer from depressive disorder [1], corresponding with a burden of disease of 7900 Disability Adjusted Life Years (DALYs), meaning that per year 7900 healthy years are lost due to depression alone in youngsters ‘Gezond Verstand’, [6]. For anxiety disorders, estimates are 113.000 adolescents (11.6% year prevalence) and 15.000 DALYs.
From epidemiological research, we know that anxiety and mood disorders often run in families: the incidence of depression and anxiety is elevated by a factor 2–6 among offspring of patients with such a disorder (e.g. [7,8]). There is considerable aetiological and phenomenological overlap between mood and anxiety disorders. Anxiety often precedes depression [9] with the age of onset of depression being typically 5 to 10 years later than that of anxiety disorders e.g. [10].
Given the high prevalence of anxiety and mood disorders, the high impact on individuals as well as the associated societal costs, there is a clear need for prevention of anxiety and mood disorders in youth. Since these disorders run in families, the family may be a good starting point for prevention.
During the last two decades, a variety of programs has been developed to prevent anxiety disorders or depression among children and adolescents [overview: [2,11]. The results of universal prevention programs are disappointing for both anxiety and mood symptomatology [e.g. [2,12]. For selective prevention (targeting high risk groups) and indicated prevention (targeting those with subclinical symptoms) results are more promising.
Despite of the relatively high risk in offspring, thus far the number of randomised controlled trials testing the efficacy of indicated prevention is very limited: Four randomised trials have aimed at offspring of depressed patients [13-16], with two studies reporting on cognitive behavioural group treatments for offspring, and two studies including more family-based treatments. Only one study reported on prevention in children of anxiety disordered parents [17].
In the first study, the effectiveness of the 15-session cognitive group training ‘Coping with stress’ was examined in adolescent offspring of a depressed parent [13]. Adolescents (N = 94) were aged 13–17 years and had subclinical depressive symptoms or a history of depression themselves. The program encompassed cognitive restructuring techniques aimed at changing maladaptive thoughts in general and dysfunctional thoughts with regard to having a depressed parent. The intervention was not only effective in reducing depressive symptomatology, but also showed a significant reduction of new depressive episodes relative to care as usual. The program was also cost-effective [18].
Second, Garber and colleagues designed the largest multicenter trial in this field, including 316 youngsters aged 13–17 years. They were offspring of a parent with a current or prior depressive disorder, and had had a depression themselves or reported depressive symptoms. Adolescents were randomized to either care as usual or an 8-session CBT group training existing of cognitive restructuring and problem solving. Parents were invited to two parent information sessions. Adolescents were less likely to suffer from a depressive episode if they had received the training (21% versus 32% onset in 6 months), but only if the parent was remitted at the time of the intervention.
The third study investigated the effectiveness of a family program, including the 8–15 year-old offspring of at least one parent with an episode of depression in the past 18 months [16]. At least one of the children in the family needed to be free of a depressive disorder. The 6–11 session family program was compared to two plenary group lectures for parents. Both interventions advocated open discussion about the parental illness and were directed at change in family dynamics. Both interventions proved equally effective in increasing family functioning and decreasing internalising behaviours up to 4.5 year follow-up (based on 105 families) [18]. Families in the more intensive treatment reported more benefits in parent-child behaviours and regarding the child’s understanding of parental mental illness.
The fourth trial also investigated the effectiveness of a family intervention for families with at least one parent with a history of depression [19]. The children did not need to report symptoms themselves to participate in the study. Participants included 111 families with 155 children aged 9–15 years, who were randomized to either written information only or to a 12-session cognitive behavioral family intervention in a group format [19]. The family intervention focused on enhancing awareness of the role of depression in a family, on ameliorating parent–child interactions by teaching parenting skills (focusing on parental warmth and structure), and on learning general coping skills (for parents and children separately). Results indicate that children in the family program showed more benefits in terms of internalizing and externalizing symptoms in both parent and child reports. These gains were maintained at two year follow-up [20].
The only trial so far focusing on offspring of patients with anxiety disorders included 40 children aged 7–12 years, who were randomized to either an 8-session family-based CBT program focusing on coping and strengths or to a waitlist control condition. Children were not allowed to have a current anxiety disorder. Current or past symptomatology was not warranted for inclusion in the study. This trial was successful in preventing the onset of anxiety disorders in the offspring: offspring in the active condition did not develop anxiety disorders, whereas 30% of waitlist children met criteria for an anxiety disorder at 1 year follow-up.
In conclusion, results on interventions for offspring of depressed patients (4 studies) and anxious patients (1 study) were positive overall, including benefits on offspring symptomatology [20,21], offspring onset of disorder [13,14,17,20], parent‐child interaction [21], and offspring knowledge on the parent’s illness [21].
The current study builds upon these studies, while adding to them in a variety of ways: (1) we use additional risk factors to select ultra high risk individuals among offspring of patients with a mood or anxiety disorder; (2) we focus on both depression and anxiety; (3) we aim at symptom reduction as well as at increasing strengths and resilience; (4) we include mediators and moderators of change; (5) we include short and long-term cost-effectiveness analyses.
The aforementioned studies were either indicated prevention programs (youth with elevated symptoms) or selective prevention programs (youth with a high risk because of parental illness only). In our study, we aim at combining the two and thus selecting ultra high risk offspring. In line with earlier studies, we select youth with current symptomatology (of anxiety or mood). In addition, we wanted to make a selection of the symptom-free children. We know that some of the offspring may develop disorders over time, even though they currently do not report such symptoms. Recently, we have developed a prognostic index that predicts the development of anxiety or mood disorders in offspring (High Risk Index (HRI; de Vries, Landman-Peeters, Burger, Reichart, Nauta, den Boer, Nolen, Ormel, & Hartman: Predicting mood- and anxiety disorders in offspring of patients with a depressive disorder, unpublished manuscript)). This was done on the basis of a study examining offspring (n = 434) of patients with a unipolar mood disorder in a large prospective study, the ARIADNE-cohort (Adolescents at Risk of Anxiety and Depression, and Neurobiological and Epidemiological approach [22]). Three factors were associated with an increased risk of developing anxiety or mood disorders: female sex, having two affected parents, and suicide attempt(s) of one of the parents. In children with two or three risk factors (20% of the sample) the cumulative incidence of mood and anxiety disorders was 70% at the age of 20. In children with one or no risk factor, percentages dropped to 45% and 25% respectively. In the current study, inclusion is therefore based on the HRI as well as on symptomatology. Thereby, this study uniquely combines selected and indicated prevention [23].
For this group of high-risk offspring, we developed an individual cognitive behavioural therapy (CBT) based intervention targeting multiple risk and protective factors known to be associated with the onset of anxiety and depression (as recommended by Cuijpers [24]). Many prevention programs have focused on symptom reduction, whereas training of positive aspects and building resilience may be of utmost importance in prevention. Some at risk children may not show any symptomatology yet, and they may especially benefit from interventions focusing on strengths rather than vulnerabilities. Important protective factors in offspring include having knowledge on parental illness [25], having a supportive social network [22,26] including a non-ill parent if available [27], as well as displaying active coping skills and flexibility in coping style across situations [28]. Therefore, the offspring intervention includes psychoeducation for offspring, psychoeducation for parents, a focus on the social network, and problem solving skills training. With regard to the risk factors, we know that offspring may have a cognitive vulnerability in information processing: they report more negative and less positive self-statements [29]. Interventions focusing on positive self-statements, positive emotions and positive events may enhance resiliency and may function as a buffer against developing negative mood or anxious feelings. A final risk factor are subclinical complaints. These symptoms are addressed by regular behavioural interventions, namely exposure exercises for anxiety and behavioural activation for depressive symptoms. Behavioural activation may be of particular importance, since engaging in activities and relationships outside of the home environment has been found to be an important protective factor in adolescent offspring [25].
So far, most prevention interventions were group-based. Individual programs allow for more tailoring to the specific needs, strengths and weaknesses of the child. This is crucial because of the heterogeneity of the target population (children with anxiety, or depressive symptoms, or no symptoms but an elevated score on the High Risk Index). In addition, living with a depressed suicidal parent differs in many ways from living with anxious dependent one, for example. An individual approach allows the therapist to tailor the intervention also to the specific background of the child.
To date, preventive interventions have been designed to prevent either mood disorders or anxiety disorders. Keeping in mind the significant overlap in symptoms between depression and anxiety disorders, prevention studies should focus on both. Indeed, epidemiological studies have found that elevated symptoms of anxiety and depression occur in offspring of both anxious [30] and depressed patients [31]. Since the aetiology and pathogenesis of anxiety and depression also have considerable overlap, including offspring from patients with both mood and anxiety disorders provides the opportunity to study common mediating factors.
From a societal point of view, it is important to study the economic impact of psychiatric illnesses and possible effects of prevention programs, to assist future policy making and resource allocation. The economic evaluation in our study will focus on the differential effects on short and long term costs and health outcomes of the treatment conditions under study: CBT or minimal information. The study will be conducted from a societal perspective [32].
Treatment outcome studies typically include variables to study the treatment mechanisms (“how does the treatment work”) as well as the moderators of treatment outcome (“for what groups does the treatment work”)[33]. With regard to mediating factors in the current study, the intervention will aim at changing coping behaviour [34], increasing activities [35], and enhancing trust in the availability of attachment figures (in the social network). Even though we do not address cognitions directly through cognitive restructuring, we nonetheless want to investigate if the child’s attributional style changed through our behaviour intervention.
Moderating factors associated with (non)response are current parental psychopathology [14] and child’s symptomatology (internalising and externalising). We additionally measured some stable child characteristics that have been associated with the onset of anxiety or mood disorders, but have not been studied in relation to treatment outcome in offspring, namely reactive and regulative temperament [36], general executive functioning, and automatic self-associations [37]. In addition, some of the presumed mediating factors may also function as moderators.
In summary, even though there is extensive evidence for the intergenerational transmission of anxiety and mood disorders, few preventive intervention studies in offspring have been carried out. Our study adds to the current state of the art in combining selective and indicative prevention, to focus on both anxiety and mood disorders in adult patients, to focus on both anxiety and depression symptoms in offspring, to work on both symptom reduction and resilience, to study cost-effectiveness, and to examine mediators and moderators of outcome.
Trial objective and purpose
The primary goal is to investigate whether a brief (10 + 2 sessions) cognitive behavioural treatment program on resilience and symptom reduction can prevent the incidence of depression or anxiety disorder in an ultra high risk sample of 8–18 year old offspring of patients with unipolar depression or anxiety disorder (sample defined by a High Risk Index or subclinical symptoms, or both). The second goal is to examine whether this intervention meets current standards for cost-effectiveness. A third goal is to explore the role of a number of factors that may potentially mediate or moderate the effect of the intervention. Mediating factors include coping, attributional style, daily activities, and optimism, while the selected moderating variables are child temperament characteristics and executive functioning, parental psychopathology (of both parents), child symptomatology, attachment, and (automatic) self-associations.
Methods/design
The present project is designed as a selected and indicated prevention program: children and adolescents at high risk for developing affective disorders will be identified and treated if they run an ultra high risk. Such an approach results in a relatively powerful design [24]. The study is further designed as a randomised controlled trial (RCT), including an intervention condition and a minimal information condition.
Participants
Participants in the study are children of patients with and anxiety or mood disorder. We aim at screening 554 children (T0), and at including 204 children in the intervention phase of the study. We have designed in- and exclusion criteria for parents and children:
Inclusion criteria (parents):
At least one of the biological parents, currently or in the past five years, treated for a unipolar mood disorder or an anxiety disorder; informed consent.
Exclusion criteria (both parents):
Mental retardation; severe alcohol or substance use disorder; schizophrenia or other primary psychotic disorder; schizoaffective disorder; bipolar disorder.
Inclusion criteria for the intervention phase (offspring): age 8–17; being at ultra high risk for developing a mood or anxiety disorder. Two pathways lead to the qualification of “ultra high risk”: (1) children report elevated symptoms of anxiety or depression, as defined as the 80th percentile of either the subscale Depression or the cluster of subscales of Anxiety on the RCADS self-report. We used data from the large Dutch epidemiological study TRAILS to set these cut-offs at the various age segments (Tracking Adolescents’ Individual Lives [38]). (2) Children meet at least 2 of 3 criteria of our High Risk Index that was developed in the ARIADNE sample: (a) being female, (b) having two affected parents, (c) having a parent with (past) suicidal behaviour.
Exclusion criteria (offspring): mental retardation; not speaking Dutch fluently; severe alcohol or substance use disorder; current diagnosis of a mental disorder that warrants regular treatment. Children with a history of a mental disorder are included, as well as children with a current disorder that had sufficiently been treated (e.g. in the case of stable medication for ADHD).
Procedure
The study has two phases, namely the screening phase and the intervention phase. Details on the procedure are described in the flow diagram (Figure 1).
Figure 1. Flow diagram.
Referral and recruitment
Adult patients are recruited through mental health services, general practitioners, and by media (newsletters, social media, website, media attention through interviews for newspapers and radio). Adult and child mental health services participate in the recruitment of participants. In child mental health services, parents are included if they have an anxiety or mood disorder themselves. All children of these parents can participate in the study.
Informed consent
Adult patients are informed about the study in two ways. First, patients within a mental health care centre (adult or youth) are informed about the study by their therapist by a full information letter, containing all information for both the parents and the children. If the patient is interested in participating, he or she can contact the researcher. The researcher then checks whether the family has understood the information on the trial. If so, the consent form is signed by both parents and children, and the family is invited for the first screening. Separate informed consent forms are available for parents, adolescents (secondary school) and children (primary school). Even though informed consent is not warranted under the age of 12 in the Netherlands, we do have younger children sign informed consents so that we are sure they are fully informed about the study.
Second, patients may contact the researchers directly, after having received information about the study via their general practitioner, the media, or the website. In that case, the researcher directly informs the family members about the study by way of the information letters described above. We then check the status parent’s past and current psychopathology through a brief telephone interview. Note that for all parents the exact diagnosis is obtained during the assessments through a structured diagnostic interview (CIDI).
Participants can always draw back from participating in the study, at any time during the assessment or intervention, without giving a reason for their withdrawal. Withdrawal from the trial will not affect the regular mental health care for either themselves or their children.
Randomisation
Since outcome may be dependent on treatment centre and the pathway of inclusion (through elevated symptoms versus no symptoms/HRI only), we decided to work with stratified allocation to treatment condition to ensure a balanced number of participants over conditions. A web-based computer program allows for dynamic on-the-spot randomisation. Randomisation is based on the defined strata as well as on the assigned treatment condition of earlier subjects within the strata. To prevent conscious or unconscious influence on the recruiting team, we choose to conceal the exact details of the randomisation process at this stage (following the recommendations of the CONSORT guidelines [39]). Randomisation takes place after the whole assessment has been completed, so that the first assessment is not dependent on the participant’s knowledge of treatment condition. The research assistant assigns a unique code to each participant. In case one family has several high risk children, the youngest child is entered for randomisation, and the siblings are assigned to the same condition. The research assistant then enters the number of the participant in the web-based randomisation program, and at that moment the computer randomly assigns the treatment condition (active intervention or minimal information; 1:1).
Intervention
The intervention has 10 child sessions and 2 sessions for the parents. To strengthen the effectiveness of our intervention, it is based on a theoretical framework including both risk and protective factors (as recommended by Cuijpers [24]).The following themes are addressed: family functioning and social network, being proud of strengths, focus on positive emotions and events, problem solving, and breaking the cycle of avoidance behaviour. The latter will either be focussed on behavioural activation (indication for depressive symptoms [35]) or on exposure exercises (indication for anxiety symptoms). The therapist addresses each of the themes in the first sessions and then elaborates on the most appropriate module(s) for each child. In collaboration with the child and the parents, the child chooses 10 steps to work on throughout the sessions. These steps are in line with the aforementioned themes, and could encompass engaging in specific activities, exposure exercises, and exercises on strengths and resilience. Throughout the sessions, the child regularly monitors the frequency and type of activities (categorised as either alone or with others, and either at home or elsewhere). Ideally, children should have satisfying activities in each of these four categories. This registration is available for mediation analyses. The first session is with the parents only. The therapist makes a plan with the parents on how to give age-appropriate information on the parental anxiety or mood disorder to the child in the next session. Parents also receive information on the possible effect on offspring and protective factors against future child psychopathology (such as having a parent or key figure they can trust, and openness in the family). Two more parent sessions further elaborate on positive parenting and defining the social network in terms of social support for the family.
Assessments
Assessment schedule
Baseline assessment takes place at T0 and comprises questionnaires on the child’s and the parent’s wellbeing (see Table 1). This first screening is used to define the high-risk study population. At T4, all children of parents that were willing to participate will be assessed again with the same measures. The latter is important to evaluate the validity of the initial selection of high risk individuals. If a relatively large proportion of the low-risk group nevertheless has developed a mood or anxiety disorder, this would imply that for future prevention programs the selection strategy should be reconsidered. Selection for the intervention phase is based on the HRI and the RCADS (see Figure 1).
Table 1. Assessment schedule for screening (T0) and 24 months follow-up screening
If a child qualifies for “ultra high risk” based on the screening, he or she may enter the intervention phase of the study. The pre-intervention assessment encompasses structured diagnostic interviews with the child and both parents, as well as a number of relevant other measures (see Table 2). Assessments in the intervention phase are planned for month 0 (T1, at the start of the intervention), month 4 (T2), month 12 (T3), and month 24 (T4). A subset of the instruments is also scheduled for month 6 and 18.
Table 2. Assessment schedule for intervention phase
Measures
Primary outcome
Our primary outcome is the time to onset of depression or anxiety disorders in the offspring, based on the Child version of Diagnostic Interview Schedule for Children Version IV NIMH DISC-IV; [40], which is a highly structured diagnostic assessment instrument designed to gather symptom presence for child and adolescent psychiatric disorders based on the symptoms and criteria variables as defined in the Diagnostic and Statistical Manual of Mental Disorders DSM-IV; [41]. The computerized DISC is administered via a computer (the interviewer reads questions from the computer screen and enters responses directly into the computer) and scored by computer algorithm [42]. There are parallel versions of the instrument: the DISC-P for parents, and the DISC-C for direct administration to children. In the present study the DISC-C is used to assess anxiety disorders and depression, and a brief assessment of alcohol and drug use. The DISC-P is used as a parent report of children’s anxiety and depression symptoms as well as questions about whole life symptomatology. At the 12- and 24-follow-up assessments, the interviewer addresses the past 12 months. If any disorder was present, the interviewer makes an estimation of the time of onset and the duration of the disorder. The interviewer combines information retrieved from the DISC with the Weekly Emotions Diary for Youth (WEDY; Festen & Nauta, Weekly Emotions Diary, unpublished manuscript) as input. All children included in the intervention trial are asked to keep a weekly diary during the study, giving scores of three items: anxiety, sad mood, and happiness on a 0–5 scale. This chart was developed for the purpose of the current study, primarily as a helpful tool to obtain a good estimate of the onset and duration of a disorder (if present by DISC-criteria), since children may not always have an adequate sense of time when retrospectively reporting over the past year. Children are encouraged to fill out the diaries either on paper or through the internet in a web-based diary. They receive an incentive of 1 euro per month for completing the weekly diary, with a maximum of 25 euros.
Secondary outcomes
As secondary outcomes to our study, we will investigate the number of days with a disorder (based on the DISC-IV), child and parent anxiety and depressive symptoms, quality of life, and cost-effectiveness.
The Revised Child Anxiety and Depression Scale (RCADS; RCADS; [43]) is a 47-item self-report and a parent-report questionnaire, with scales corresponding to separation anxiety disorder, social phobia, generalized anxiety disorder, panic disorder, obsessive-compulsive disorder and major depressive disorder.
The Inventory of Depressive Symptomatology IDS; [44] is a 30-item measure of depressive signs and symptoms in adults. In the current study the Dutch translation of the self-report (SR) version was used to assess current depressive symptoms of the parents
The Beck Anxiety Inventory BAI; [45] is a 21-item self-report instrument that assesses the overall severity of anxiety in adults. In this study the BAI is used to assess current anxiety symptoms of parents.
To assess quality of life, we included the EuroQol (EQ-5D[46]), being a brief, easy to administer questionnaire comprised of 2 components: a description of the respondent’s own health using a health status classification system with 5 items and a rating of “own health” by means of a visual analogue scale (VAS; 0–100). We included a child version, a parent version and a regular adult self-report in the current study.
Information on healthcare consumption will be registered with a comprehensive questionnaire capturing (mental) healthcare consumption and other illness-related economic consequences for society. The instrument is administered to the parents and assesses various cost aspects of the child and each parent, including contacts with healthcare professionals, informal care and absence from school or work. The instrument is a revision and adjustment of the youth care version of the TIC-p [47] and has been adopted to the specific situation of the current study. The intervention costs are also monitored including therapist time spent on the actual intervention, the preparation of sessions, course material, travelling costs, and the costs of the training of the therapists.
Mediators and moderators of change
To examine potential mediators and moderators of change we assessed the following measures focused on child characteristics and parent characteristics:
Measures on the child’s characteristics
The Youth Life Orientation (YLOT;[48]) is a 12-item measure of dispositional optimism and pessimism that was developed as a child analogue of the widely used Life Orientation Test.
The Children’s Attributional Style Questionnaire - Revised CASQ-R; [49] is a 24-item shortened measure designed to assess children’s causal explanations for positive and negative events.
The Rosenberg Self-Esteem Scale RSES; [50] is developed as a 15-item self-esteem scale for children and adults and translated into different languages.
An Extrinsic Affective Simon Task (EAST; [51]) is a computerized reaction time task to indirectly measure attitudes. The current EAST was designed for this study and intends to assess the strength of the children’s automatic associations between themselves and sad (or happy) mood, as well as anxious (or calm) feelings. It is a categorization task, during which target words like “myself”, “them”, “anxious”, or “table” appear in the middle of the computer screen, and children have to assign the target words to one of the target labels (me, not-me, feeling, or object) that are set at either the left or the right side of the screen. In correspondence, children press a right or left response key as quickly as possible. The underlying principle is that a person will be faster in categorizing anxiety or depression words to the key that is defined as both “feeling” and “me” label if the person regards him or herself as anxious or depressed. In contrast, the person may be slower in categorizing the words related to calmth or happiness to a key that is defined as both a “feeling” and “me” label. These types of automatic anxious- and depressed self-associations have been found to be predictive of symptomatology in adults [37].
The Coping Strategies Checklist for Children CCSC-R1; Dutch version: CSLK; [52,53] contains 14 subscales, including a variety of cognitive coping strategies. Earlier research in offspring has shown that it may be important to distinguish between coping at home and coping elsewhere [28]. Therefore, we administered two versions of the coping questionnaire. The scale contains five coping dimensions (Seeking understanding, Control, Optimism, Wishful thinking, Support for feeling and Support for actions).
The Brief Impairment Scale BIS; [54] is a multidimensional scale of functional impairment for children and adolescents. The BIS is a 23-item instrument that evaluates three domains of functioning: interpersonal relations, school/work functioning, and self-care/self-fulfillment.
The Behaviour Rating of Executive Functioning BRIEF; [55] is a 86-item standardized rating scale used to assess children’s executive functions in home and school environments. The Early Adolescent Temperament Questionnaire – Revised version (EATQ-R; [56]) is a parent-report questionnaire that was developed to measure child temperamental aspects associated with self-regulation. Three factors were included in the present study with a total of 44 items, namely Effortful control (including activation control, attentional control, and inhibitory control), Negative affect (including Fear, Frustration, and Shyness) and High intensity pleasure/Surgency.
The SNAP-IV Parent Rating Scale (SNAP; [57]) is a parent report questionnaire including 18 items for ADHD (inattention and hyperactivity/impulsivity) and 8 items for ODD symptoms.
The Dutch version of the Inventory of Parent and Peer Attachment IPPA; [58,59] is an 11-item self-report instrument that is used to assess attachment to each parent and one significant other.
Mother-child attachment was also administered through a computer task, the Attentional Breadth Task[60], that was programmed in e-prime. The task is based on the assumption that information processing may be distorted in individuals with insecure attachment when it comes to attachment-relevant information. Insecurely attached children may be more alert to stimuli that are related to the mother, and may be more likely to have a smaller attention span when the mother is involved. During the task, children are shown a picture of either their mother or an unfamiliar woman, as well as a dark dot that appears either close to the picture or further away. Children have to report on whether the woman was their mother or the unfamiliar woman, and must then identify where the dot appeared. For further details and specifications, see [60]. Attentional Narrowing Indices (ANI) are presumed to be a proxy for implicit attachment security and can be derived from the child’s reaction times (ANI = stimulus close to picture – stimulus far from picture).
The Five Minute Speech Sample[61] is used to assess perceived expressed emotion by the father and the mother. Each parent is asked to talk for five minutes about his or her child and the relationship they have with their child. After coding the text, two components can be derived: criticism (CRIT) and emotional overinvolvement (EOI).
Measures on parental well-being and psychopathology
The WMH Survey version of the World Health Organization (WHO) Composite International Diagnostic Interview WMH-CIDI, now CIDI 3.0; [62] is a comprehensive, fully-structured interview designed to be used by trained lay interviewers for the assessment of mental disorders according to the definitions and criteria of DSM-IV [41]. We used the Dutch translation [63] in a computerized version, containing of the following sections: Depression, Mania, Panic Disorder, Social Phobia, Separation Anxiety Disorder, Specific Phobia, Generalized Anxiety Disorder, Obsessive Compulsive Disorder.
The Alcohol Use Disorders Identification Test[64,65] was developed by the World Health Organization (WHO) as a simple method of screening for excessive drinking. Seven of its items reflect harmful and dependent drinking, while three items assess alcohol consumption behaviour in terms of quantity and frequency of drinking.
The Positive and Negative Affect Schedule (PANAS) is a 20-item self-report measure of positive and negative affect [66]. Negative Affect and Positive Affect reflect dispositional dimensions, with high NA epitomized by subjective distress and unpleasurable engagement, and low NA by the absence of these feelings. By contrast, PA represents the extent to which an adults experiences pleasurable engagement with the environment.
Sample size calculation
Our sample size calculation is based on the conventional significance (alpha) and power (1-beta) levels of 0.05 and 0.80 respectively, planning one-sided testing. We assume a baseline incidence rate of mood and anxiety disorders of 0.11/person*year for the control condition, based on our own unpublished analyses in high risk offspring from the ARIADNE study; in the ultra-high risk subgroup of children with 2 or 3 risk factors we found a 10-year cumulative incidence of anxiety- and mood-disorders of 0.67 (time frame: age 10–20), which corresponds to an incidence rate of 0.11/person*year, assuming a constant rate. With an intended follow-up duration of 2 years, we would then need a minimum of 81 participants per condition to give our study sufficient power to detect a clinically meaningful effect of the intervention on the time to onset of episodes of mood- and anxiety disorders. We compared our estimated incidence rates with two prevention studies. Clarke et al. [13], who studied the effect of a preventive program in subsyndromal offspring of depressed patients, found a 1 year cumulative incidence of 0.25 for depression alone (rate 0.29/person*year). Therefore, our incidence assumption is relatively conservative. We assume a risk reduction of 70% for the treatment condition, based on the Clarke study; the 1 year cumulative incidence of depression in the intervention group is 0.08, compared to 0.25 in the control group (unadjusted hazard ratio 0.29). The reported adjusted hazard ratio in this study is 0.18. Dadds et al. [67] report a hazard ratio of 0.22 in favor of a program aimed at preventing anxiety disorders in children. Again, we choose the more conservative estimate. Nevertheless, realizing that above-mentioned assumptions remain uncertain and that participants may drop out, we decided to include another 25%, resulting in 2 groups of 102 children for the intervention phase (N = 204).
Including 554 children for the screening (T0), we estimate that 388 children will be in the ultra high risk group (70%) and 166 children in the no ultra high risk group (30%). We anticipate 20% of the eligible children to already suffer from a mental disorder that warrants treatment, and another 20% to not want to participate in the intervention phase of the study for various reasons (leaving N = 204 for randomization). In order to include 554 children in the screening, we anticipate that we need to select 2770 adult patient files (80% no children in the right age range or no interest in participating in the study). This percentage was based on our earlier experience with the epidemiological ARIADNE study, following offspring over time.
Statistical analyses
Survival analysis will be used to answer the first research question (effect of treatment on the possible onset of depression or anxiety disorder). It encompasses a wide variety of methods for analyzing the timing of events. The logrank test (sometimes called the Mantel-Cox test) is a hypothesis test and will be used to compare the ‘survival’ distribution between the intervention and the control group. The measurement is the time to event (clinical onset of anxiety disorder or depression). Therefore ‘survival’ is ‘no onset of an anxiety or mood disorder’ in the study period of 2 years.
All data will be analyzed using the intent-to-treat principle. Multilevel analysis is a general term referring to statistical methods appropriate for the analysis of data sets comprising several types of units of analysis. Multilevel analysis holds two important features that are relevant to our data, namely the handling of missing data, as well as the possibility to work with dependent data. In our case, siblings are dependent (“nested”) data and can be analyzed as such. Intention to treat analyses are done to avoid the effects of crossover and drop-out, which may break the randomization to the treatment groups in the study. Mediators and moderators can be included as explanatory variables into the multilevel model.
Economic evaluation
An economic evaluation will be conducted alongside the current study to assist future policy making and resource allocation. The economic evaluation focuses on the balance between costs and health outcomes of the treatment conditions. Both short-term and long-term consequences are taken into account.
For the short-term economic analyses, data will be collected prospectively during the 24 months of this study. Both a cost-effectiveness and cost-utility analysis will be conducted to provide information on the short-term economic outcomes. In the cost-effectiveness analysis, the incremental costs per depression & anxiety-free year gained are assessed. The cost-utility analysis will provide information on the incremental costs per Quality Adjusted Life Year (QALY) gained. QALYs will be derived from the EQ-5D [46], which is a brief instrument commonly used in economic evaluations. Since the economic evaluation is conducted from a societal perspective, both medical costs and costs outside the healthcare sector will be assessed. Costs and health outcomes will be discounted in accordance with Dutch guidelines. Bootstrap analyses are planned to provide information on the uncertainty surrounding the economic results. Subsequently, cost-effectiveness acceptability curves will be used to inform decision-makers on the probability that the intervention is cost-effective.
We will also conduct a long-term analysis. The relatively short follow-up period of the prospective part of the study has the drawback of potential underestimation of future beneficial effects of the program. In the proposed long-term analysis we will use decision analytic modeling to explore the cost-effectiveness of the program with a longer time horizon (10 yrs). Primary data from the trial will be combined with secondary data sources, parameter-estimates from the literature, and where necessary other sources such as expert opinions. Where needed, meta-analyses will be performed to aggregate available literature data. A Markov-type decision model will be used in the analysis, which is in general well suited to model chronic diseases, characterized by repeated relapses and remissions over time. In a Markov- (or state-transition) model, health states are defined, together with the probabilities of making the transition from one health state to another. These models simulate the accumulation of health/quality of life effects and costs over time under different strategies e.g. [68]. We plan to use data from NESDA (the Netherlands Epidemiological Study on Depression and Anxiety [69]), a large ongoing naturalistic study in patients with mood and anxiety disorders, to model long-term disease history (e.g. to model duration and frequency of episodes or transitions between mood- and anxiety disorders). The decision analysis will also look at long-term productivity effects of the program; Fergusson et al. [70] demonstrated, for example, a dose‐response relationship between number of depressive episodes during adolescence and productivity later in life. Modeling allows for exploration of cost-effectiveness of the program under study in different scenarios, e.g. to model cost-effectiveness under different assumptions regarding the duration of the treatment effect. Sensitivity analyses can also be used to reveal the parameters that are most crucial to the outcome of the study, which will help to efficiently allocate future research resources.
Ethical approval
The Medical Ethical Committee of the University Medical Center in Groningen gave ethical approval for the study (nr 2009.200). Multi-center ethical approval was obtained for the sites in Groningen (UMCG/Accare), Friesland (GGZ-Friesland), and Leiden (LUMC/Curium-LUMC).
Discussion
Given the high prevalence of anxiety and mood disorders in offspring of adults with these disorders, prevention interventions are needed to prevent internalising mental disorders in children and adolescents. The current STERK-study is a randomised controlled prevention trial in high-risk offspring (aged 8–17 years) of anxious and depressed patients. We select youth on either elevated symptoms or on the basis of the High Risk Index that we developed in an earlier epidemiological offspring study (ARIADNE). The present study is the first to focus on both anxiety and depression, since these disorders are often comorbid, and since epidemiological findings in offspring show that anxious and depressive symptoms are prevalent in offspring of patients with anxiety disorders [30] and just as well in patients suffering from unipolar depression [31]. With this study, we hope to contribute to the prevention of mental disorders in offspring, as well as to the knowledge on mediators and moderators of change.
Developing prevention studies, getting funding, gaining ethical approval, and including participants is a time-consuming trajectory. For the current study/project, the grant application was in 2007, the grant was awarded in 2008, and we received ethical approval by the end of 2009. The inclusion of participants into the project is still ongoing. Due to this timeframe, we have not been able to incorporate some of the most recent findings into our design. In fact, the current design is an adaptation of an earlier design. In the first wave of the study, we only included adult patients that were currently in treatment, and we excluded all children with a history of mental illness. However, we noticed that quite some eligible and interested participants were excluded in this way. In addition, the Garber study [14] got published in 2009, showing that prevention interventions may be only fruitful if parents were remitted in terms of their own mental health problems. Therefore, we decided to broaden the inclusion scope of our trial (approved of by both the governmental funding organization ZonMw and the Medical Ethical Committee).
A preventive intervention of this kind should not be a stand-alone in clinical practice. Many youth departments primarily work on the youth’s psychopathology and hardly identify parental psychopathology. Likewise, mental health centers for adult patients often do not consider the mental health status of offspring. During the process of implementing this study, we noticed that therapists are often unaware if the adult patient has children. The electronic patient files usually do not map age or emotional well being of children. It would be helpful in clinical practice to pay attention to the psychopathology in the family as a whole, and to have more cooperation between the youth and adult departments for cross-referrals. In line with Garber’s findings it might be helpful to address the emotional well being of the children in the remitted instead of the acute phase of the parent’s disorder. The STERK-study may provide valuable tools within such an infrastructure: a way of screening for high-risk children, as well as an intervention aiming at symptom reduction and resilience.
Competing interests
During the years 2007–2012 W.A. Nolen has received grants from the Netherlands Organisation for Health Research and Development, the European Union, the Stanley Medical Research Institute, Astra Zeneca, Eli Lilly, GlaxoSmithKline and Wyeth; has received honoraria/speaker’s fees from Astra Zeneca, Lundbeck, Pfizer and Wyeth; and has served in advisory boards for Astra Zeneca. All other authors report no competing interests.
Authors’ contributions
MN, HF, SdV, and CR drafted this paper which was added to and modified by all other authors. MN and HF developed the content of the STERK-intervention in collaboration with therapists at Accare. All authors contributed to the design of the study and MN, DS and SdV to the analytic strategy. All authors read and approved the final manuscript.
Acknowledgements
This study has been funded by the Prevention program of the Netherlands Organization for Health Research and Development (ZonMw prevention, nr 120620024).
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China
Geography:
China
Ancient terracotta warriors, Xi'an @ C.Michael Hogan
China (officially the People's Republic of China or PRC) is one of the major nations of the world, with the largest population (one-and-a-third billion people or about one-fifth of the world's population) and the fourth largest land area (after Russia, Canada and the United States), and one of the oldest histories of continuous cultural and political history.
China has a very diverse topography with mountains, high plateaus, and deserts in the west; and, plains, deltas, and hills in east. It's climate is equally diverse, ranging from troptical in the south to subarctic in north. The world's tallest peak, Mount Everest on the border between China and Nepal.
Deterioration in the environment - notably air pollution, soil erosion, and the steady fall of the water table, especially in the north - is another long-term problem. China continues to lose arable land because of erosion and economic development. The Chinese government is seeking to add energy production capacity from sources other than coal and oil, focusing on nuclear and alternative energy development.
Its major environmental issues include:
China is susceptible to frequent typhoons (about five per year along southern and eastern coasts); damaging floods; tsunamis; earthquakes; droughts; and, land subsidence.
For centuries China stood as a leading civilization, often outpacing the rest of the world in the arts and sciences, but in the 19th and early 20th centuries, the country was beset by civil unrest, major famines, military defeats, and foreign occupation.
After World War II, the Communists under Mao Zedong established an autocratic socialist system that, while ensuring China's sovereignty, imposed strict controls over everyday life and cost the lives of tens of millions of people.
After 1978, Mao's successor Deng Xiaoping and other leaders focused on market-oriented economic development and by 2000 output had quadrupled. For much of the population, living standards have improved dramatically and the room for personal choice has expanded, yet political controls remain tight.
In 2008, China was estimated to be the second-largest economy in the world after the United States, although in per capita terms the country is still lower middle-income.
Restrictions of family size introduced in 1979 have contributed to a steady decline in China's population growth rate (with fertility rates dropping from over five children per woman to less than two) with significant implications for the country's and the world's environment, as well as the nation's ability to provide infrastructure and services for its people.
For much of the population, living standards have improved dramatically and personal choice has expanded, yet political controls remain tight, and human rights abuses from the government are a major issue. China since the early 1990s has increased its global outreach and participation in international organizations.
Source: NASA
Geography
Location: Eastern Asia, bordering the East China Sea, Korea Bay, Yellow Sea, and South China Sea, between North Korea and Vietnam.
Geographic Coordinates: 35 00 N, 105 00 E
Area: 9,596,960 km2 (9,326,410 km2 land and 270,550 km2 water)
arable land: 14.86%
permanent crops: 1.27%
other: 83.87% (2005)
Land Boundaries: 22,117 km - border countries: Afghanistan 76 km, Bhutan 470 km, Myanmar (Burma) 2185 km, India 3380 km, Kazakhstan 1533 km, North Korea 1416 km, Kyrgyzstan 858 km, Laos 423 km, Mongolia 4,677 km, Nepal 1236 km, Pakistan 523 km, Russia (northeast) 3605 km, Russia (northwest) 40 km, Tajikistan 414 km, Vietnam 1281 km - Regional borders: Hong Kong 30 km, Macau 0.34 km
Coastline: 14,500 km
Maritime Claims:
Territorial sea: 12 nautical miles
Contiguous zone: 24 nautical miles
Exclusive economic zone: 200 nautical miles
Continental shelf: 200 nautical miles or to the edge of the continental margin
Natural Hazards: Frequent typhoons (about five per year along southern and eastern coasts); damaging floods; tsunamis; earthquakes; droughts; land subsidence.
Terrain: Mostly mountains, high plateaus, deserts in west; plains, deltas, and hills in east . The lowest point is Turpan Pendi (-154 metres) and its highest point is Mount Everest (8850 metres).
Climate: Extremely diverse; tropical in south to subarctic in north.
Topography of China. Source: Wikimedia Commons
Ecology and Biodiversity
Ecoregions of China. Source: World Wildlife Fund
1. Changbai Mountains mixed forests
2. Manchurian mixed forests
3. Suiphun-Khanka meadows and forest meadows
4. Amur meadow steppe
5. Da Hinggan-Dzhagdy Mountains conifer forests
6. Nenjiang River grassland
7. Northeast China Plain deciduous forests
8. Mongolian-Manchurian grassland
9. Central China loess plateau mixed forests
10. Bohai Sea saline meadow
11. Huang He Plain mixed forests
12. Yellow Sea saline meadow
13. Changjiang Plain evergreen forests
14. Jian Nan subtropical evergreen forests
15. South China-Vietnam subtropical evergreen forests
16. Hainan Island monsoon rain forests
17. South China Sea Islands
18. Gizhou Plateau broadleaf and mixed forests
19. Sichuan Basin evergreen broadleaf forests
20. Daba Mountains evergreen forests
21. Qin Ling Mountains deciduous forests
22. Ordos Plateau steppe
23. Helanshan montane conifer forests
24. Eastern Gobi desert steppe
25. Daurian forest steppe
26. Alashan Plateau semi-desert
27. Qilian Mountains subalpine meadows
1. Qilian Mountains conifer forests
2. Southeast Tibet shrub and meadows
3. Qionglai-Minshan conifer forests
4. Yunnan Plateau subtropical evergreen forests
5. Hengduan Mountains subalpine conifer forests
6. Northern Indochina subtropical forests
7. Nujiang Langcang Gorge alpine conifer and mixed forests
8. Eastern Himalayan alpine shrub and meadows
9. Northeastern Himalayan subalpine conifer forests
10. Eastern Himalayan broadleaf forests
11. Yarlung Zambo arid steppe
12. Tibetan Plateau alpine shrub and meadows
13. Central Tibetan Plateau alpine steppe
14. Qaidam Basin semi-desert
15. North Tibetan Plateau-Kunlun Mountains alpine desert
16. Karakoram-West Tibetan Plateau alpine steppe
17. Pamir alpine desert and tundra
18. Taklimakan desert
19. Tarim Basin deciduous forests and steppe
20. Tian Shan montane steppe and meadows
21. Tian Shan foothill arid steppe
22. Tian Shan montane conifer forests
23. Junggar Basin semi-desert
24. Altai montane forest and forest steppe
25. Altai alpine meadow and tundra
26. Altai steppe and semi-desert
27. Emin Valley steppe
See also:
See also:
People and Society
The Meridian Gate - the largest gate in the Forbidden City with five arches - is the southern entrance to the Forbidden City in Beijing. Built from 1406 to 1420 AD, the Forbidden City was the Chinese imperial palace from the Ming Dynasty, which began in 1368, to the end of the Qing Dynasty in 1912.
The concentric street patterns of Beijing are clearly visible in this photo taken from the International Space Station. The rectangular area in the center is the Palace Museum also known as the Forbidden City. The area of buildings north of the Forbidden City contains a number of universities. Beijing is surrounded by six ring roads or beltways, four of which may be seen in this photo. The 1st Ring Road no longer functions as an expressway. Image courtesy of NASA.
The Juyongguan section of the Great Wall is closest to Beijing and is therefore its most visited portion. Most of the existing Great Wall was built during the Ming Dynasty (14th to 17th centuries) to protect the northern borders of the Chinese Empire. The Manchus conquered the Empire in the mid-17th century and established the Qing Dynasty; they added so much more territory to the Empire beyond the Great Wall that the structure was no longer needed to protect the Empire from outside invaders.
Construction of the Three Gorges Dam on the Yangtze River in central China. On 15 May 2006, Chinese engineers were pouring the last of the concrete to finish the construction of the massive dam, which is designed to provide flood control and to be the largest electricity-generating plant in the world. By 15 May 2006, the dam spanned the entire river, and a large reservoir had filled behind it to the northwest. White spray shoots through gates in the center portion of the dam. The former locks are much less prominent, and the new ones to the north appear as a linear arrangement of thin, blue rectangles. Photos courtesy of NASA.
Population: 1,343,239,923 (July 2012 est.)
Ethnic groups: Han Chinese 91.5%, Zhuang, Manchu, Hui, Miao, Uighur, Tujia, Yi, Mongol, Tibetan, Buyi, Dong, Yao, Korean, and other nationalities 8.5% (2000 census)
The largest ethnic group is the Han Chinese, who constitute about 91.5% of the total population (2000 census). The remaining 8.5% are Zhuang (16 million), Manchu (10 million), Hui (9 million), Miao (8 million), Uighur (7 million), Yi (7 million), Mongol (5 million), Tibetan (5 million), Buyi (3 million), Korean (2 million), and other ethnic minorities.
Age Structure:
0-14 years: 17.6% (male 126,634,384/female 108,463,142)
15-64 years: 73.6% (male 505,326,577/female 477,953,883)
65 years and over: 8.9% (male 56,823,028/female 61,517,001) (2011 est.)
Median age: 35.5 years
Population Growth Rate: 0.481% (2012 est.)
Birthrate: 12.31 births/1,000 population (2012 est.)
Death Rate: 7.17 deaths/1,000 population (July 2012 est.)
Net Migration Rate: -0.33 migrant(s)/1,000 population (2012 est.)
Urbanization: 47% of total population (2010) growing at an annual rate of change of 2.3% (2010-15 est.)
Life Expectancy at Birth: 74.84 years
male: 72.82 years
female: 77.11 years (2012 est.)
Total Fertility Rate: 1.55 children born/woman (2012 est.)
Languages: Standard Chinese or Mandarin (Putonghua, based on the Beijing dialect), Yue (Cantonese), Wu (Shanghainese), Minbei (Fuzhou), Minnan (Hokkien-Taiwanese), Xiang, Gan, Hakka dialects, minority languages.
There are seven major Chinese dialects and many subdialects. Mandarin (or Putonghua), the predominant dialect, is spoken by over 70% of the population. It is taught in all schools and is the medium of government. About two-thirds of the Han ethnic group are native speakers of Mandarin; the rest, concentrated in southwest and southeast China, speak one of the six other major Chinese dialects. Non-Chinese languages spoken widely by ethnic minorities include Mongolian, Tibetan, Uighur and other Turkic languages (in Xinjiang), and Korean (in the northeast). Some autonomous regions and special administrative regions have their own official languages. For example, Mongolian has official status within the Inner Mongolian Autonomous Region of China.
Literacy: 91.6%
The Pinyin System of Romanization
On January 1, 1979, the Chinese Government officially adopted the pinyin system for spelling Chinese names and places in Roman letters. A system of Romanization invented by the Chinese, pinyin has long been widely used in China on street and commercial signs as well as in elementary Chinese textbooks as an aid in learning Chinese characters. Variations of pinyin also are used as the written forms of several minority languages.
Pinyin has now replaced other conventional spellings in China's English-language publications. The U.S. Government also has adopted the pinyin system for all names and places in China. For example, the capital of China is now spelled "Beijing" rather than "Peking."
Religion
A February 2007 survey conducted by East China Normal University and reported in state-run media concluded that 31.4% of Chinese citizens ages 16 and over are religious believers. While the Chinese constitution affirms “freedom of religious belief,” the Chinese Government places restrictions on religious practice, particularly on religious practice outside officially recognized organizations. The five state-sanctioned “patriotic religious associations” are Buddhism, Taoism, Islam, Catholicism, and Protestantism. Buddhism is most widely practiced; the state-approved Xinhua news agency estimates there are 100 million Buddhists in China. According to the State Administration for Religious Affairs (SARA), there are more than 21 million Muslims in the country. Christians on the mainland number nearly 23 million, accounting for 1.8% of the population, according to The Blue Book of Religions (compiled by the Chinese Academy of Social Sciences' Institute of World Religions and released in August 2010). Other official figures indicate there are 5.3 million Catholics, though unofficial estimates are much higher. The Pew Research Center estimated in 2007 that 50 million to 70 million Christians practice in unregistered religious gatherings or “house” churches. There are no official statistics confirming the number of Taoists in China.
Although officially restricted from 1949 until the 1980s, Buddhism has regained popularity in China and has become the largest organized religion in the country. There continue to be strict government restrictions on Tibetan Buddhism.
Of China's 55 officially recognized minorities, 10 groups are predominately Muslim. According to government figures, there are 36,000 Islamic places of worship and more than 45,000 imams.
Only two Christian organizations--a “patriotic” Catholic association without official ties to Rome and the "Three-Self-Patriotic" Protestant church--are sanctioned by the Chinese Government. Unregistered “house” churches exist in many parts of the country. The extent to which local authorities have tried to control the activities of unregistered churches varies from region to region. However, the government suppresses the religious activities of "underground" Roman Catholic clergy who are not affiliated with the official patriotic Catholic association and have avowed loyalty to the Vatican, which the government accuses of interfering in the country's internal affairs. The government also severely restricts the activities of groups it designates as "evil cults," including several Christian groups and the Falun Gong spiritual movement.
Population Policy
With a population officially over 1.3 billion and an estimated population growth rate of 0.593% (2011 est.), China is very concerned about its population growth and has attempted with mixed results to implement a strict birth limitation policy. China's 2002 Population and Family Planning Law and policy permits one child per family, with allowance for a second child under certain circumstances, especially in rural areas, and with guidelines looser for ethnic minorities with small populations. Enforcement varies and relies largely on "social compensation fees" to discourage extra births. Official government policy prohibits the use of physical coercion to compel persons to submit to abortion or sterilization, but in some localities there are instances of local birth-planning officials using physical coercion to meet birth limitation targets. The government's goal is to stabilize the population in the first half of the 21st century, and 2009 projections from the U.S. Census Bureau were that the Chinese population would peak at around 1.4 billion by 2026.
History
Dynastic Period
China is the oldest continuous major world civilization, with records dating back about 3,500 years. Successive dynasties developed a system of bureaucratic control that gave the agrarian-based Chinese an advantage over neighboring nomadic and hill cultures. Chinese civilization was further strengthened by the development of a Confucian state ideology and a common written language that bridged the gaps among the country's many local languages and dialects. Whenever China was conquered by nomadic tribes, as it was by the Mongols in the 13th century, the conquerors sooner or later adopted the ways of the "higher" Chinese civilization and staffed the bureaucracy with Chinese.
The last dynasty was established in 1644, when the Manchus overthrew the native Ming dynasty and established the Qing (Ch'ing) dynasty with Beijing as its capital. At great expense in blood and treasure, the Manchus over the next half-century gained control of many border areas, including Xinjiang, Yunnan, Tibet, Mongolia, and Taiwan. The success of the early Qing period was based on the combination of Manchu martial prowess and traditional Chinese bureaucratic skills.
During the 19th century, Qing control weakened, and prosperity diminished. China suffered massive social strife, economic stagnation, explosive population growth, and Western penetration and influence. The Taiping and Nian rebellions, along with a Russian-supported Muslim separatist movement in Xinjiang, drained Chinese resources and almost toppled the dynasty. Britain's desire to continue its opium trade with China collided with imperial edicts prohibiting the addictive drug, and the First Opium War erupted in 1840. China lost the war; subsequently, Britain and other Western powers, including the United States, forcibly occupied "concessions" and gained special commercial privileges. Hong Kong was ceded to Britain in 1842 under the Treaty of Nanking, and in 1898, when the Opium Wars finally ended, Britain executed a 99-year lease of the New Territories, significantly expanding the size of the Hong Kong colony.
As time went on, the Western powers, wielding superior military technology, gained more economic and political privileges. Reformist Chinese officials argued for the adoption of Western technology to strengthen the dynasty and counter Western advances, but the Qing court played down both the Western threat and the benefits of Western technology.
Early 20th Century China
Frustrated by the Qing court's resistance to reform, young officials, military officers, and students--inspired by the revolutionary ideas of Sun Yat-sen--began to advocate the overthrow of the Qing dynasty and creation of a republic. A revolutionary military uprising on October 10, 1911, led to the abdication of the last Qing monarch. As part of a compromise to overthrow the dynasty without a civil war, the revolutionaries and reformers allowed high Qing officials to retain prominent positions in the new republic. One of these figures, Gen. Yuan Shikai, was chosen as the republic's first president. Before his death in 1916, Yuan unsuccessfully attempted to name himself emperor. His death left the republican government all but shattered, ushering in the era of the "warlords" during which China was ruled and ravaged by shifting coalitions of competing provincial military leaders.
In the 1920s, Sun Yat-sen established a revolutionary base in south China and set out to unite the fragmented nation. With Soviet assistance, he organized the Kuomintang (KMT or "Chinese Nationalist People's Party"), and entered into an alliance with the fledgling Chinese Communist Party (CCP). After Sun's death in 1925, one of his proteges, Chiang Kai-shek, seized control of the KMT and succeeded in bringing most of south and central China under its rule. In 1927, Chiang turned on the CCP and executed many of its leaders. The remnants fled into the mountains of eastern China. In 1934, driven out of their mountain bases, the CCP's forces embarked on a "Long March" across some of China's most desolate terrain to the northwestern province of Shaanxi, where they established a guerrilla base at Yan'an.
During the "Long March," the communists reorganized under a new leader, Mao Zedong (Mao Tse-tung). The bitter struggle between the KMT and the CCP continued openly or clandestinely through the 14-year-long Japanese invasion (1931-45), even though the two parties nominally formed a united front to oppose the Japanese invaders in 1937. The war between the two parties resumed after the Japanese defeat in 1945. By 1949, the CCP occupied most of the country.
Chiang Kai-shek fled with the remnants of his KMT government and military forces to Taiwan, where he proclaimed Taipei to be China's "provisional capital" and vowed to re-conquer the Chinese mainland. Taiwan still calls itself the "Republic of China."
The People's Republic of China
In Beijing, on October 1, 1949, Mao Zedong proclaimed the founding of the People's Republic of China (P.R.C.). The new government assumed control of a people exhausted by two generations of war and social conflict, and an economy ravaged by high inflation and disrupted transportation links. A new political and economic order modeled on the Soviet example was quickly installed.
In the early 1950s, China undertook a massive economic and social reconstruction program. The new leaders gained popular support by curbing inflation, restoring the economy, and rebuilding many war-damaged industrial plants. The CCP's authority reached into almost every aspect of Chinese life. Party control was assured by large, politically loyal security and military forces; a government apparatus responsive to party direction; and the placement of party members in leadership positions in labor, women's, and other mass organizations.
The "Great Leap Forward" and the Sino-Soviet Split
In 1958, Mao broke with the Soviet model and announced a new economic program, the "Great Leap Forward," aimed at rapidly raising industrial and agricultural production. Giant cooperatives (communes) were formed, and "backyard factories" dotted the Chinese landscape. The results were disastrous. Normal market mechanisms were disrupted, agricultural production fell behind, and China's people exhausted themselves producing what turned out to be shoddy, un-salable goods. Within a year, starvation appeared even in fertile agricultural areas. From 1960 to 1961, the combination of poor planning during the Great Leap Forward and bad weather resulted in one of the deadliest famines in human history.
The already-strained Sino-Soviet relationship deteriorated sharply in 1959, when the Soviets started to restrict the flow of scientific and technological information to China. The dispute escalated, and the Soviets withdrew all of their personnel from China in August 1960. In 1960, the Soviets and the Chinese began to have disputes openly in international forums.
The Cultural Revolution
In the early 1960s, State President Liu Shaoqi and his protege, Party General Secretary Deng Xiaoping, took over direction of the party and adopted pragmatic economic policies at odds with Mao's revolutionary vision. Dissatisfied with China's new direction and his own reduced authority, Party Chairman Mao launched a massive political attack on Liu, Deng, and other pragmatists in the spring of 1966. The new movement, the "Great Proletarian Cultural Revolution," was unprecedented in communist China’s history. For the first time, a section of the Chinese communist leadership sought to rally popular opposition against another leadership group. China was set on a course of political and social anarchy that lasted the better part of a decade.
In the early stages of the Cultural Revolution, Mao and his "closest comrade in arms," National Defense Minister Lin Biao, charged Liu, Deng, and other top party leaders with dragging China back toward capitalism. Radical youth organizations, called Red Guards, attacked party and state organizations at all levels, seeking out leaders who would not bend to the radical wind. In reaction to this turmoil, some local People's Liberation Army (PLA) commanders and other officials maneuvered to outwardly back Mao and the radicals while actually taking steps to rein in local radical activity. In this period massive and widespread destruction of historical and religious properties was encouraged by the communist government, in order to diminish the stature of any ideology in conflict with communism.
Gradually, Red Guard and other radical activity subsided, and the Chinese political situation stabilized along complex factional lines. The leadership conflict came to a head in September 1971, when Party Vice Chairman and Defense Minister Lin Biao reportedly tried to stage a coup against Mao; Lin Biao allegedly later died in a plane crash in Mongolia.
In the aftermath of the Lin Biao incident, many officials criticized and dismissed during 1966-69 were reinstated. Chief among these was Deng Xiaoping, who reemerged in 1973 and was confirmed in 1975 in the concurrent posts of Party Vice Chairman, Politburo Standing Committee member, PLA Chief of Staff, and Vice Premier.
The ideological struggle between more pragmatic, veteran party officials and the radicals re-emerged with a vengeance in late 1975. Mao's wife, Jiang Qing, and three close Cultural Revolution associates (later dubbed the "Gang of Four") launched a media campaign against Deng. In January 1976, Premier Zhou Enlai, a popular political figure, died of cancer. On April 5, Beijing citizens staged a spontaneous demonstration in Tiananmen Square in Zhou's memory, with strong political overtones of support for Deng. The authorities forcibly suppressed the demonstration. Deng was blamed for the disorder and stripped of all official positions, although he retained his party membership.
The Post-Mao Era
Mao's death in September 1976 removed a towering figure from Chinese politics and set off a scramble for succession. Former Minister of Public Security Hua Guofeng was quickly confirmed as Party Chairman and Premier. A month after Mao's death, Hua, backed by the PLA, arrested Jiang Qing and other members of the "Gang of Four." After extensive deliberations, the Chinese Communist Party leadership reinstated Deng Xiaoping to all of his previous posts at the 11th Party Congress in August 1977. Deng then led the effort to place government control in the hands of veteran party officials opposed to the radical excesses of the previous 2 decades.
The new, pragmatic leadership emphasized economic development and renounced mass political movements. At the pivotal December 1978 Third Plenum (of the 11th Party Congress Central Committee), the leadership adopted economic reform policies aimed at expanding rural income and incentives, encouraging experiments in enterprise autonomy, reducing central planning, and attracting foreign direct investment to China. The plenum also decided to accelerate the pace of legal reform, culminating in the passage of several new legal codes by the National People's Congress in June 1979.
After 1979, the Chinese leadership moved toward more pragmatic positions in almost all fields. The party encouraged artists, writers, and journalists to adopt more critical approaches, although open attacks on party authority were not permitted. In late 1980, Mao's Cultural Revolution was officially proclaimed a catastrophe. Hua Guofeng, a protege of Mao, was replaced as premier in 1980 by reformist Sichuan party chief Zhao Ziyang and as party General Secretary in 1981 by the even more reformist Communist Youth League chairman Hu Yaobang.
Reform policies brought improvements in the standard of living, especially for urban workers and for farmers who took advantage of opportunities to diversify crops and establish village industries. Controls on literature and the arts were relaxed, and Chinese intellectuals established extensive links with scholars in other countries.
At the same time, however, political dissent as well as social problems such as inflation, urban migration, and prostitution emerged. Although students and intellectuals urged greater reforms, some party elders increasingly questioned the pace and the ultimate goals of the reform program. In December 1986, student demonstrators, taking advantage of the loosening political atmosphere, staged protests against the slow pace of reform, confirming party elders' fear that the current reform program was leading to social instability. Hu Yaobang, a protege of Deng and a leading advocate of reform, was blamed for the protests and forced to resign as CCP General Secretary in January 1987. Premier Zhao Ziyang was made General Secretary and Li Peng, former Vice Premier and Minister of Electric Power and Water Conservancy, was made Premier.
1989 Student Movement and Tiananmen Square
After Zhao became the party General Secretary, the economic and political reforms he had championed, especially far-reaching political reforms enacted at the 13th Party Congress in the fall of 1987 and subsequent price reforms, came under increasing attack. His proposal in May 1988 to accelerate price reform led to widespread popular complaints about rampant inflation and gave opponents of rapid reform the opening to call for greater centralization of economic controls and stricter prohibitions against Western influence. This precipitated a political debate, which grew more heated through the winter of 1988-89.
The death of Hu Yaobang on April 15, 1989, coupled with growing economic hardship caused by high inflation, provided the backdrop for a large-scale protest movement by students, intellectuals, and other parts of a disaffected urban population. University students and other citizens camped out in Beijing's Tiananmen Square to mourn Hu's death and to protest against those who would slow reform. Their protests, which grew despite government efforts to contain them, called for an end to official corruption, a greater degree of democracy, and for defense of freedoms guaranteed by the Chinese constitution. Protests also spread to many other cities, including Shanghai, Chengdu, and Guangzhou.
Martial law was declared on May 20, 1989. Late on June 3 and early on the morning of June 4, military units were brought into Beijing. They used armed force to clear demonstrators from the streets. There are no official estimates of deaths in Beijing, but most observers believe that casualties numbered in the hundreds.
After June 4, while foreign governments expressed horror at the brutal suppression of the demonstrators, the central government eliminated remaining sources of organized opposition, detained large numbers of protesters, and required political reeducation not only for students but also for large numbers of party cadre and government officials. Zhao was purged at the Fourth Plenum of the 13th Central Committee in June and replaced as Party General Secretary by Jiang Zemin. Deng’s power was curtailed as more orthodox party leaders, led by Chen Yun, became the dominant group in the leadership.
Following this resurgence of conservatives in the aftermath of June 4, economic reform slowed until given new impetus by Deng Xiaoping's return to political dominance 2 years later, including a dramatic visit to southern China in early 1992. Deng's renewed push for a market-oriented economy received official sanction at the 14th Party Congress later in the year as a number of younger, reform-minded leaders began their rise to top positions. Hu Jintao was elevated to the Politburo Standing Committee at the Congress. Deng and his supporters argued that managing the economy in a way that increased living standards should be China's primary policy objective, even if "capitalist" measures were adopted. Subsequent to the visit, the Communist Party Politburo publicly issued an endorsement of Deng's policies of economic openness. Though continuing to espouse political reform, China has consistently placed overwhelming priority on the opening of its economy.
Post-Deng Leadership
Deng's health deteriorated in the years prior to his death in 1997. During that time, Party General Secretary and P.R.C. President Jiang Zemin and other members of his generation gradually assumed control of the day-to-day functions of government. This "third generation" leadership governed collectively with Jiang at the center.
In the fall of 1987, Jiang was re-elected Party General Secretary at the 15th Party Congress, and in March 1998 he was re-elected President during the 9th National People's Congress. Premier Li Peng was constitutionally required to step down from that post. He was elected to the chairmanship of the National People's Congress. The reform-minded pragmatist Zhu Rongji was selected to replace Li as Premier.
In November 2002, the 16th Communist Party Congress elected Hu Jintao as the new General Secretary. In 1992 Deng Xiaoping had informally designated Hu Jintao as the leading figure among the "fourth generation" leaders. A new Politburo and Politburo Standing Committee was also elected in November.
In March 2003, General Secretary Hu Jintao was elected President at the 10th National People's Congress. Jiang Zemin retained the chairmanship of the Central Military Commission. At the Fourth Party Plenum in September 2004, Jiang Zemin retired from the Central Military Commission, passing the Chairmanship and control of the People's Liberation Army to President Hu Jintao.
The Chinese Communist Party’s 17th Party Congress, held in October 2007, saw the elevation of key “fifth generation” leaders to the Politburo and Standing Committee, including Xi Jinping, Li Keqiang, Li Yuanchao, and Wang Yang. At the National People’s Congress plenary held in March 2008, Xi was elected Vice President of the government, and Li Keqiang was elected Vice Premier. The 18th Party Congress is scheduled to be held in the fall of 2012. It is expected that President Hu Jintao, in keeping with precedent, will step down as the party's General Secretary at that time, and the Congress will elect the 18th Central Committee of the Communist Party of China.
Government
Chinese Communist Party
The estimated 78 million-member CCP, authoritarian in structure and ideology, continues to dominate government. Nevertheless, China's population, geographical vastness, and social diversity frustrate attempts to rule by fiat from Beijing. Central leaders must increasingly build consensus for new policies among party members, local and regional leaders, influential non-party members, and the population at large.
In periods of greater openness, the influence of people and organizations outside the formal party structure has tended to increase, particularly in the economic realm. This phenomenon is most apparent today in the rapidly developing coastal region. Nevertheless, in all important government, economic, and cultural institutions in China, party committees work to see that party and state policy guidance is followed and that non-party members do not create autonomous organizations that could challenge party rule. Party control is tightest in government offices and in urban economic, industrial, and cultural settings; it is considerably looser in the rural areas, where roughly half of the people live.
Theoretically, the party's highest body is the Party Congress, which traditionally meets at least once every 5 years. The 17th Party Congress took place in fall 2007. The primary organs of power in the Communist Party include:
• The Politburo Standing Committee, which currently consists of nine members;
• The Politburo, consisting of 25 full members, including the members of the Politburo Standing Committee;
• The Secretariat, the principal administrative mechanism of the CCP, headed by Politburo Standing Committee member and executive secretary Xi Jinping;
• The Central Military Commission;
• The Central Discipline Inspection Commission, which is charged with rooting out corruption and malfeasance among party cadres.
State Structure
Since 1949, the Chinese Government has always been subordinate to the Chinese Communist Party; the govenment's chief role is to implement party policies. The primary organs of state power are the National People's Congress (NPC), the President (the head of state), and the State Council. Members of the State Council include Premier Wen Jiabao (the head of government), a variable number of vice premiers (now four), five state councilors (protocol equivalents of vice premiers but with narrower portfolios), and 25 ministers, the central bank governor, and the auditor-general.
Under the Chinese constitution, the NPC is the highest organ of state power in China. It meets annually for about 2 weeks to review and approve major new policy directions, laws, the budget, and major personnel changes. These initiatives are presented to the NPC for consideration by the State Council after previous endorsement by the Communist Party's Central Committee. Although the NPC generally approves State Council policy and personnel recommendations, various NPC committees hold active debate in closed sessions, and changes may be made to accommodate alternative views.
When the NPC is not in session, its permanent organ, the Standing Committee, exercises state power.
Government Type: Communist state
Capital: Beijing - 12.214 million (2009)
Other Major Cities: Shanghai 16.575 million; Chongqing 9.401 million; Shenzhen 9.005 million; Guangzhou 8.884 million (2009)
Administrative Divisions: 23 provinces (sheng, singular and plural), 5 autonomous regions (zizhiqu, singular and plural), and 4 municipalities (shi, singular and plural)
• provinces: Anhui, Fujian, Gansu, Guangdong, Guizhou, Hainan, Hebei, Heilongjiang, Henan, Hubei, Hunan, Jiangsu, Jiangxi, Jilin, Liaoning, Qinghai, Shaanxi, Shandong, Shanxi, Sichuan, Yunnan, Zhejiang; (see note on Taiwan)
• autonomous regions: Guangxi, Nei Mongol (Inner Mongolia), Ningxia, Xinjiang Uygur, Xizang (Tibet)
• municipalities: Beijing, Chongqing, Shanghai, Tianjin
note: China considers Taiwan its 23rd province; Hong Kong and Macau are special administrative regions
Source: Wikimedia Commons
Legal System: Based on civil law influenced by Soviet and continental European civil law systems; legislature retains power to interpret statutes; constitution ambiguous on judicial review of legislation. China has not submitted an International Court of Justice (ICJ) jurisdiction declaration; and is a non-party state to the International Criminal Court (ICCt).
The government's efforts to promote rule of law are ongoing. After the Cultural Revolution, China's leaders aimed to develop a legal system to restrain abuses of official authority and revolutionary excesses. In 1982, the National People's Congress adopted a new state constitution that emphasized the rule of law under which even party leaders are theoretically held accountable.
Since 1979, when the drive to establish a functioning legal system began, more than 300 laws and regulations, most of them in the economic area, have been promulgated. The use of mediation committees--informed groups of citizens who resolve about 90% of China's civil disputes and some minor criminal cases at no cost to the parties--is one innovative device. There are more than 800,000 such committees in both rural and urban areas.
Legal reform became a government priority in the 1990s. Legislation designed to modernize and professionalize the nation's lawyers, judges, and prisons was enacted. The 1994 Administrative Procedure Law allows citizens to sue officials for abuse of authority or malfeasance. In addition, the criminal law and the criminal procedures laws were amended to introduce significant reforms. The criminal law amendments abolished the crime of "counter-revolutionary" activity, although many persons are still incarcerated for that crime. Criminal procedures reforms also encouraged establishment of a more transparent, adversarial trial process. The Chinese constitution and laws provide for fundamental human rights, including due process, but these are often ignored in practice. In addition to other judicial reforms, the constitution was amended in 2004 to include the protection of individual human rights and legally-obtained private property, but it is unclear how some of these provisions will be implemented. Since this amendment, there have been new publications in bankruptcy law and anti-monopoly law, and modifications to company law and labor law. Although new criminal and civil laws have provided additional safeguards to citizens, previously debated political reforms, including expanding elections to the township level beyond the current trial basis, have been put on hold.
Environment
One of the serious negative consequences of China's rapid industrial development has been increased pollution and degradation of natural resources. China surpassed the United States as the world's largest emitter of carbon dioxide and other greenhouse gases in 2007. A World Health Organization report on air quality in 272 cities worldwide concluded that seven of the world's 10 most polluted cities were in China. According to China's own evaluation, two-thirds of the 338 cities for which air-quality data are available are considered polluted--two-thirds of those moderately or severely so. Almost all of the nation's rivers are considered polluted to some degree and half of the population lacks access to clean water. Ninety percent of urban bodies of water are severely polluted. Various studies estimate pollution costs the Chinese economy 7%-10% of GDP each year.
Water scarcity also is an issue, particularly in Northern China, where groundwater is being extracted at an increasingly unsustainable rate, seriously constricting future economic growth if stronger conservation measures are not taken or additional water not diverted. The central government is currently focused on the latter option, investing an estimated $60 billion in the South-North Water Diversion Project, a large-scale diversion of water from the Yangtze River to northern cities, including Beijing and Tianjin.
The question of environmental impacts associated with the Three Gorges Dam project has generated controversy among environmentalists inside and outside China. Critics claim that erosion and silting of the Yangtze River threaten several endangered species, while Chinese officials say the dam will help prevent devastating floods and generate clean hydroelectric power that will enable the region to lower its dependence on coal, thus lessening air pollution. There are also major concerns about whether water supply in the Yangtze is adequate to support the project.
China's leaders are increasingly paying attention to the country's severe environmental problems. In 1998, the State Environmental Protection Administration (SEPA) was officially upgraded to a ministry-level agency, the Ministry of Environmental Protection (MEP). In recent years, China has strengthened its environmental legislation and made some progress in stemming environmental deterioration. Beijing invested heavily in pollution control as part of its campaign to host a successful Olympiad in 2008, though some of the gains were temporary in nature. Some cities have seen improvement in air quality in recent years. The United States and China have been engaged in an active program of bilateral environmental cooperation since the mid-1990s, with a more recent emphasis on clean energy technology and the design of effective environmental policy. China has similar energy and environmental cooperation programs with Japan and European Union countries.
In 2008, China and the United States formed the Ten-Year Framework on Energy and Environment (TYF). The TYF facilitates the exchange of information and best practices between the two countries to foster innovation and develop solutions to the pressing energy and environment problems both countries face. The framework is comprised of seven action plans (clean air, clean water, clean and efficient transportation, clean and efficient electricity, energy efficiency, protected areas, and wetlands conservation) as well as the EcoPartnerships program, which seeks to encourage action plan collaboration at the sub-national level (states, cities, businesses, and universities) between the U.S. and China. Seven original EcoPartnerships were announced with the formation of the TYF in 2008, with six new partnerships signed during the third annual S&ED in May 2011. (For more information about the TYF and EcoPartnerships see: http://www.state.gov/e/oes/env/tenyearframework/index.htm)
During the July 2009 S&ED, the two countries negotiated an MOU to enhance cooperation on climate change, energy, and the environment, which further elaborated the role of the TYF and established a new dialogue and cooperation mechanism on climate change. During the May 2011 S&ED, the U.S. and China affirmed their efforts to work together to achieve a positive outcome at the UN Climate Change Conference in Durban, South Africa.
The first U.S.-China Renewable Energy Forum was held concurrently with the second annual S&ED in May 2010 in Beijing. Forums were held on energy efficiency, biofuels, and on promoting opportunities for U.S.-China collaboration to advance clean energy, including through $150 million in bilateral private and public funding for the CERC. Five-year work plans for the U.S. and Chinese CERC research teams were signed during President Hu Jintao’s January 2011 visit.
International Environmental Agreements
China is party to international agreements on Antarctic-Environmental Protocol, Antarctic Treaty, Biodiversity, Climate Change, Climate Change-Kyoto Protocol, Desertification, Endangered Species, Environmental Modification, Hazardous Wastes, Law of the Sea, Marine Dumping, Ozone Layer Protection, Ship Pollution, Tropical Timber 83, Tropical Timber 94, Wetlands, and Whaling.
China is an active participant in climate change talks and other multilateral environmental negotiations, taking environmental challenges seriously but pushing for the developed world to help developing countries. China is a member of the Major Economies Forum on Energy and Climate, and participates actively in the bilateral Climate Change Policy Dialogue. It signed on to the 2009 Copenhagen Accord in 2010 and inscribed a commitment to reducing its carbon intensity levels by 40%-45% by 2020 from 2005 levels. During President Hu’s January 2011 visit, the U.S. and China agreed to implement the 2010 Cancun agreements and support efforts to achieve positive outcomes at the 2011 UN conference in South Africa.
China is a signatory to the Basel Convention governing the transport and disposal of hazardous waste and the Montreal Protocol for the Protection of the Ozone Layer, as well as the Convention on International Trade in Endangered Species and other major environmental agreements.
Water
See Water profile of China
Total Renewable Water Resources: 2,829.6 cu km (1999)
Freshwater Withdrawal: Total: 549.76 cu km/yr (7% Domestic, 26% Industrial, 68% Agricultural). Per capita: 415 cu m/yr (2000)
Water scarcity is a critical issue in China. Recently, severe drought in northern China posed a serious threat to sustained economic growth and local livelihoods. Since the 1980s, China has experienced increased severity and frequency of water shortages due to variations in rainfall; excessive withdrawals of groundwater sources, polluted water resources, and inefficiencies in water usage. In normal water years, half of China’s 662 cities have insufficient water supplies. Almost 94% of metropolitan areas with populations of more than one million people struggle to meet their annual water demands. Eleven percent of China’s population lack access to improved drinking water sources (up from 33% in 1990); while 45% of the population lacks access to improved sanitation.
In addition, poor water quality continues to pose a challenge to environmental and human health. On a daily basis 300 million people drink contaminated water in China. Nine million cases of diarrhea linked to water pollution occur annually in China, based on China’s 2003 National Health Survey. Approximately 61,000 people in China die annually from diarrhea related to polluted water--half of them are rural children.
The Government of China has responded to this crisis through large investments in the water sector, including storage, conveyance and treatment. Recent water and energy policies stressed conservation measures requiring municipalities and industry to consume less water. Large construction projects, such as the South-North Water Transfer project, are directed at addressing the water crisis. However, the question of environmental impacts associated with such projects has generated controversy among environmentalists inside and outside China. Critics assert that the magnitude and cost of building and operating large conveyance systems could result in unintended consequences that may overwhelm planned benefits. These consequences may include higher water prices, damage to local and downstream environments, additional treatment facilities for water that is currently too polluted to use, or further water shortages. China has announced its intention to funnel billions of renminbi of additional investment into water conservation projects during the 12th Five-Year Plan (2011-2015).
Agriculture
China is the world's most populous country and one of the largest producers and consumers of agricultural products. According to the UN World Food Program, in 2003, China fed 20% of the world's population with only 7% of the world's arable land (estimated at 121.7 million hectares in 2010, down from 129.9 million hectares in 1997). Almost 40% of China's labor force is engaged in agriculture, even though only 15% of the land is suitable for cultivation and agriculture contributes only about 10.3% of China's GDP (2009). China is among the world's largest producers of rice, corn, wheat, soybeans, vegetables, tea, and pork. Cotton is the major non-food commodity. China hopes to further increase agricultural production through improved plant stocks, fertilizers, new technologies (such as biotechnology), irrigation, and using more sustainable methods of production. The Chinese Government has also acknowledged that climate change poses a severe threat to the farming sector. Incomes for Chinese farmers are increasing more slowly than for urban residents, leading to an increasing wealth gap between the cities and countryside. Inadequate port facilities and a lack of warehousing and cold storage installations impede both domestic and international agricultural trade.
China is now one of the most important markets for U.S. exports; in 2010, U.S. exports to China totaled $91.9 billion, an all-time high. U.S. agricultural exports continue to play a major role in bilateral trade, totaling $17.9 billion in 2010 and thus making China the United States' largest agricultural export market. Leading categories include: soybeans ($11.3 billion), cotton ($1.988 billion), and hides and skins ($822 million).
Agricultural products: Rice, wheat, potatoes, corn, peanuts, tea, millet, barley, apples, cotton, oilseed; pork; fish
Irrigated Land: 545,960 sq km (2003)
Energy
See Energy profile of China, Three Georges Dam
Driven by strong economic growth, China's demand for energy is surging rapidly. China is the world's largest energy consumer and the world's second-largest net importer of crude oil after the United States. China is also the fifth-largest energy producer in the world. The International Energy Agency estimates that China will contribute 36% to the projected growth in global energy use, with its demand rising by 75% between 2008 and 2035. China's electricity generation is expected to increase to 10,555 billion kilowatt hours (Bkwh) by 2035, over three times the amount in 2009, according to U.S. Energy Information Administration. In 2010, China led the world in clean energy investment with $51.1 billion and had installed wind capacity of 41.8 gigawatts, the most in the world.
Coal continues to make up the bulk of China's energy consumption (71% in 2009), and China is the largest producer and consumer of coal in the world. As China's economy continues to grow, China's coal demand is projected to rise significantly, although coal's share of China's overall energy consumption is expected to decrease. China's continued reliance on coal as a power source has contributed significantly to China's emergence as the world's largest emitter of acid rain-causing sulfur dioxide and green house gases, including carbon dioxide.
China's 12th Five-Year Plan (2011-2015) continues the government’s policies encouraging greater energy conservation measures, development of renewable energy sources, and increased attention to environmental protection. China is exploring cleaner energy sources, including natural and shale gas, wind, solar, biomass, hydropower, and nuclear power, to reduce reliance on coal. China's renewable energy law calls for 15% of its energy to come from non-fossil fuel sources by 2020. In addition, the share of electricity generated by nuclear power is projected to grow from 1% in 2000 to 5% in 2020.
Since 1993, China has been a net importer of oil, a large portion of which comes from the Middle East. Net imports were approximately 4.3 million barrels per day in 2009. China's use of oil will continue to increase rapidly, particularly in response to the quick expansion of its vehicle fleets. Vehicle sales in China in 2010 rose 32% to over 18 million. China is interested in diversifying the sources of its oil imports and has invested in oil fields around the world. China recently concluded long-term loan-for-oil deals totaling $50 billion with Russia, Brazil, Venezuela, Kazakhstan, Angola, and Ecuador. In recent years, China’s National Offshore Oil Corporation (CNOOC) has also invested in several U.S. oil and natural gas fields in Texas, Colorado, and Wyoming. Beijing also plans to increase China's natural gas use through imports and domestic production. Gas currently accounts for only 4% of China's total energy consumption. China has set an ambitious target of increasing the share of natural gas in its overall energy mix to 10%.
During the July 2009 inaugural meeting of the U.S.-China Strategic and Economic Dialogue (S&ED), the two countries negotiated a memorandum of understanding (MOU) to enhance cooperation on climate change, energy, and the environment in order to expand and enhance cooperation on clean and efficient energy, to protect the environment, and to ensure energy security. The two sides also signed an MOU on cooperation on energy efficiency in buildings.
In November 2009, during U.S. President Obama’s state visit to China, the United States and China announced the establishment of the U.S.-China Clean Energy Research Center (CERC), which will focus on energy efficiency, clean coal including carbon capture and storage, and clean vehicles; signed the Renewable Energy Partnership; launched the U.S.-China Electric Vehicles Initiative; announced the bilateral Energy Efficiency Action Plan under the Ten-Year Framework on Energy and Environment; and inaugurated the U.S.-China Energy Cooperation Program, a public-private partnership focused on joint collaborative projects on renewable energy, smart grid, clean transportation, green building, clean coal, combined heat and power, and energy efficiency. The two countries also announced the launch of the U.S.-China Shale Gas Initiative, which will accelerate China's development of shale gas resources.
During President Hu’s January 2011 state visit to the United States, the U.S. Department of Energy announced joint work plans under the U.S.-China CERC on building efficiency, clean coal, and clean vehicles, and started negotiations on a U.S.-China Eco-City Initiative to integrate energy efficiency and renewable energy into city design and operation in the two countries. In May 2011, the United States hosted the second U.S.-China Energy Efficiency Forum, and similar forums on biofuels and renewable energy are currently being planned.
Resources
Natural Resources: Coal, iron ore, petroleum, natural gas, mercury, tin, tungsten, antimony, manganese, molybdenum, vanadium, magnetite, aluminum, lead, zinc, uranium, hydropower potential (world's largest). See also: Phosphorus use in China.
Economy
Efforts to stimulate the economy have led to widespread air pollution issue, Beijing motorways. @ C.Michael Hogan
Since the late 1970s China has moved from a closed, centrally planned system to a more market-oriented one that plays a major global role - in 2010 China became the world's largest exporter. Reforms began with the phasing out of collectivized agriculture, and expanded to include the gradual liberalization of prices, fiscal decentralization, increased autonomy for state enterprises, creation of a diversified banking system, development of stock markets, rapid growth of the private sector, and opening to foreign trade and investment. China has implemented reforms in a gradualist fashion. In recent years, China has renewed its support for state-owned enterprises in sectors it considers important to "economic security," explicitly looking to foster globally competitive national champions.
Since 1978, China has reformed and opened its economy. The Chinese leadership has adopted a more pragmatic perspective on many political and socioeconomic problems and has reduced the role of ideology in economic policy. China's ongoing economic transformation has had a profound impact not only on China but on the world. The market-oriented reforms China has implemented over the past 2 decades have unleashed individual initiative and entrepreneurship. The result has been the largest reduction of poverty and one of the fastest increases in income levels ever seen. In 2010, China overtook Japan to become the world’s second-largest economy in terms of gross domestic product, behind the United States. It has sustained average economic growth of over 9.3% since 1989. In 2010 its $5.88 trillion economy was just over one-third the size of the U.S. economy.
China is firmly committed to economic reform and opening to the outside world. The Chinese leadership has identified reform of state industries, the establishment of a social safety net, reduction of the income gap, protection of the environment, and development of clean energy as government priorities. Government strategies for achieving these goals include large-scale privatization of unprofitable state-owned enterprises, development of a pension system for workers, establishment of an effective and affordable health care system, building environmental requirements into promotion criteria for government officials, and increasing rural incomes to allow domestic demand to play a greater role in driving economic growth. The leadership has also downsized the government bureaucracy.
In the 1980s, China tried to combine central planning with market-oriented reforms to increase productivity, living standards, and technological quality without exacerbating inflation, unemployment, and budget deficits. It pursued agricultural reforms, dismantling the commune system and introducing a household-based system that provided peasants greater decision-making in agricultural activities. The government also encouraged nonagricultural activities such as village enterprises in rural areas, promoted more self-management for state-owned enterprises, increased competition in the marketplace, and facilitated direct contact between Chinese and foreign trading enterprises. China also relied more upon foreign financing and imports.
During the 1980s, these reforms led to average annual growth rates of 10% in agricultural and industrial output. Rural per capita real income doubled. China became self-sufficient in grain production; rural industries accounted for 23% of agricultural output, helping absorb surplus labor in the countryside. The variety of light industrial and consumer goods increased. Reforms began in the fiscal, financial, banking, price-setting, and labor systems.
By the late 1980s, however, the economy had become overheated, with increasing rates of inflation. At the end of 1988, in reaction to a surge of inflation caused by accelerated price reforms, the leadership introduced an austerity program.
China's economy regained momentum in the early 1990s. During a visit to southern China in early 1992, China's paramount leader at the time, Deng Xiaoping, made a series of political pronouncements designed to reinvigorate the process of economic reform. The 14th Party Congress later in the year backed Deng's renewed push for market reforms, stating that China's key task in the 1990s was to create a "socialist market economy." The 10-year development plan for the 1990s stressed continuity in the political system with bolder reform of the economic system.
Following the Chinese Communist Party's October 2003 Third Plenum, Chinese legislators unveiled several proposed amendments to the state constitution. One of the most significant was a proposal to provide protection for private property rights. Legislators also indicated there would be a new emphasis on certain aspects of overall government economic policy, including efforts to reduce unemployment, which was officially 4.1% for urban areas in 2010 but is much higher when migrants are included. Other areas of emphasis include rebalancing income distribution between urban and rural regions and maintaining economic growth while protecting the environment and improving social equity. The National People's Congress approved the amendments when it met in March 2004. The Fifth Plenum in October 2005 approved the 11th Five-Year Plan aimed at building a "harmonious society" through more balanced wealth distribution and improved education, medical care, and social security.
After keeping its currency tightly linked to the US dollar for years, in July 2005 China revalued its currency by 2.1% against the US dollar and moved to an exchange rate system that references a basket of currencies. From mid 2005 to late 2008 cumulative appreciation of the renminbi against the US dollar was more than 20%, but the exchange rate remained virtually pegged to the dollar from the onset of the global financial crisis until June 2010, when Beijing allowed resumption of a gradual appreciation. The restructuring of the economy and resulting efficiency gains have contributed to a more than tenfold increase in GDP since 1978.
Measured on a purchasing power parity (PPP) basis that adjusts for price differences, China in 2010 stood as the second-largest economy in the world after the US, having surpassed Japan in 2001. The dollar values of China's agricultural and industrial output each exceed those of the US; China is second to the US in the value of services it produces. Still, per capita income is below the world average. The Chinese government faces numerous economic challenges, including:
(a) reducing its high domestic savings rate and correspondingly low domestic demand;
(b) sustaining adequate job growth for tens of millions of migrants and new entrants to the work force;
(c) reducing corruption and other economic crimes; and
(d) containing environmental damage and social strife related to the economy's rapid transformation.
Economic development has progressed further in coastal provinces than in the interior, and by 2011 more than 250 million migrant workers and their dependents had relocated to urban areas to find work. One consequence of population control policy is that China is now one of the most rapidly aging countries in the world.
Deterioration in the environment - notably air pollution, soil erosion, and the steady fall of the water table, especially in the North - is another long-term problem. China continues to lose arable land because of erosion and economic development. The Chinese government is seeking to add energy production capacity from sources other than coal and oil, focusing on nuclear power and alternative energy development.
In 2010-11, China faced high inflation resulting largely from its credit-fueled stimulus program. Some tightening measures appear to have controlled inflation, but GDP growth consequently slowed to near 9% for 2011. An economic slowdown in Europe is expected to further drag Chinese growth in 2012.
Debt overhang from the stimulus program, particularly among local governments, and a property price bubble challenge policy makers currently.
The 12th Five-Year Plan was debated in mid-October 2010 at the fifth plenary session of the 17th Central Committee of the CCP, and approved by the National People's Congress during its annual session in March 2011. The 12th Five-Year Plan seeks to transform China's development model from one reliant on exports and investment to a model based on domestic consumption. It also seeks to address rising inequality and create an environment for more sustainable growth by prioritizing more equitable wealth distribution, increased domestic consumption, and improved social infrastructure and social safety nets.
GDP: (Purchasing Power Parity): $11.3 trillion (2011 est.)
GDP: (Official Exchange Rate): $6.989 trillion
Note: because China's exchange rate is determine by fiat, rather than by market forces, the official exchange rate measure of GDP is not an accurate measure of China's output; GDP at the official exchange rate substantially understates the actual level of China's output vis-a-vis the rest of the world; in China's situation, GDP at purchasing power parity provides the best measure for comparing output across countries (2011 est.)
GDP- per capita (PPP): $8,400 (2011 est.)
GDP- composition by sector:
agriculture: 9.6%
industry: 47.1%
services: 43.3% (2011 est.)
Industries: World leader in gross value of industrial output; mining and ore processing, iron, steel, aluminum, and other metals, coal; machine building; armaments; textiles and apparel; petroleum; cement; chemicals; fertilizers; consumer products, including footwear, toys, and electronics; food processing; transportation equipment, including automobiles, rail cars and locomotives, ships, and aircraft; telecommunications equipment, commercial space launch vehicles, satellites
Currency: Renminbi yuan (RMB)
Industry
Industry accounts for about 46.8% of China's GDP (2010 est.). Major industries are mining and ore processing; iron; steel; aluminum; coal; machinery; textiles and apparel; armaments; petroleum; cement; chemicals; fertilizers; consumer products including footwear, toys, and electronics; automobiles and other transportation equipment including rail cars and locomotives, ships, and aircraft; telecommunications equipment; commercial space launch vehicles; and satellites. China has become a preferred destination for the relocation of global manufacturing facilities. Its strength as an export platform has contributed to incomes and employment in China. The state-owned sector still accounts for about 40% of GDP (2010 est.). In recent years, authorities have been giving greater attention to the management of state assets--both in the financial market as well as among state-owned enterprises--and progress has been noteworthy.
Regulatory Environment
Though China's economy has expanded rapidly, its regulatory environment has not kept pace. Since Deng Xiaoping's open market reforms, the growth of new businesses has outpaced the government's ability to regulate them. This has created a situation where businesses, faced with mounting competition and poor oversight, will be willing to take drastic measures to increase profit margins, often at the expense of consumer safety. This issue acquired more prominence starting in 2007, with the United States placing a number of restrictions on problematic Chinese exports. The Chinese Government recognizes the severity of the problem, concluding in 2007 that nearly 20% of the country's products are substandard or tainted, and is undertaking efforts in coordination with the United States and others to better regulate the problem. The U.S. Food and Drug Administration (FDA) takes advantage of its presence in Beijing, Shanghai, and Guangzhou to monitor food safety issues, and in early 2011 the U.S. Consumer Product Safety Commission opened its first-ever foreign office in Beijing to enhance cooperation and intensify exchanges with Chinese product safety regulators.
Trade with the United States
The U.S. trade deficit with China rose to $273.1 billion in 2010. This represents almost 55% of the total U.S. trade deficit. While U.S. exports to China grew by a third in 2010 to an all-time high of $91.9 billion, U.S. imports from China increased 23.1% to $364.9 billion. The top three U.S. exports to China in 2010 were electrical machinery ($11.5 billion), nuclear reactors and related machinery ($11.2 billion), and oil seeds and related products ($11 billion).
China remained the third-largest market for U.S. exports, accounting for 7.2% of U.S. goods exports in 2010. U.S. agricultural exports continue to play a major role in bilateral trade, totaling $17.9 billion in 2010 and thus making China the United States' largest agricultural export market. Leading categories include: soybeans ($11.3 billion), cotton ($1.988 billion), and hides and skins ($822 million).
Export growth continues to play an important role in China's rapid economic growth. To increase exports, China pursues policies such as fostering the rapid development of foreign-invested factories, which assemble imported components into consumer goods for export, and liberalizing trading rights. Since the adoption of the 11th Five-Year Program in 2005, however, China has placed greater emphasis on developing a consumer demand-driven economy to sustain economic growth and address global imbalances.
Foreign Investment
China's investment climate has changed dramatically in a quarter-century of reform. In the early 1980s, China restricted foreign investments to export-oriented operations and required foreign investors to form joint-venture partnerships with Chinese firms. Foreign direct investment (FDI) grew quickly during the 1980s, but slowed in late 1989 in the aftermath of Tiananmen. In response, the government introduced legislation and regulations designed to encourage foreigners to invest in high-priority sectors and regions. Since the early 1990s, China has allowed foreign investors to manufacture and sell a wide range of goods on the domestic market and authorized the establishment of wholly foreign-owned enterprises, now the preferred form of FDI. However, the Chinese Government's emphasis on guiding FDI into manufacturing has led to market saturation in some industries, while leaving China's services sectors underdeveloped. China is one of the leading FDI recipients in the world, receiving a record $105.7 billion in 2010 according to the Chinese Ministry of Commerce.
As part of its World Trade Organization (WTO) accession, China undertook to eliminate certain trade-related investment measures and to open up specified sectors that had previously been closed to foreign investment. Many new laws, regulations, and administrative measures to implement these commitments have been issued. Despite some reforms, major barriers to foreign investment remain, including restrictions on entire sectors, opaque and inconsistently enforced laws and regulations, and the lack of a rules-based legal infrastructure.
Opening to the outside remains central to China's development. Foreign-invested enterprises produce about half of China's exports, and China continues to attract large investment inflows. Foreign exchange reserves were $2.622 trillion at the end of 2010, and have now surpassed those of Japan, making China's foreign exchange reserves the largest in the world. As a result of its “going out” policy, China's outbound foreign direct investment, especially in energy and natural resources, has also surged in recent years, reaching $59 billion in 2010, up from a yearly average of $2 billion in the 1990s.
See also: Eco-industrial parks in China
Science and Technology
Science and technology have always been a priority for China's leaders. Deng called it "the first productive force." Distortions in the economy and society created by party rule have severely hurt Chinese science, according to some Chinese science policy experts. The Chinese Academy of Sciences, modeled on the Soviet system, puts much of China's greatest scientific talent in a large, underfunded apparatus that remains largely isolated from industry, although the reforms of the past decade have begun to address this problem.
China is making significant investments in science and technology. Chinese science strategists see China's greatest opportunities in fields such as biotechnology and computers, where China is becoming an increasingly significant player. More overseas Chinese students are choosing to return home to work after graduation, and they have built a dense network of trans-Pacific contacts that will greatly facilitate U.S.-China scientific cooperation in coming years. The Chinese Government has increased incentives for students to return, such as salaries similar to those they would receive in the West. The U.S. space program is often held up as the standard of scientific modernity in China. China’s growing space program, which successfully completed its third manned orbit in September 2008, is a focus of national pride. During National Aeronautics and Space Administration (NASA) Administrator Charles Bolden’s October 2010 visit to China both sides agreed that transparency, reciprocity, and mutual benefit should serve as the foundation for future dialogue.
The U.S.-China Science and Technology Agreement remains the framework for bilateral cooperation in this field. During President Hu’s January 2011 visit, the U.S. and China renewed the science and technology agreement, extending the framework for an additional five years. The agreement is among the longest-standing U.S.-China accords, and includes over 11 U.S. Federal agencies and numerous branches that participate in cooperative exchanges under the science and technology agreement and its nearly 60 protocols, memoranda of understanding, agreements, and annexes. The agreement covers cooperation in areas such as marine conservation, renewable energy, and health. Biennial Joint Commission Meetings on Science and Technology bring together policymakers from both sides to coordinate joint science and technology cooperation. Executive Secretaries meetings are held biennially to implement specific cooperation programs. Japan and the European Union also have high-profile science and technology cooperative relationships with China.
Foreign Relations
Since its establishment, the People's Republic has worked vigorously to win international support for its position that it is the sole legitimate government of all China, including Hong Kong, Macau, Tibet, and Taiwan. In the early 1970s, most world powers diplomatically recognized Beijing. Beijing assumed the China seat in the United Nations (UN) in 1971 and has since become increasingly active in multilateral organizations. Japan established diplomatic relations with China in 1972, and the United States did so in 1979. As of 2011, the number of countries that had diplomatic relations with Beijing had risen to 171, while 23 maintained diplomatic relations with Taiwan.
After the founding of the P.R.C., China's foreign policy initially focused on solidarity with the Soviet Union and other communist countries. In 1950, China sent the People's Liberation Army into North Korea to help North Korea halt the UN offensive that was approaching the Yalu River. After the conclusion of the Korean conflict, China sought to balance its identification as a member of the Soviet bloc by establishing friendly relations with Pakistan and other Third World countries, particularly in Southeast Asia.
In the 1960s, Beijing competed with Moscow for political influence among communist parties and in the developing world generally. Following the 1968 Soviet invasion of Czechoslovakia and clashes in 1969 on the Sino-Soviet border, Chinese competition with the Soviet Union increasingly reflected concern over China's own strategic position.
In late 1978, the Chinese also became concerned over Vietnam's efforts to establish open control over Laos and Cambodia. In response to the Vietnamese invasion of Cambodia, China fought a brief border war with Vietnam (February-March 1979) with the stated purpose of "teaching Vietnam a lesson."
Chinese anxiety about Soviet strategic advances was heightened following the Soviet Union's December 1979 invasion of Afghanistan. Sharp differences between China and the Soviet Union persisted over Soviet support for Vietnam's continued occupation of Cambodia, the Soviet invasion of Afghanistan, and Soviet troops along the Sino-Soviet border and in Mongolia--the so-called "three obstacles" to improved Sino-Soviet relations.
In the 1970s and 1980s China sought to create a secure regional and global environment and to foster good relations with countries that could aid its economic development. To this end, China looked to the West for assistance with its modernization drive and for help in countering Soviet expansionism, which it characterized as the greatest threat to its national security and to world peace.
China maintained its consistent opposition to "superpower hegemony," focusing almost exclusively on the expansionist actions of the Soviet Union and Soviet proxies such as Vietnam and Cuba, but it also placed growing emphasis on a foreign policy independent of both the United States and the Soviet Union. While improving ties with the West, China continued to follow closely economic and other positions of the Third World nonaligned movement, although China was not a formal member.
In the immediate aftermath of Tiananmen crackdown in June 1989, many countries reduced their diplomatic contacts with China as well as their economic assistance programs. In response, China worked vigorously to expand its relations with foreign countries, and by late 1990, had reestablished normal relations with almost all nations. Following the collapse of the Soviet Union in late 1991, China also opened diplomatic relations with the republics of the former Soviet Union.
In recent years, Chinese leaders have been regular travelers to all parts of the globe, and China has sought a higher profile in the UN through its permanent seat on the United Nations Security Council and other multilateral organizations. Closer to home, China has made efforts to reduce tensions in Asia, hosting the Six-Party Talks on North Korea's nuclear weapons program. The United States and China share common goals of peace and stability on the Korean Peninsula and North Korean denuclearization. The U.S. continually consults with China on how it can best use its influence with North Korea and discusses the importance of fully implementing U.N. Security Council Resolutions 1718 and 1874, including sanctions to prevent North Korean proliferation activities.
China has cultivated a more cooperative relationship with members of the Association of Southeast Asian Nations (ASEAN), and actively participated in the ASEAN Regional Forum. China has also taken steps to improve relations with countries in South Asia, including India, with which it has a longstanding border dispute. Marking the 60th year of diplomatic ties between the two countries, Premier Wen visited India in December 2010 to further develop the bilateral relationship between the two countries; trade in goods between the two countries reached nearly $60 billion in 2010. In April 2011, Prime Minister Manmohan Singh met President Hu on the margins of the Brazil, Russia, India and China (BRIC) Summit in Hainan.
China currently has warm ties with Russia, and President Hu chose Moscow for his first state visit after his assumption of office in 2003. China and Russia conducted a first round of joint military exercises in August 2005, and have since conducted regular joint exercises, often under the auspices of the Shanghai Cooperation Organization (SCO), a regional grouping that includes China, Russia, and the Central Asian nations of Kazakhstan, Kyrgyzstan, Tajikistan, and Uzbekistan.
Relations with Japan improved following Japanese Prime Minister Shinzo Abe's October 2006 visit to Beijing, and have seen a gradual improvement under successive Japanese administrations. Tensions persist with Japan, however, on longstanding and emotionally charged disputes over history and competing claims to portions of the East China Sea, and relations suffered a new dip following Japan's September 2010 arrest of a Chinese fishing trawler captain for ramming a Japanese Coast Guard vessel in the vicinity of the Japanese-administered Senkakus (Diaoyu) islands. A pause in tensions followed the March 11, 2011 earthquake and tsunami disaster, when China donated more than $4.5 million in humanitarian assistance and sent a 15-person search-and-rescue team to Japan--the first disaster team China had ever sent to Japan. In July 2011, Japan's then-Foreign Minister Takeaki Matsumoto visited Beijing for the first time since he had taken office.
Since 2000, Beijing has resolved territorial disputes by demarcating boundaries with Kazakhstan, Kyrgyzstan, Russia, Tajikistan, and Vietnam. Land boundary negotiations continue with Bhutan and India. China established a maritime boundary with Vietnam in the Gulf of Tonkin in 2000 but has no maritime boundaries in the Yellow Sea, East China Sea, and South China Sea, where it lays competing claims to islands and waters.
While it is one of Sudan's primary diplomatic patrons, China has played a role in support of peacekeeping operations in the country and deployed 315 engineering troops in support of UN-African Union (AU) operations in Darfur. In January 2011, China sent a team of observers to Sudan to monitor the Southern Sudan referendum. In February 2011, the Ministry of Foreign Affairs stated China’s respect for the referendum results as announced by the Southern Sudan Referendum Commission and expectations for the full implementation of the Comprehensive Peace Agreement (CPA). Following Southern Sudan's vote for secession, China maintained political relations with both Sudan and Southern Sudan, hosting the June 2011 visit of Sudanese President Omar al-Bashir to sign an oil and gas cooperation MOU. On July 9, 2011, after the official declaration of Independence by the Republic of South Sudan, China officially announced its recognition and its intent to promote peace and good relations between the north and south.
China has stated publicly that it shares the international community's concern over Iran's nuclear program and has voted in support of UN sanctions resolutions on Iran, most recently voting in favor of further sanctions on Iran in June 2010's UN Security Council Resolution 1929. The United States and China, both active participants in the “P5+1” process, called for Iran to fulfill its international obligations in a January 2011 joint statement. Set against these positive developments has been an effort on the part of China to maintain close ties to countries such as Iran, Sudan, Zimbabwe, and Venezuela that are sources of oil and other resources and which welcome China's non-conditional assistance and investment.
International Disputes
Continuing talks and confidence-building measures work toward reducing tensions over Kashmir that nonetheless remains militarized with portions under the de facto administration of China (Aksai Chin), India (Jammu and Kashmir), and Pakistan (Azad Kashmir and Northern Areas)
India does not recognize Pakistan's ceding historic Kashmir lands to China in 1964.
China and India continue their security and foreign policy dialogue started in 2005 related to the dispute over most of their rugged, militarized boundary, regional nuclear proliferation, and other matters.
China claims most of India's Arunachal Pradesh to the base of the Himalayas.
Lacking any treaty describing the boundary, Bhutan and China continue negotiations to establish a common boundary alignment to resolve territorial disputes arising from substantial cartographic discrepancies, the largest of which lie in Bhutan's northwest and along the Chumbi salient.
Burmese forces attempting to dig in to the largely autonomous Shan State to rout local militias tied to the drug trade, prompts local residents to periodically flee into neighboring Yunnan Province in China.
Chinese maps show an international boundary symbol off the coasts of the littoral states of the South China Seas, where China has interrupted Vietnamese hydrocarbon exploration; China asserts sovereignty over Scarborough Reef along with the Philippines and Taiwan, and over the Spratly Islands together with Malaysia, the Philippines, Taiwan, Vietnam, and Brunei. The 2002 "Declaration on the Conduct of Parties in the South China Sea" eased tensions in the Spratly's but is not the legally binding "code of conduct" sought by some parties. Vietnam and China continue to expand construction of facilities in the Spratly's and in March 2005, the national oil companies of China, the Philippines, and Vietnam signed a joint accord on marine seismic activities in the Spratly Islands.
China occupies some of the Paracel Islands also claimed by Vietnam and Taiwan.
China and Taiwan continue to reject both Japan's claims to the uninhabited islands of Senkaku-shoto (Diaoyu Tai) and Japan's unilaterally declared equidistance line in the East China Sea, the site of intensive hydrocarbon exploration and exploitation.
Certain islands in the Yalu and Tumen rivers are in dispute with North Korea.
North Korea and China seek to stem illegal migration to China by North Koreans, fleeing privations and oppression, by building a fence along portions of the border and imprisoning North Koreans deported by China.
China and Russia have demarcated the once disputed islands at the Amur and Ussuri confluence and in the Argun River in accordance with their 2004 Agreement.
China and Tajikistan have begun demarcating the revised boundary agreed to in the delimitation of 2002.
The decade-long demarcation of the China-Vietnam land boundary was completed in 2009.
Citing environmental, cultural, and social concerns, China has reconsidered construction of 13 dams on the Salween River, but energy-starved Burma, with backing from Thailand, remains intent on building five hydro-electric dams downstream despite regional and international protests.
Chinese and Hong Kong authorities met in March 2008 to resolve ownership and use of lands recovered in Shenzhen River channelization, including 96-hectare Lok Ma Chau Loop.
Hong Kong is developing plans to reduce 2,000 out of 2,800 hectares of its restricted Closed Area by 2010.
Citation
Central Intelligence Agency, World Wildlife Fund, US State Department (Lead Author);CIA World Factbook (Content Source); "China". In: Encyclopedia of Earth. Eds. Cutler J. Cleveland (Washington, D.C.: Environmental Information Coalition, National Council for Science and the Environment). [First published in the Encyclopedia of Earth October 13, 2009; Last revised Date August 10, 2012; Retrieved May 18, 2013 <http://www.eoearth.org/article/China?topic=49460>
The Authors
The Central Intelligence Agency was created in 1947 with the signing of the National Security Act by President Harry S. Truman. The act also created a Director of Central Intelligence (DCI) to serve as head of the United States intelligence community; act as the principal adviser to the President for intelligence matters related to the national security; and serve as head of the Central Intelligence Agency. The Intelligence Reform and Terrorism Prevention Act of 2004 amended the National Securit ... (Full Bio)
Known worldwide by its panda logo, World Wildlife Fund (WWF) leads international efforts to protect endangered species and their habitats. Now in its fifth decade, WWF works in more than 100 countries around the globe to conserve the diversity of life on Earth. With nearly 1.2 million members in the U.S. and another 4 million worldwide, WWF is the world's largest privately financed conservation organization. WWF directs its conservation efforts toward three global goals: 1) saving endangered ... (Full Bio)
Department Mission Statement Shape and sustain a peaceful, prosperous, just, and democratic world and foster conditions for stability and progress for the benefit of the American people and people everywhere. --From the FY 2011 Agency Financial Report, released November 2011 Alphabetical List of Bureaus and Offices Links in the f ... (Full Bio)
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Pages that link to "Talk:Austria"
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CaliforniaEdit This Page
From FamilySearch Wiki
Revision as of 17:28, 13 October 2011 by Evancol (Talk | contribs)
This article is about a state of the United States. For other uses, see California (disambiguation).
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Click on the map below to go to a county page. Hover over a county to see its name. To see a larger version of the map, click here.
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FamilySearch Wiki:Help wanted on the Dominica pagesEdit This Page
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(diff) ← Older revision | Latest revision (diff) | Newer revision → (diff)
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Residual Data
From Forensics Wiki
Revision as of 14:39, 29 September 2008 by Simsong (Talk | contribs)
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Residual Data is data that is unintentionally left behind on computer media. In forensic usage, remnant data is typically left behind after attempts have been made to delete the data, after the data has been forgotten, or after the media on which the data resides has been decomissioned.
Residual data appears at all levels of modern computer systems:
• Computer systems that are discarded.
• Partitions in hard drives that are deleted.
• Files on hard drives that are deleted but not overwritten.
• Snippets of text in Microsoft Word files.
• Heap variables that are freed with free()
• Automatic variables left on the stack of languages like C or garbage collected in languages like Java.
Papers
Byers, Simon. Scalable Exploitation of, and Responses to Information Leakage Through Hidden Data in Published Documents, AT&T Research, April 2003
Chow, J., B. Pfaff, T. Garfinkel, K. Christopher, M. Rosenblum, Understanding Data Lifetime via Whole System Simulation, Proceedings of the 13th USENIX Security Symposium, 2004.
Garfinkel, S. and Shelat, A., "Remembrance of Data Passed: A Study of Disk Sanitization Practices," IEEE Security and Privacy, January/February 2003.
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Wesley Long - Summary Bibliography
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Pseudonym. See: George O. Smith (or view all titles by this pseudonym here)
Copyright (c) 1995-2011 Al von Ruff.
ISFDB Engine - Version 4.00 (04/24/06)
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Bibliography: The K-Y Warriors
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Title: The K-Y Warriors
Author: Bob Shaw
Year: 1989
Type: SHORTFICTION
Storylen: shortstory
ISFDB Record Number: 62488
User Rating: This title has fewer than 5 votes. VOTE
Current Tags: None Add Tags
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Copyright (c) 1995-2011 Al von Ruff.
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Moderate Activity
Contributors : Bryan McLellan
Analyzed about 6 hours ago based on code collected about 6 hours ago.
Activity on opscode-ohai by Bryan McLellan (see full profile for Bryan McLellan)
All-time Commits: 225
12-Month Commits: 42
30-Day Commits: 0
Overall Kudo Rank:
First Commit: 24-Jan-2009
Last Commit: 15-Apr-2013
Names in SCM: Bryan McLellan, Bryan McLellan, Bryan McLellan
Commit history:
Recent Kudos...
... for opscode-ohai given by:
jesserobbins
Project Commits
Approximately one year of commit activity shown
Project Languages
Language Aggregate Coding Time Total Commits Total Lines Changed Comment Ratio
Ruby 2y 4m 219 258,006 1.4%
Copyright © 2013 Black Duck Software, Inc. and its contributors, Some Rights Reserved. Unless otherwise marked, this work is licensed under a Creative Commons Attribution 3.0 Unported License . Ohloh ® and the Ohloh logo are trademarks of Black Duck Software, Inc. in the United States and/or other jurisdictions. All other trademarks are the property of their respective holders.
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Very Low Activity
Estimated Cost
Analyzed 4 days ago based on code collected 4 days ago.
Project Cost Calculator
$ .00
20,835 lines
5 person-years
$ 257,027 *
*Using the Basic COCOMO Model
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Ohloh lets you exclude files and direc-tories from this calculation on the Code Locations page. You can get a more realistic estimate by excluding:
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• For those familiar with the details, we are using coeffcients a=2.4 and b=1.05.
• Please note that COCOMO was created to model large institutional projects, which often don't compare well with distributed open-source projects.
• COCOMO is meant to include the design, specification drafting, reviewing and management overhead that goes along with producing quality software.
• This model seems to be most accurate with mature, large projects. Young projects with little activity are typically overvalued.
Copyright © 2013 Black Duck Software, Inc. and its contributors, Some Rights Reserved. Unless otherwise marked, this work is licensed under a Creative Commons Attribution 3.0 Unported License . Ohloh ® and the Ohloh logo are trademarks of Black Duck Software, Inc. in the United States and/or other jurisdictions. All other trademarks are the property of their respective holders.
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OpenWetWare:Steering committee next meeting
From OpenWetWare
Revision as of 10:33, 13 May 2008 by Lorrie LeJeune (Talk | contribs)
Jump to: navigation, search
The OpenWetWare Steering Committee is charged with leading the future direction of OpenWetWare. The steering committee is open to all OWW members, and we are actively seeking participants. You can add yourself to the discuss mailing list.
Members
Who's Involved?
Action List
Action items this month
Next Meeting
Suggested topics
Meetings
Agendas & Notes
Please post any topics you would like the SC to consider at the next meeting -- you don't need to be on the committee to post something here!
Next Meeting: Wednesday, May 14, at 12 noon
The monthly meeting is both online (join the chat here) AND has teleconferencing (call 617-324-7520, or sip:sc@openwetware.org).
Everyone is welcome to participate simply by calling in and joining the chat. It tends to work best if participants do both to fully take part in the meeting.
New items:
• Focus of OWW over the next 6 months should be the promotion of open science and use of lab notebook
• Talk about chairs and how to group different members around different areas
• Each month, SC to come up with a small, fun activity that can be picked up by a new member.
• "idea of bottom-up development, where new features of OWW are suggested by and in part built by members of the community" - OpenWetWare Platform/API (a la Facebook)?
• How should we work with/integrate social networking sites such as Epernicus, SciLink, and others?
• Profiling the OpenWetWare user... Who are John and Jill Openwetware?
Older items:
Browse archive
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Gerber:What We Do
From OpenWetWare
Jump to: navigation, search
Home What We Do Publications Resources People Photos Links Contact
Global analysis of post-transcriptional gene regulation
Post-transcriptional control of gene expression involves RNA processing, transport, turnover and mRNA translation. Regulation of these steps has substantial effects on the expression and function of genes in diverse processes such cytokinesis, embryonic development, neurogenesis and cancer progression. RNA-binding proteins (RBPs) have been implicated in diverse aspects of post-transcriptional gene expression. Hundreds of RBPs are encoded in eukaryotic genomes, and whereas many classical studies explored the cellular role of RBPs with specific mRNA substrates, the recent development of genome-wide analysis tools enables systematic identification of mRNA substrates of RBPs, and the study of post-transcriptional gene regulation on a global scale. Importantly, these studies revealed that many RBPs bind to and regulate subsets of mRNAs, which encode proteins that are localized to the same subcellular compartment, act in the same pathway or are components of macromolecular complexes. Moreover, these sets of mRNAs often contain characteristic sequence elements in the 3'-untranslated regions, which are potential binding sites for regulatory RBPs (Gerber et al. 2004). These findings strongly indicate the presence of extensive post-transcriptional regulatory systems in eukaryotic cells, which may be comparable in its extent and richness to that of transcriptional regulatory networks.
We are interested in exploring this RBP-mediated post-transcriptional program. We use genome-wide analysis tools like DNA microarrays to elucidate basic principles (e.g. systematically map RNA-protein interactions), and we apply ‘classical' biochemical, genetic and cell-biological methods to further investigate specific functional aspects of the RNA-protein network. We use yeast as model system to establish techniques for the global analysis of RNA regulation, and to investigate basic principles. In addition, we study the post-transcriptional program in mammalian cells and investigate how it may be perturbed in certain disease states (e.g. tumorigenic cells).
Reviews:
• Imig, J, Kanitz, A, Gerber, AP (2012) RNA regulons and the RNA-protein interaction network. BioMol. Concepts, 3, 403-417.
• Kanitz, A, Gerber, AP (2010) Circuitry of mRNA regulation. Wiley Interdisciplinary Reviews: Systems Biology and Medicine 2, 245-251.
• Halbeisen, R, Galgano A, Scherrer T, Gerber AP (2008) Post-transcriptional gene regulation: From genome-wide studies to principles. Cellular and Molecular Life Sciences 65(5):798-813.
Different proteins assemble on a given message to form an mRNP, the composition of which changes dynamically, depending on the cellular context. The combinatorial control of associated regulatory, scaffolding and accessory proteins ultimately determines the mRNA fate ("mRNP code").
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Search Engine Marketings Threats and Opportunities
Jul 12, 2004 • 9:27 am | (0) by | Filed Under Web Promotion
An excellent thread over at Search Engine Watch discusses what are the major threats and opportunities in the search engine marketing industry.
Here is an outline of some of the responses:
Threats: - Unscrupulous SEO firms hurting the name of the industry - PPC Click-Fraud
Opportunities: - Personalization - Localization
Join the thread to discuss.
Previous story: Steal the Source of Alta Vista
blog comments powered by Disqus
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CSF (ConfigServer Security and Firewall) May Be Blocking GoogleBot
Nov 3, 2008 • 7:39 am | (2) by | Filed Under Google Search Engine Optimization
A webmaster at Google Groups may have uncovered an issue with a specific firewall program named CSF (ConfigServer Security and Firewall). In short, this webmaster found that his host used this firewall and it was blocking GoogleBot from accessing his web pages.
If you are noticing that GoogleBot cannot access your site, check to see your firewall. If any of the GoogleBot IPs are listed in the "Firewall Deny IP's" area, then remove them asap. The webmaster documented some of those current IP ranges (note, they may change):
• 216.239.32.0/19 # Googlebot
• 64.233.160.0/19 # Googlebot
• 72.14.192.0/18 # Googlebot
• 209.85.128.0/17 # Googlebot
• 66.102.0.0/20 # Googlebot
• 74.125.0.0/16 # Googlebot
• 66.249.64.0/19 #Googlebot
Make sure to verify those IPs are GoogleBot before preceding yourself.
Then add the range of Googlebot IP addresses to bot the FIREWALL ALLOW IP'S and the LFD IGNORE IP'S in the firewall setup.
It is important that you regularly check Google Webmaster Tools and/or your log files for accessibility issues. You can be missing traffic and not even know about it.
Forum discussion at Google Groups.
Previous story: Is Ask.com's Web Search Technology Falling Apart?
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Bing Ties Facebook Into Search, Is It Too Much?
May 11, 2012 • 8:54 am | (4) by | Filed Under Bing Search
I have to hand it to Microsoft, they are exploiting the one thing Google can't get their hands on fully, Facebook data and integration. Yes, Microsoft Bing has been integrating Facebook personalization into Bing search results for a while but yesterday, Bing went over the top with it.
Bing announced a new level of integration where you can interact with your Facebook friends directly in the Bing search results.
I am not going to go through the changes here, Danny does an outstanding job at Search Engine Land on the new Bing features and then comparing Bing vs Google on how they handle social integration into the search results.
Here is a quick video demo on the changes:
But will this last - I mean, is it too much? Are the search results useful or are they being overpowered by Facebook? Is it too confusing for users? Will they understand when to use search, when to use social and then how to use both at certain times?
Personally, I really don't see this version of Bing lasting more than a year. I hope I am wrong but I can't see this being easy for users to use.
More coverage on Techmeme.
Forum discussion at WebmasterWorld.
Previous story: Google: Can't Recover From Penguin? Start A New Site
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Tell me more ×
Answers OnStartups is a question and answer site for entrepreneurs looking to start or run a new business. It's 100% free, no registration required.
When converting from an LLC to a C Corp, can we use the same EIN for the C Corp?
share|improve this question
1 Answer
No. You'll likely need a new EIN. Per the IRS website:
Generally, businesses need a new EIN when their ownership or structure has changed.
Also,
Partnerships
You will be required to obtain a new EIN if any of the following statements are true.
• You incorporate.
The following EIN document created by the IRS may also be helpful: Understanding Your EIN
Someone is likely to point out that the OP has an LLC, not a partnership. Please note the following from the same website:
Limited Liability Company (LLC)
An LLC is an entity created by state statute. The IRS did not create a new tax classification for the LLC when it was created by the states; instead IRS uses the tax entity classifications it has always had for business taxpayers: corporation, partnership, or disregarded as an entity separate from its owner, referred to as a “disregarded entity.” An LLC is always classified by the IRS as one of these types of taxable entities.
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White House Announces Launch of “Change The Equation” (aka Algorithms) Program –CEO Efforts With Support of the Melinda and Bill Gates Foundation– for STEM*
What does STEM and Change the Equation stand for:
Science, Technology, Engineering and Math, that’s STEM and working with Algorithms (there’s that word again).
Of course readers around the Medical Quack here the technology end of this all the time and enough about the non participants we have both as citizens and in Congress.
The point of the program with the initial $5 Million dollar grant is to allow more students to engage in robotics (good for healthcare) improve development for math and science too. Life Sciences is all about math and algorithms. So far there are 100 CEO members and one of the big leaders is Craig Barrett from Intel. He’s been beating this drum for years and rightly so as well as current Intel CEO Paul Otellini.
Intel CEO States the US Faces Decline in Tech Jobs–Announces Purchase of German Wireless Chip Company Infineon
I posted this article back in September of 2007 where Craig Barrett stated we need to get into the education of technology, and here we are at 2010 at around the same place and our leaders don’t offer anything as far as role models, but rather more of a soap opera effect in Washington today, sad.
Well spoken - Craig Barrett.... Intel Corporation
Here’s a short breakdown of the bullet points highlighted and yes when you look at the third item perhaps we will have students helping Congress on how to create policies some day.
Transforming Libraries and Museums into 21st Century Learning Labs
National STEM Video Game Challenge:
Raytheon’s New STEM Tool for State Policymakers
National Math Science Initiative’s (NMSI) To Assist Military Families:
Nature Publishing’s “Bridge to Science” Program for Parents and Scientists:
The programs are to be privately funded and will increase the number of teachers who enter the profession to help with a STEM undergraduate degree. I found this to be one heck of good step in the right direction and I think it may have been overshadowed this week with all the news insanity of the crazy folks out there in the elections. When you watch the video you hear Craig Barrett emphasize engineering is one of the key areas for focus, as students with this major will have many choices in which direction they may want to go.
We need scientists as that is where the work lies in Life Sciences to find cures. If nothing else this article brings home the fact that some smart people are listening and realize what changes are needed as technology is rapidly changing the way we live today and the students and teachers are the future so we don’t end up as a country that gets left behind. BD
Change the Equation was founded by astronaut Sally Ride, former Intel Chairman Craig Barrett, Xerox CEO Ursula Burns, Time Warner Cable CEO Glenn Britt, and Eastman Kodak CEO Antonio Perez, with support from Bill and Melinda Gates Foundation and Carnegie Corporation of New York. With a membership of 100 CEOs, and funding of $5 million for its first year of operations
Today, President Obama announced the launch of Change the Equation, a CEO-led effort to dramatically improve education in science, technology, engineering, and math (STEM), as part of his “Educate to Innovate” campaign. Change the Equation is a non-profit organization dedicated to mobilizing the business community to improve the quality of STEM education in the United States.
The United States is falling behind our foreign competitors in STEM subjects. According to one, study American 15-year-olds ranked 21st in science and 25th in math compared to other countries. In his remarks to day, the President emphasized the importance of providing American students with a solid foundation in these subjects in order to compete in the global economy:
Changing the Equation in STEM Education | The White House
Jon Stewart and Stephen Colbert: 'Rally To Restore Sanity'–(And Maybe Help Stamp Out Some Magpie Healthcare too) On Their October 30th March on Washington
These 2 are my absolute favorites when it comes to making points and using humor – it works! We all like to laugh and there’s a lot of news out there that tells us that it is good for us to laugh! Since we are talking humor and satire, let’s take a real look at how consumers value personal health records, not their fault as the value with mobility has not been given to them yet, slow, slow non participants at the heart of this issue.
What’s On the Agenda Tonight–World of Warcraft or Work on My Personal Health Record
We are looking at the terms of “ridiculous” every time we turn around today and most of this comes down to “non participants” in general consumer IT knowledge not working and this goes for our leaders in Congress. You know a little marketing could go a long way here as we see websites with happy people using their products, so what’ wrong with seeing our leaders using and benefiting from technology instead of the old paradigm of “its for those guys over there”.
The Daily Show With Jon Stewart Mon - Thurs 11p / 10c
Rally to Restore Sanity
www.thedailyshow.com
Daily Show Full Episodes Political Humor Tea Party
This guy at the post below makes a lot of sense here more on a serious note, but explores one big question:
How do you use technology to solve some of the problems that technology has created? If you are a tech non participant, this goes over your head.
The Importance of Being Connected and Disconnected–We Need Both and the Balance There Of In Our Business and Personal Lives
Well I’m in there to restore sanity as I get a little touch of it too with doing the blog and Mr. Stewart and Colbert are consumed and see it by the minute. I’ll be watching this one for sure! These guys have their hearts in the right place too! BD
Jon Stewart and Steven Colbert will march together on Washington.
Or against each other in Washington.
Either way, expect plenty of Comedy Central fans to show up on October 30 when Stewart's "Rally To Restore Sanity" will meet Colbert's "March To Keep Fear Alive" in the nation's capital.
Stewart, Colbert: 'Rally To Restore Sanity' vs. 'March To Keep Fear Alive' (VIDEO)
FDA And CMS to Collaborate on Reviewing Medical Products To Help Speed Up the Coverage Decisions–Big Thumbs Up On this Decision
This is truly a good thing as I have interviewed companies such as Cook Medical for one in the past and this is one item they is always a bear for them, the FDA stamp of approval is one thing, but coverage, which is what makes the product available is the other big mountain to climb.
I think this decision makes absolute sense from all areas as collaboration is what it is all about. CMS stands to delve deeper into the reasoning for FDA approval and on the other hand the FDA gets a glimpse too at how coverage is decided for the products. Not too long ago I said the FDA stand to become the most connected government entity out there as they touch so many other government and private areas of healthcare and have the responsibility to protect US citizens weighing heavily on their decisions. Here’s one more recent example with the FCC and the FDA working together with wireless devices.
FDA and FCC To Partner on Telehealth Innovation and Implementation – FDA Stands to Become One of the “Most Connected” Federal Agencies
There has been a lot of discussion of late too on what resources the FDA has and where new technology needs to be added. They need the latest and greatest technologies as their educated decision depend on being 100% up to date on what’s happening out there from both the business and consumer side of healthcare.
FDA's Sentinel Initiative Will Need to Embrace Mobility Sooner or Later–Better Sooner Than Later–Data Beyond the Desktop
As a consumer product becomes available, it’s not always that easy and fast to connect it to the healthcare infrastructure as one may think, and yes it pretty much can be done, but it takes time and safety is the all out mission here too. Now if they can start augmenting a non existent recall system, I’ll be happy! BD
Stolen Advair Demonstrates Need for Tag Bar Coding of Drugs – Encrypted Bar Codes Could Identify Stolen and Counterfeits When Scanned With a Cell Phone
(Reuters) - A new process to review medical products at the U.S. Food and Drug Administration in tandem with the nation's Medicare insurance program could help speed up coverage decisions, the FDA said in announcing the move on Thursday.
Under the proposal, the FDA would review and make approval decisions alongside the Centers for Medicare and Medicaid Services, which decides whether and how to pay for new medical products for its elderly and disabled patients once they are approved for the U.S. market.
To start, the agencies proposed a pilot project for devices after both FDA and CMS had time to review public comments on the proposal.
FDA to review medical products alongside Medicare | Reuters
Wendell Potter Tell All Book–Deadly Spin–One to Put On My List as “He Knows Algorithms and How they Create Profits”
Who knows better than one who served on the inside and had the responsibilities that lead to creating profits. This is someone we need to pay attention too as he offers a glimpse inside the world of corporate healthcare that we normally do not get to see. He can share the mathematical processes and how this is calculated from the beginning up, something we all need to pay attention to instead of the next OMG stories as this is where the action takes place
And Now A Word From Wendell Potter About Healthcare Reform and Medical Loss Ratios..
I think Mr. Potter might in some way agree with something I wrote over a year ago suggesting a Department of Algorithms as digital laws are needed today as the old format of words and more words is becoming dated and almost impossible to police.
“Department of Algorithms – Do We Need One of These to Regulate Upcoming Laws?
You can read all the stories of unfairness in this business and how people are denied care due to profitability and yes there needs to be work done here but decisions made coldly on an algorithm presented on a screen when someone’s life it at hand is cold and unethical, there’s tons of this in the news, but as a society we need to acknowledge and grasp where this reality comes from and understand the folks with the data and the accelerated intelligence for profit drive this.
No drama queens or kings are going to make any difference from consumers all the way up to Congress as they can’t govern and create laws for a process they do not understand or acknowledge. It is what it is. Unfortunately today though as it is just how we are geared, the OMG stories seem to take precedence at times in keeping us fully distracted from dealing with what is really going on behind the scenes. The folks with the data and intelligence have all the money, can’t you see this? That part is not brain surgery.
Mr Potter has been featured on many shows such as Dateline to explain, but again we need to pay more attention to the processes here and get with it and drop the OMG stories that keep us distracted with not getting to the core of the problems.
Dateline NBC – Critical Condition” Investigation Into the Practices of Health Insurance Companies
Algorithms giveth and they take away as there are algorithms run for accurate results and those run for “desired” results.
Wendell Potter Speaks About the Health Insurance Industry’s Lethal Bottom Line – The Algorithms
So in summary, this one book I will find time to read as with today’s busy schedule my reading time is so limited with books, but I get a ton of reading material from the web so no lack of information in that respect! With the information and facts he has provided could I almost be hearing the potential of Oliver Stone perhaps knocking on his door soon! BD
I’m about halfway through the book, which I got as an advance reading copy. Those looking for news can safely skip the parts of the book that recount the history of the public relations industry and recap the health reform debate. Mixed in with those topics Potter gets more personal, describing his life as a journalist, then a PR man in the health care industry, and later as a whistle blower.
*A week in the life of a corporate PR exec: Monday meetings with lobbyists and executives. Daily compilations of all news coverage. Writing speeches, annual reports, investor communications. And: “I decided who was worthy of interviewing our CEO…I never let in a reporter I didn’t know…I always sat in on the interviews so I could cut them short.”
*Potter argues that the movement toward “consumer-driven healthcare” in which patients pay a bigger share of the expenses in order to give them an incentive not to over utilize care, is really just a way for the insurers to make money by deterring people from getting care they need. He describes how internally at Cigna nobody really understood why customers would want to shift to these kinds of plans unless they were young and healthy.
Spying On Michael Moore And Dumping Sick People Overboard: Highlights From Wendell Potter’s Harsh HMO Memoir (Part I) - David Whelan - Health Dollars - Forbes
Johns Hopkins Hospital Shooting–Doctor Expected to Survive–Hospital has Over 80 Entrances to Police
We hear about more incidents as such as hospitals today and with 80 entrances someone got by with a gun as security police do check for this but can’t get everyone or have metal detectors at every door.
From what is stated here the fact that his mother’s condition was not corrected with surgery is what set him off as she had suffered from arthritis and rheumatism for years. The hospital of course will review security procedures. The shooter’s mother had been in the hospital for a number of months and he was pretty much living there with here to be at her side.
Johns Hopkins is the largest employer in Baltimore. The Joint Commission reports acts of violence at hospitals are getting higher every year. BD
BALTIMORE — A man who became distraught as he was being briefed on his mother's condition by a surgeon at Johns Hopkins Hospital pulled a gun and shot and wounded the doctor Thursday, then killed his mother and himself in her room at the world-famous medical center, police said.
The gunman, 50-year-old Paul Warren Pardus, had been listening to the surgeon around midday when he "became emotionally distraught and reacted ... and was overwhelmed by the news of his mother's condition," Police Commissioner Frederick H. Bealefeld III said.
Pardus pulled a semiautomatic gun from his waistband and shot the doctor once in the abdomen, the commissioner said. The doctor is expected to survive.
Pardus then holed up in the room in a more than two-hour standoff. When officers made their way in, they found Pardus and his mother, 84-year-old Jean Davis, shot to death, he on the floor, she in her bed.
"I guess he just couldn't bear to see her the way she was," said Pardus' brother, 59-year-old Alvin Gibson of Remington, Va. He said their mother suffered from arthritis and rheumatism and had surgery last week, but it didn't help her.
Johns Hopkins Hospital Shooting: Doctor Reportedly Shot In Baltimore
GE To Begin Trials of the “Smart Hospital Room”–Using a Multitude of Sensors and Algorithms
GE has been working on this for a while. I first started talking about Smart Rooms here back in 2008. Technology will track things like facial recognition, using an algorithm and track when the patient is in and out of the bed. Of course this means lots of RFID at work with computer vision algorithms. The facial recognition is interesting as it sends out alerts if you have a perhaps not so pleasant look on your face too, so if you cry here comes someone to check on you. <grin>.
The Hospital "Smart Room"
Another one of the features is hygiene compliance, washing hands and there’s been a couple of posts around here that talk about automated systems. Cerner has a smart room developing too. You can read a bit more at the link below and watch a video.
Cerner Receives FDA Clearance for CareAware iBus to Connect Devices and EHR Systems
Here’s a video from the GE Website that shows how this will work with a nice big white screen above the patient bed. BD
GE Healthcare has received the go-ahead from the Institutional Review Board at Bassett Medical Center, in Cooperstown, N.Y., to begin testing its Smart Patient Room health-monitoring technology at the facility.
Part of GE's Healthymagination initiative, the Smart Patient Room can determine whether soap and sanitizer dispensers are used by medical personnel before and after seeing a patient.
According to Scott Gallagher, a senior consultant for GE Healthcare, RFID sensors are installed in dispensers for soap or alcohol-based hand sanitizers to determine when medical personnel are using them and following hygiene protocol.
The technology was developed at GE's Global Research Center in Niskayuna, N.Y., and will be tested at the Bassett Medical Center inpatient teaching facility. The pilot project marks GE's first implementation of the Smart Patient Room in a clinical environment, according to Gallagher.
GE Tests Smart Patient Room to Monitor Patient Safety, Cut Medical Errors - Health Care IT from eWeek
The Importance of Being Connected and Disconnected–We Need Both and the Balance There Of In Our Business and Personal Lives
Multitasking is constantly shifting attention and the consequences are constant distractions. This is an interesting video that discussed what we deal with every day and the the author David Berlind gives some very interesting points. We are all certainly under pressure to feel the need to be connected.
How do you use technology to solve some of the problems that technology has created?
It’s hard to disconnect and still remain competitive. When constantly connected we begin to lose our ability to determine what is trivial and what really contains important information. Screening out interruptions is important and paying attention to one thing – Conceptual thinking is only possible when focusing on one thing at a time and this has value both in business and is needed in personal life too. Mr. Berlind is ahead of his time with his thinking but I believe is right on the money.
IT systems do influence the way we think and behave he states, and I have said one many times here. The need for speed, which is how IT organizations pace themselves and find their value has negatives too which corporations are now learning exist. A shift of paradigms he says of “more is better” to a shift of “what’s really important here” he says is key.
BEHAVIOR NEEDS TO CHANGE IN BOTH DIRECTIONS AND IF TECHNOLOGY CAN PLAY A ROLE IN THAT, THEN ALL THE BETTER.
Ethics get lost in our excitement to do new things (bingo). Sometimes folks may not see as enthusiastic enough on every bit of technology that rolls out, which is not necessarily true, as I mention ethics on this blog until it’s coming out our ears!
He addresses one thing is is the crux of many errors in healthcare and that is “DISTRACTION” , which over done leads to deadly disruptions, thus there’s a time to stop the wheels of multi tasking to focus and not spread ourselves too thin with too many technologies all at once. Anyone else reading this relate? I do as I find myself in the same predicament at times and do have to shut out the distractions of those things are are not critical. BD
David Berlind interviews the author Nicholas Carr
David Berlind interviews the author Nicholas Carr - InformationWeek
West Wireless Center Hosting First Health Care Innovation Day in Washington DC In October–Bring on The Mobile Aggregators
If you are a regular reader here then you have probably heard about the West Wireless Institute in San Diego and Dr. Eric Topol who spoke at the TED conference this year and is the Scripps Director of of Translational Science.
CareFusion, Cisco and Medtronic to Collaborate With West Wireless Health Institute on Technology – Additional Grants Awarded From Philanthropists Gary and Mary West
The following month we have the mHealth Summit also being held in Washington DC with some big heavy hitters speaking and that event to me is looking to be probably one of the biggest mobile healthcare events to take place this year as it involves the National Institute of Health with their contributions from the science and genealogy side of things.
Bill Gates Named Keynote Speaker at 2010 mHealth Summit To Be Held November 8-10
Mobile technology is almost developing at a pace that is faster than we can consume and understand before the next new wave appears and thus my comments in the title about aggregating some of these software programs, like what has been done on the desktop side of healthcare. We see that in the news all the time and mergers and acquisitions are based on combining technologies to make systems more comprehensive and hopefully easier for the end users and consumers. Speaking of consumers we need to organize the software efforts as they continue to work smartly with devices and not over run and over do the consumer too as if you have a person busy responding and having to work with too many systems, they zone out.
This is why studies on Participatory Sensing are important so we can basically see how we can be productive and not fry consumers and doctors at the same time as the old story goes if you walk into a store with too many choices you end up walking out with zero, so if you innovate all over the place with nobody using enough of the technology then we haven’t completed the mission.
Participatory Sensing – Medical Devices Reporting Data for Patient Compliance
Bring on the aggregators and with companies such as Cisco and Medtronic involved, perhaps we will see this start developing. BD
Here’s the information from the website below:
WWHI Health Care Innovation Day DC (HCI-DC)
Tuesday, October 12, 2010
Ronald Reagan Building
In keeping with the its mission to accelerate low cost health care solutions through innovation, the West Wireless Health Institute (WWHI) will host its first Health Care Innovation Day in Washington D.C. (HCI-DC) on October 12. HCI–DC will focus on bridging the gap between industry and government to enable a thriving ecosystem.
HCI–DC will deliver:
• Exclusive access and valuable content: will provide 300 attendees unprecedented, interaction with industry leaders, government stakeholders and public/private funders through a combination of keynotes, panels, roundtable discussions and one-on-one networking opportunities.
• Innovation at the Department of Veterans Affairs (VA): will provide insight into the $100 million VA Innovation Initiative (VAi2) including the announcement of telehealth winners from the 2010 Industry Innovation Competition. Be the first to see what projects VA is funding in the wireless health and telehealth areas. Learn directly from VA how the nation’s largest hospital system is deploying telehealth solutions. Discover what is required to submit the most competitive proposals and business plans to obtain funding for innovative solutions.
• Industry perspective: will showcase exciting demonstrations of wireless health solutions from a variety of leading companies.
Who should attend:
HCI–DC is open to policy makers, strategic leads, business development executives, product and technology specialists with a focus on or interest in health care innovation particularly in the areas of wireless health or telehealth. The event is free of charge, however space is limited and we will not accept onsite registration.
http://www.hcidc.org/index.php/component/content/article/20
Diabetes Police Telephone Solicitation Patrol–4 Calls Today In 2 Hours Mom Asking If There Was A Diabetic in the House
This is just a post with marketing and compliance issues with diabetes. Mom was not sure exactly who it was but within about 2 hours there were 4 phone calls from a call center, asking if anyone in the house was a diabetic. Mom of course is and stated so. The company identified themselves as a “Diabetes Association” and which one, we don’t know. If you do a search on the web, there are quite a few of them.
Everyone seemed to have a foreign accent she stated and this leads me to believe this is a call center of some sort with computerized number dialing. She could not get the number to call back – unavailable when she called back.
Last week she had the compliance police from her Medicare Part D plan and her pharmacy, Walgreens on the phone call patrol.
Compliance Police Out In Force for Seniors–Health Plans and Drug Stores Making Phone Calls-Business Models & Caller Behavior Sucks -A Result of Pay for Performance Efforts?
Everyone was asking old is your glucose device for testing and were telling her she needed a new one. She said she had had her device for a while and it was working fine. Each caller was telling her she needed to get a new device and that she should call Medicare and see what new devices were available and that she might not be getting accurate readings
She couldn’t understand why all of them were asking her to call Medicare! There was no particular product being pushed, but just get a new glucose reader so she could be assured she was getting accurate readings.
I know we are all trying to get the word out and educate all, but having a call center functioning this way doesn’t seem to be getting the job done. The whole focus of all the calls she said were for her to get a new glucose reader and the solicitors had a “canned speech” they read off and were not able to answer even some very simple questions she asked when inquiring about what type of glucose reader she should have.
We can’t market like this with phone calls coming out our ears like we did in the 70s as people are busier today and there’s better ways to educate and help. This sounded like a real circus event as she described it. BD
Johnson and Johnson Consumer Group Chairman Colleen Goggins Announces Retirement Effective March 1, 2011
The letter of announcement from Bill Weldon is shown below. We keep seeing many top executives from all areas of healthcare and government following this process. It’s complicated out there today and technology is running a muck on those who may not be up to date as the decision making processes depend on the information we receive from our computer screens.
Johnson and Johnson McNeil Healthcare Group Recalls Children’s Over the Counter Liquid Medications
With the recent recalls and consumer product issues from the various areas of Johnson and Johnson, I guess it’s time for a new face at the top of the helm. With retooling the factories and closing one, the consumer group has had their share of being under the public spotlight for sure.
Johnson and Johnson (McNeil) Lays Off 300 Employees and Will Re-Tool the Tylenol Factory
Perhaps new leadership might entertain a better recall system too and get the FDA and DEA in on this too for a pilot program….hint…hint…
This news may not be too shocking as it has gone on for years that heads eventually roll when things are not going right with big corporations so here’s one. BD
Microsoft Tags on CBS Early Show – Wake Up FDA, Pharma and Medical Device Companies –Scan Those Drugs, Medical Devices and Synchronize with an FDA Tag Data Base – Recalls, Theft Tracking and More….
“After a long, successful and distinguished career, spanning almost 30 years, Colleen Goggins, Worldwide Chairman, Consumer Group has decided to retire effective March 1, 2011. Colleen and I will work to ensure a smooth and successful transition of her responsibilities. We will make a timely announcement of succession plans for this critical position for the Company.
Colleen joined Johnson & Johnson in 1981, working in various assignments of increasing responsibility. She became President of Johnson & Johnson Canada in 1992; President, Personal Products Company, U.S. in 1994; and President, Johnson & Johnson Consumer Companies Inc. in 1995. She was promoted to Company Group Chairman in 1998. Colleen assumed her current position as a member of the Executive Committee in June 2001 and has overseen a remarkable period of growth, expansion and profitability in the Consumer Group.
Throughout her tenure, Colleen has demonstrated our commitment to our consumers and our people, and has made major contributions to our success. Please join me in thanking Colleen for her dedication and extraordinary service, and in wishing her all the best in the years to come.”
Bill Weldon
Chairman and Chief Executive Officer”
Microsoft Tags Doing Their Job on Boxes of Special K At the Grocery Store-Working with Lucky Magazine to Encourage Healthy Eating to Lose Weight
The idea here is to push the Special K Challenge to lose weight. Are you still just using your cell phone for phone calls?
If you like this idea and would like to be able to scan and find FDA recalls at the drug store cast a vote for a yes if you would. You can read more about how Microsoft Tags and barcoding would work here:
Microsoft Tags – Microsoft MSDN Posts Ideas from the Medical Quack About Use in Healthcare!
This same technology is available and in the works for entering information into your HeatlhVault, Google Health or Dossia personal health record and I touched on that a bit today when discussing the new revised portal announced today for Google Health. BD
Google Health PHR Gets a Facelift and Adds Some New Features–Augmentation for the Consumers
Swipe your smartphone across the 2D bar code on a box of Special K cereal in the US, and you may be surprised to see Lucky magazine editor-at-large Elise Loehnen pop up in a video with tips about finding figure-flattering jeans. It’s a, well, fitting and organic partnership from the cereal whose mantra is how to feel better in your jeans, and a magazine featuring the latest jeans and other styles.
http://www.brandchannel.com/home/post/2010/09/07/Special-K-Lucky.aspx
Rite Aid Distribution Center in Rome New York To Close by Next Year–Some Employees May Be Able To Transfer
The facility will be completely closed by July of next year so it sounds like there’s some time for employees to begin looking or trying to make alternative plans. According to the article the building was old, the roof leaked and there was no additional money invested in the facility for a while.
Some jobs may go to their Liverpool warehouse and they can apply there. 3 Rite Aid stores have been closed in recent years in the City as well. BD
Officials, business owners and residents were disheartened Tuesday at the news that Rite Aid Distribution Center will close next year.
But they also said the community will rally around the nearly 400 employees that will begin getting laid off in January.
“We’ve got a pretty solid community,” said Brian Miller, owner of Teddy’s Restaurant, a popular Black River Boulevard restaurant. “We help each other out when we’re down.”
Rite Aid workers, Rome businesses ponder future after layoff announcement - Utica, NY - The Observer-Dispatch
Heritage Provider Network May Join Prime Healthcare in Bidding for Bankrupt Victor Valley Community Hospital
If Heritage does not place a bid, then Prime Healthcare would move in as the new owner as by law the process has to be open for bidding. Prime bid last year unsuccessfully for the 4 hospital chain IHHI in Orange County, CA which returned to the original owner who was run out a few years ago.
IHHI Hospital Bids Continue for the Mortgage –Prem Reddy at 57M and Kali Chaudhuri at 55M
I live in an area where 2 of Prime hospitals are located and compared to the busy days before acquisition, they are like ghost towns and you can roll bowling balls through the once crowded parking lots, but they do run first class emergency rooms as Prime does not sign contracts with any insurers, thus the customary and ordinary fees he files on record are charged. BD
San Fernando Valley-based Heritage Provider Network is expected to bid on the hospital, an attorney for Prime Healthcare Services and the Prime Healthcare Services Foundation said Wednesday. Prime was expected to acquire Victor Valley Community Hospital under the bankruptcy plan but by law the medical facility is subject to an open bidding process.
Mike Sarrao, an attorney for Prime Healthcare, said by phone from federal court in Riverside that Heritage has at expressed an interest in the 101-bed medical facility. Sarrao was in court for the hospital’s first bankruptcy reorganization hearing.
Heritage may bid for Victor Valley hospital | victorville, bid, heritage - Local News - Victorville Daily Press
Skull Base Institute in Los Angeles Developed Minimally Invasive Approach to Removing Pineal Tumors–Small Incision Behind the Ear
I have heard about procedures that go through the nose and now for tumors in other areas the endoscopic procedure can be done via a small incision done behind the ear. Of course with less cutting, recovery time is better for the patient. The video below talks about one of their other procedures performed at the institute. Even tumors that are not cancerous can push on the brain and create problems. Pineal tumors can be some of the most challenging brain tumors to remove.
You can visit the website which as a ton of information and there are a few additional videos here on You Tube. BD
Press Release:
One of the most difficult-to-remove tumors located deep in the midbrain area can now be safely excised thanks to the work of one Los Angeles surgeon. Hrayr Shahinian, M.D., medical director of The Skull Base Institute in Los Angeles, has developed a minimally invasive approach to removing pineal tumors so called as they are shaped like pine cones. The new procedure is expected to replace the more invasive open brain approach favored by neurosurgeons, which leaves patients more vulnerable to brain damage and other side effects as well as long and difficult recoveries. Shahinian says that his patients are enjoying healthier asymptomatic lives not to mention much shorter treatment and recovery times.
Hrayr Shahinian, M.D.
More common in children than adults (average age of diagnosis is 13), pineal tumors can cause headaches, nausea, fatigue, visual impairments, double vision, memory problems, seizures and, in children,precocious puberty. While 20% of pineal tumors are benign or relatively benign, 80% are highly malignant and their exact cause is unknown. Even benign tumors can be problematic as they can press on nearby brain structures causing painful and serious reactions.
The new procedure developed by Shahinian involves making a dime-size opening behind the ear, inserting a small endoscope over the top of the cerebellum and through a natural pathway accessing the deep-seated pineal tumor. This eliminates the need for any metal retractors or having to go through brain tissue to reach the problem area.
“I’m delighted that my endoscopic approach is bringing hope and relief to patients suffering from pineal tumors,” said Hrayr Shahinian, M.D. “For patients suffering from significant symptoms, open brain surgery is often the first option. When surgery is required, this minimally invasive approach is an excellent and safe alternative and results in much shorter surgery and hospitalization times and fewer complications.”
For more information, call the Skull Base Institute at (310) 691-8888 or visit www.skullbaseinstitute.com.
SURGEON DEVELOPS REVOLUTIONARY ENDOSCOPIC PROCEDURE FOR REMOVAL OF MOST DIFFICULT TO ACCESS BRAIN TUMOR « Frank Groff Inc.
FDA's Sentinel Initiative Will Need to Embrace Mobility Sooner or Later–Better Sooner Than Later–Data Beyond the Desktop
This is one “huge” project and the targets and technologies change frequently, maybe hourly if we really had all the data to look at. Technology is out there throwing us a new left curve every day and when it available and simple, consumers want it now. No longer are we in the days to where the IT folks could spent a few weeks and build the system or systems someone wants, it’s one big ass job today, as many are finding out – why – there’s a huge mother load of code that needs to be written.
As more software applications come on to the market, there’s more code to make them work with other applications on the desktop and on mobile devices. The FDA is probably working as fast as they can but as each day progresses, guess what, we have more potential information and data to add. When it came to safety last year, the FDA had to give a contract to an insurance agency to pilot, as they were not ready for it yet and the insurance company had the IT infrastructure.
FDA Awards a Big Grant to Health Insurance Company For Pilot Program To Monitor Safety of Drugs and Medical Devices
When we get right down to what the Sentinel project is, it is business intelligence.
FDA's Sentinel Initiative Information Revealed – Business Intelligence
Not only is new technology creating a bit of a rush, but add on 8 years of a leadership there that didn’t embrace technology for the most part so we some catch up going on here too.
Wireless Healthcare Medical Devices and the FDA – The Reasons They Are Slow to Come to Terms
As a consumer product becomes available, it’s not always that easy and fast to connect it to the healthcare infrastructure as one may think, and yes it pretty much can be done, but it takes time. You want to make sure those coders are getting it right, and let’s think about medical devices that use software, as those have been heavy in the news today with imaging and other types of devices, don’t rush the code heads on those issues. Even big companies don’t get everything 100% and deal with growing and changing technologies as we are reminded every week with our Tuesday updates.
In the news today the FBI said they were going to take a lot of their Sentinel IT issues back in house and rely less on contractors, so perhaps this is maybe what the FDA might be looking at too, but the infrastructure needs to be built first! There’s no magic want to wave. The FDA stands to become the “most connected” government agency out there due to all the various areas they touch and are responsible for.
FDA and FCC To Partner on Telehealth Innovation and Implementation – FDA Stands to Become One of the “Most Connected” Federal Agencies
Mobility has this to offer and a whole lot more…..
Stolen Advair Demonstrates Need for Tag Bar Coding of Drugs – Encrypted Bar Codes Could Identify Stolen and Counterfeits When Scanned With a Cell Phone
Take this data base of recalls and stick in the cloud on SQL server or the equivalent and get things rolling so we can start creating some real value.
FDA Plans Recall Data Base – Nice Still Need Tags on the Products ...
Certainly I’m a bit of a broken record but this is where it’s at with mobile data and showing and finding value. This is part of the reason I made the comments about being connected as this same technology could authenticate MDS for e-prescribing too, so one technology goes a long, long way and with using the cloud it could be built faster too. It’s time to seriously start thinking about mobile technology since they are going to be participating in approving such devices more and more. First hand experience says all. BD
A national electronic system that will transform FDA’s ability to track the safety of drugs, biologics, medical devices--and ultimately all FDA-regulated products once they reach the market--is now on the horizon. Launched in May 2008 by FDA, the Sentinel Initiative aims to develop and implement a proactive system that will complement existing systems that the Agency has in place to track reports of adverse events linked to the use of its regulated products.
http://www.fda.gov/Safety/FDAsSentinelInitiative/default.htm
'Stand Up to Cancer' Show Raises Over $80 Million
One of the big areas to where the “dream teams” want to focus is with Pancreatic Cancer as all the researchers and doctors working together want to get something working as all are frustrated on the fact that not enough progress is being made with this particular area of cancer. Below is one of the dream team reports.
If you missed the show you can visit the website here and donations are welcome at any time, not just during the show. BD
Pancreatic Cancer
Sequencing the genome is high on the list for finding cures and treatments for cancer of the pancreas too. Pancreatic cancer is caught usually in late stages and thus the rush to find cures and treat patients quickly. BD
A Progress Report on Stand Up To Cancer
Johns Hopkins
The successful one-hour fundraiser was hosted by network news anchors Katie Couric, Diane Sawyer and Brian Williams, and was simulcast live on ABC, CBS, FOX, NBC, Bio, Current TV, Discovery Health, E!, G4, HBO, HBO Latino, MLB Network, mun2, Showtime, Smithsonian Channel, The Style Network, TV One and VH1.
'Stand Up to Cancer' Raises $80 Mil! | Extra
Former Doctor in Massachusetts Gets Jail Time Over Death of Patient with Botched Abortion Surgery
The MD did not have the resuscitation equipment, and was not certified for cardiopulmonary resuscitation. He also failed to monitor her vital signs and as the video states the doctor did admit his guilt in this unfortunate loss of life. He received 30 months in prison but will serve only 6 months. He stopped practicing medicine 2 years ago and when the case came up it they found out he had tried to update his office after the fact to prove he had the necessary equipment, that is sad.
The board also found he didn’t call 911 fast enough either when complications arose. BD
BARNSTABLE — She arrived at the Smith household almost 18 years ago, a small raven-haired girl with tattered and dirty clothing, a black eye, and all her possessions in a plastic grocery bag, except for the doll she held in her hand. Tom and Eileen Smith wrapped the neglected, abused, and abandoned girl with their love, only to lose her later to a botched medical procedure.
By all accounts, Laura Smith lived life to the fullest, according to her family and friends.
Former doctor gets prison for death of Cape abortion patient - The Boston Globe
California's Telehealth Networks Receives $14M From the American Recovery and Reinvestment Acts (ARRA)
In August the California Telehealth Network was announced by our governor and was also attended by Aneesh Chopra from the Executive Branch. What’s nice is that Governor Arnold uses a technology to announce these events too so if I am working in the office I can tune in. You can use the link below to watch a couple videos of the event that used Twitter to announce them. Mentioned here in the kick off is UCI Irvine who also works with Miller’s Children’s Hospital in Long Beach where I did an interview and walk through with the CFO and was able to see the educational side of being able to connect the operating rooms in Long Beach to those in Irvine, CA
Nation’s Largest Telehealth Network Launches-California Telehealth Network With Governor Schwarzenegger & Aneesh Chopra
This new funding is in addition to the $30 Million given by the FCC and the California Emerging Technology Fund and the California PUC. BD
The participating organizations are: The National Coalition for Health Integration, United HealthCare, the California HealthCare Foundation and the University of California.
The grant award, announced Sept. 13 by U.S. Commerce Secretary Gary Locke, will fund telehealth and eHealth equipment and training for healthcare providers implementing broadband-based technologies designed to improve care and expand access to services.
The new funding, part of the American Recovery and Reinvestment Act's Broadband Technology Opportunities Program, follows $30 million from the Federal Communications Commission, the California Emerging Technology Fund and the California Public Utilities Commission to build and connect the network.
California's new telehealth network gets $14M boost | Healthcare IT News
Google Health PHR Gets a Facelift and Adds Some New Features–Augmentation for the Consumers
I can say this was needed as things have progressed in the last couple of years since Google Health was introduced. We now see some consumer devices that can now connect and make it easier for one to get the data in place.
Cardio Trainer and Fitbit were named as 2 new devices that connect. Be sure and read all privacy disclosures on devices though as 3rd party companies do have an effect here on who you grant access to your data. If you have received a device as part of an employer wellness program, ask questions as to who gets your data and where it goes.
Fitbit Wireless Device Monitors your Daily Activity and Movements Released
If you are doing this on your own and connect to Google Health then you are in control. You can always find a link to Google Health on the Medical Quack under the Personal Health Records section. In addition, the Medical Quack has a section with over 300 posts on personal health records you might want to check out and there’s a permanent link at the top of the page, or you can simply use the Google search boxes (#2 is fast) and find all kinds of relative information here as there’s over 2 years of posts.
I do have to admit it has been a few months since I have logged in to my account so here’s a brief screenshot of the new portal and how it looks. On the Fitbit integration you can read what others think here from the West Wireless Institute.
CareFusion, Cisco and Medtronic to Collaborate With West Wireless Health Institute on Technology – Additional Grants Awarded From Philanthropists Gary and Mary West
Google Health has added a section to where you can list an insurance company now too. Here’s a couple past posts that may be of interest too. If you want to automate getting your labs imported, you can do that.
Quest Diagnostics and Google Empower Patients and Physicians to Share Diagnostic Test Results Online
The link below gives a summary of some of the other options available.
Google Health Online Services – Connections Beyond Medications – Personal Health Records
Back to my favorite subject in healthcare, bar coding with Microsoft Tags too so you can use a bar code to import your data too so get your digital token. If you read here often enough I have several posts with this same technology becoming an avenue for the FDA, and drug and device companies to use for FDA recalls.
Digital Health Tokens – Connect Google Health to HealthJibe – RAZCODE With Microsoft Tags
The video at the link above will show you how to connect your Google Health account and have the ability to add information to your Google Health account simply by snapping the code with your cell phone.
Anyway I hope I covered some areas with Google Health that you may not see in other posts here and show where all of this is headed with augmentation to make things easier for the consumer all the way around. You can put the bar code reader on your phone and play around at the grocery store with some Wheaties and Cheerios to see how this works, it’s very cool and almost easier than making a phone call! BD
Via a new dashboard, Google Health will now organize all of your health and wellness (i.e. fitness) information in one place. The new platform will give provide graphs on your progress with weight loss goals, and you’ll be able to create custom trackers for wellness issues like dietary habits, daily sleep, frequency of exercise, pregnancy or even how many cups of coffee you drink a day.
Of course, one the keys to the overall success of Google Health are partnerships with insurance companies and hospitals to make data more available to consumers. As of last Fall, Google Health still needed to sign up hundreds of insurers in the U.S. Today, Google is announcing relationships with the Lucile Packard Children’s Hospital at Stanford, University of Pittsburgh Medical Center (UPMC) and Sharp HealthCare. Last year, Google announced a partnership with CVS to import prescription data into the platform.
Google Health Gets A Wellness Makeover, Now Integrated With Fitbit And CardioTrainer
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Clinic for high school boys interested in lacrosse Saturday in Edmonds
Pacific Northwest Lacrosse is hosting a new player clinic this Saturday from 10 a.m. to noon at Edmonds School District Stadium. All high school boys interested in lacrosse are welcome to attend and receive instruction.
This free clinic is designed for new players to get the skills needed to hit the ground running in the spring.
To encourage constructive community dialogue, all commenters must use their real names, first and last. Comments from users with names that don't comply with this policy will be removed. Thank you for your cooperation.
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Evolution of open source and commercial providers for learning management systems
Image credits: Image source: Public domain
(2 votes)
The recent announcement by Blackboard (Bb) that it was acquiring two Moodle service providers was quite interesting to anyone who follows open source in higher education. Over the years, Blackboard has emerged as a market leader in the learning management system (LMS) arena, through both product development and acquisition. At the same time, Blackboard has attracted considerable heat and a large dose of scorn for a patent the company filed and tried to enforce. That patent was viewed by many to be an attempt to corner the LMS market and to claim invention of many LMS features in use well before Blackboard’s supposed date of invention. (Read coverage of the long story and eventual Blackboard loss in the courts.) Particularly for fans of open source, this sort of behavior does not make Blackboard an admired company, and acquisitions in the Moodle niche are much more likely to raise eyebrows than cheers.
It’s interesting however to see how Blackboard explains this latest move. It’s also important to note that Blackboard recently returned to being a private company after trading publicly for some years. That switch may have provided increased flexibility in strategy formation.
Blackboard’s strategy already includes multiple learning platforms due to acquisitions. The company has also broadened its scope beyond the LMS niche to address a range of educational institution application needs, including a push into areas like student services. Finally, Blackboard also grows by providing services, not just software. Taken together this means that accommodating the open source world makes sense for Blackboard in two ways:
• Enterprise sales–In the push to cover the education enterprise, Blackboard will sometimes be sole provider for an institution across its whole product line. But much more often, like any enterprise vendor, Blackboard will sell some applications and need to co-exist with products from other vendors in other applications. Open source is just another flavor with which to co-exist.
• Services–To the extent that Blackboard is a service provider, large open source projects like Moodle and Sakai create a business opportunity. Blackboard clearly is moving to be a service player for both of these open source communities.
In spite of the history that seems to make Blackboard an unlikely candidate for good citizenship in open source communities, it’s not hard to see a business case for moving in that direction. And this step in the evolution of Blackboard makes an interesting case study for the continuing evolution of open source as a significant, not-to-be-ignored part of the software industry. Of course, the case study is still being written And open source advocates who have followed Blackboard over the years will be excused if they want to wait to see how this plays out!
* This article was originally posted on Notes from Greg Hislop.
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You are here
Articles of Incorporation
ARTICLES OF INCORPORATION OF
OPEN SOURCE INITIATIVE
A California Nonprofit Public Benefit Corporation
One: The name of the corporation is Open Source Initiative.
Two: This corporation is a nonprofit public benefit corporation and is not organized for the private gain of any person. It is organized under the Nonprofit Public Benefit Corporation Law for public purposes. This corporation is also organized for educational purposes within the meaning of Section 501(c)(3) of the Internal Revenue Code of 1954 or the corresponding provision of any future United States internal revenue law. The specific purposes of the corporation are to (1) educate the public about the advantages of open source software [software that users are free to modify and redistribute]; (2) encourage the software community to participate in open source software development; (3) identify how software users' objectives are best served through open source software; (4) persuade organizations and software authors to distribute source software freely they otherwise would not distribute; (5) provide resources for sharing information about open source software and licenses; (6) assist attorneys to craft open source licenses; (7) manage a certification program to allow use of one or more certification marks in association with open source software; and (8) advocate for open source principles.
Three: Notwithstanding any other provision of these articles, this corporation shall not, except to an insubstantial degree, engage in any activities or exercise any powers that are not in furtherance of the specific purposes of this corporation, and the corporation shall not carry on any other activities not permitted to be carried on (a) by a corporation exempt from federal income tax under Section 501(c)(3) of the Internal Revenue Code of 1954 or the corresponding provision of any future United States internal revenue law, or (b) by a corporation, contributions to which are deductible under Section 170(c)(2) of the Internal Revenue Code of 1954 or the corresponding provision of any future United States internal revenue law.
Four: The name and address of the corporation's initial agent for service of process are Lawrence E. Rosen, Esq., ROSENLAW.COM, LLP, 702 Marshall St., Suite 301, Redwood City, California 94063.
Five:
1. No substantial part of the activities of this corporation shall consist of carrying on propaganda, or otherwise attempting to influence legislation, and this corporation shall not participate in or intervene in (including publishing or distributing statements) any political campaign on behalf of any candidate for public office.
2. All corporate property is irrevocably dedicated to the purposes set forth in Article Two, above. No part of the net earnings of this corporation shall inure to the benefit of any of its directors, trustees, officers, private shareholders or members, or to individuals.
3. On the winding up and dissolution of this corporation, after paying or adequately providing for the debts, obligations, and liabilities of the corporation, the remaining assets of this corporation shall be distributed to such organization (or organizations) organized and operated exclusively for educational purposes which has established its tax-exempt status under Section 501(c)(3) of the Internal Revenue Code of 1954 (or the corresponding provision of any future Unites States internal revenue law), and which has established its tax-exempt status under Section 23701d of the California Revenue and Taxation Code (or the corresponding provision of any future California revenue and tax law).
4. The corporation will distribute its income for each tax year at such time and in such manner as not to become subject to the tax on undistributed income imposed by Section 4942 of the Internal Revenue Code of 1954 or corresponding provisions of any later federal tax laws.
5. The corporation will not engage in any act of self-dealing as defined in Section 4941(d) of the Internal Revenue Code of 1954, or corresponding provisions of any later federal tax laws.
6. The corporation will not retain any excess business holdings as defined in Section 4943(c) of the Internal Revenue Code of 1954, or corresponding provisions of any later federal tax laws.
7. The corporation will not make any investments in such manner as to subject it to tax under Section 4944 of the internal Revenue Code of 1954, or corresponding provisions of any later federal tax laws.
8. The corporation will not make any taxable expenditures as defined in Section 4945(d) of the Internal Revenue Code of 1954, or corresponding provisions of any later federal tax laws.
Six: The name of the existing unincorporated association now being incorporated by the filing of these articles is Open Source Initiative.
Dated: 3/7/00 (signed)
Lawrence E. Rosen, Esq., Incorporator
DECLARATION
Eric S. Raymond and Ian Murdock declare under penalty of perjury under the laws of California that they are the president and secretary, respectively, of Open Source Initiative, the unincorporated association referred to in the Articles of Incorporation to which this declaration is attached, and that that association has duly authorized and approved in accordance with its rules and procedures its incorporation by means of those articles.
Executed at MALVERN, PA on December 31 , 1999.
(signed)
Eric S. Raymond, President
Executed at TUCSON, AZ on December 29 , 1999.
(signed)
Ian Murdock, Secretary
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Lidstrom:Oligo Orders
From OpenWetWare
Revision as of 18:09, 15 August 2012 by Janet B. Matsen (Talk | contribs)
Jump to: navigation, search
Back to Protocols
Contents
Invitrogen
• Most people order from Invitrogen. Ask Melissa for the excel sheet with which to order, and return it to her filled in.
• They ship for free, and have a good price.
IDT
• IDT is the synthetic biology industry standard.
• Janet and Amanda use IDT for larger oligo orders because it is cheap, we can enter orders ourselves, and they are delivered the next day if you order by 3pm. (Technically next-day delivery is not a rule, but it is true 99.9% of the time.)
• Janet routinely gets primers the next day, even when the order is submitted at 5pm (7/24/2012)
• We have two accounts:
• One (in Ginger's name) ships for free to the biochemistry store no matter the order size.
• When you go to pick them up, know that it is under Ginger's name, and the budget number they should be billed to.
• The other (in Melissa's name) ships to the lab for free for orders over $50.
• IF you don't make the $50 cutoff, shipping is ~$13. Conveniently when you check out they quote $0.35/bp so it is not hard to meet the $50 minimum; the price is adjusted to $0.14/bp after you finish checking out.
• Ordering through invitrogen includes free delivery to the lab no matter the order size, but usually takes ~ 2 days.
• Don't bother with same-day oligo orders. It just costs a lot extra to have a guarantee that your oligos will arrive ~10:30am the next day when you order by 1pm. Sometimes they come in the afternoon, though.
• Click "ship order when complete" not "ship items as available" because then you will lose your free shipping privileges.
• If you are wondering if your primer will ship the next day, you can log in and look at the order history. They update the website within a few hours to "shipped." You can ask customer service (chat or phone) if your status is "in production" and they can track it down if it is important.
IDT prices
When ordering to Biochemistry store on campus:
• Free shipping +
• Tubes:
• 25nmole $0.18 (up to 60 bp)
• 100nmole $0.37 (up to 90 bp)
• 250nmole $0.58 (up to 100 bp)
• 1umole $1.06
• 5umole $7.65
• 10umole $14.42
• Plates:
• 25nmole $0.13
• 100nmole $0.20
• 250nmole $0.34
• 1umole $0.70
Ordering through "mtsl" account:
• Free shipping if order price is >$50, or ~$14 if order price is <$50 +
• Tubes:
• 25nmole $0.15 (up to 60 bp)
• 100 nmole $0.35 (up to 90 bp)
• 250 nmole $0.55 (up to 100 bp)
• Ultramers (up to 200 bp) in tubes
• 4 nmole $0.55 (discounted past University of Washington price)
• 20 nmole $1.50 (we don't have a "deal" on this scale of ultramer)
• add PAGE purification to your ultramer: add $105/ultramer (don't do this for Gibson cloning)
Personal tools
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Malabo
From Wikitravel
Jump to: navigation, search
Malabo is the largest city in, and capital of, Equatorial Guinea. It is located on the island of Bioko.
[edit] Understand
[edit] History
The city was first founded by the British in 1827, who leased the island from Spain during the colonial period. Named Port Clarence, it was used as a naval station in the effort to suppress the slave trade. Many newly freed slaves were also settled there, prior to the establishment of Sierra Leone as a colony for freed slaves. While many of them later relocated to Sierra Leone, some of their descendants, called Fernandinos, can still be found in Malabo and the surrounding area, where they constitute a distinct ethnic group, speaking their own Afro-Portuguese pidgin dialect. When the island reverted to complete Spanish control, Malabo was renamed Santa Isabel. It was chosen to replace the mainland town of Bata as the capital of the country in 1969, and was renamed Malabo in 1973 as part of President Francisco Macías Nguema's campaign to replace European place names with "authentic" African ones.
During his "reign of terror," Macías Nguema led a near-genocide of the country's Bubi minority, which formed the majority on Bioko Island, and brought many of his own tribespeople, the Fang, to Malabo. In the final years of his rule, when Equatorial Guinea was sometimes known as the "Auschwitz of Africa," much of the city's population fled as, indeed, did about one-third of the country's population. Malabo has yet to recover from the scars of that period.
[edit] Orientation
Despite its status as the capital of Equatorial Guinea for several decades, Malabo's street network remains poorly developed. Malabo itself has few paved roads leading into it, and fewer than one hundred paved and developed streets. Many of the street names reflect an African nationalist or anti-colonial theme, with names such as "Independence Avenue" or "Patrice Lumumba Road" being main roads. The few large roads not named for an African nationalist ideal or person are named for cities in Equatorial Guinea or other places or countries in Africa, as well as the road leading to the presidential palace. The palace and grounds consume a substantial part of the eastern side of Malabo, and are off-limits. The heart of the city is the colonial cathedral at Independence Place. Many buildings in the city from the Spanish colonial era are still standing. The south of Malabo is bordered by the Rio Consul. Across this lies the hospital to the southeast. To the west is the recently renovated airport. The coastal northern region of the city is pierced by headlands and bays. The largest headland is the crescent-shaped Tip of African Unity behind the presidential palace. Encompassing the entire eastern side of Malabo Bay, it is almost as long as Malabo is tall. Malabo is part of a wider bay that represents most of the northern coast of Bioko; it stretches from Europe Point in the west (home to the airport), to barren lands in the east. Notable buildings in Malabo include Malabo Cathedral, Malabo Government Building and the Malabo Court Building. The city is served by Malabo International Airport, while ferries sail from its port to Douala and Bata.
[edit] Get in
Malabo is well served by several international carriers including Iberia, Spanair, Air France, KLM, Astraeus (charter to Gatwick), Kenya Airways, Aero Contractors, Royal Air Maroc and Lufthansa as well as a few regional airlines offering service to surrounding counties as well as to the mainland (Bata). Travel on these internal carriers should be duly considered, as there is no capability of enforcing airworthiness standards in Equatorial Guinea and air traffic control is marginal at best. Ethiopian Airlines, the airline with the highest number of International destinations within Africa, will launch service to Malabo three times a week (Tuesdays, Thursdays and Sundays) starting on Tuesday, June 2, 2009. Flights will be operated to/from Malabo to/from Addis Ababa via Douala using Boeing 767 or 757. Delta has announced that they intend to service Malabo weekly starting on Tuesday, June 16, 2009. Service will be from Atlanta via Sal Island, Cape Verde. [4] Aero Contractors flies to Malabo from Lagos, Nigeria en route Libreville every Tuesday and Saturday. A Boeing 737-400 equipment is currently being used for this route.
[edit] Get around
Malabo is quite walkable. Taxis are cheap. 500 cfa during the day should get you anywhere within the city.3,000 cfa should get you from the city to the Marathon Oil compound. Be prepared to pay more at night or when the police are out enforcing traffic laws.
[edit][add listing] See
• Bioko Biodiversity Protection Program, Moka, Bioko Island, Equatorial Guinea, [1]. Visitors, including tourists and school children, are welcome to stop in for educational programs. A striking series of 4 backlit posters, designed by BBPP’s Outreach Coordinator Jessica Weinberg and funded by a grant from the International Primate Protection League illustrate the importance of controlling the bushmeat trade. Post cards featuring Bioko Island wildlife, also the work of Jessica Weinberg, are for sale. Research Center staff can arrange for guides to the local attractions (the Cascades of the Ilyadi River and the Pico Biao Crater Lake). Because of its cool climate and central location, Moka is the ideal place from which to explore and study Bioko Island's rich flora and fauna. edit
• Universidad Nacional de Guinea Ecuatorial, Luba Road, [2]. UNGE’s campus surrounds a common grass covered area with a statue of Teodoro Obiang, the current president of Equatorial Guinea. The original buildings on the UNGE campus were built by the Spanish when the Spanish governed the island. The original buildings reflect a Spanish colonial architectural style with frequent use of arches and low sprawling buildings. The classrooms in the older part of the university are arranged in a semi-circle around the lawn. There is a new building on the south side of the university built in a more modern style. The walls are light colored and reflective, reducing the amount of passive solar heat produced in the building. The rooms are large and have large windows, which take advantage of natural lighting. The building is square and glossy. Aula 5 has a long tile-covered table down the center and a desk-height shelf wide enough to hold desktop computers on the two long walls in the room. These shelves hold three Internet-equipped computers. These computers are connected to the campus Internet via Ethernet cords and can connect more reliably than computers using the wireless connection. There are two air conditioning units and four fans in the classroom. A blackboard, white board and outlets to plug in computers and the program’s projector provide a variety of choices for lecture format for professors and guest lecturers. There are three computer labs on campus, including the one used by the study abroad program. Wireless Internet is available intermittently on campus, provided by the university. The air conditioning units in Aula 5 were replaced midway through the quarter. The new units kept the room cool as long as the electricity was on at the school. Although the school has a generator to back up city power, there were times when city power went out and the generator was not turned on. There is a small library at the university. edit
[edit][add listing] Buy
[edit][add listing] Eat
• Deme's Favorite Chicken Place, Malabo, Equatorial Guinea. Get the fried plantain (sweet is better) and chicken. Top with picante and mayonnaise. edit
[edit][add listing] Drink
[edit] Cope
[edit] Embassies
• United States, K-3, Carretera de Aeropuerto, Al lado de Restaurante El Paraíso, +240 098-895 (fax: +240 098-894), [3]. M-Th 8AM-5:30PM, F 8AM-noon. edit
[edit] Get out
Many Equatorial Guinea-based airlines are blocked from operating inside the EU, and thus only a few international airlines operate from Malabo, including, but not limited to, Air France, Lufthansa, Iberia, Kenya Airways, and Danish air transport.
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Silkeborg
From Wikitravel
Jump to: navigation, search
Silkeborg [1] is in Jutland.
Torvet
Tourist Office and Information
[edit] Get in
Rail or bus from Aarhus or Copenhagen via Skanderborg
[edit] Get around
Hjejlen [YAI-len] sails between Silkeborg and Himmelbjerget (1hr 15 min). Bookings tel: 86820766. Hjejlen is both the name of the oldest boat and the company that now operates several boats. The Hjejle-boast stop at many interesting places and with a return ticket, you can go on and off. This also gives you the opportunity to ride at least once with the original steam paddleboat.
[edit][add listing] See
Gudenåen
fish stairs
• AQUA [2]. Freshwater aquarium with fish, otters, birds. The big tanks can be viewed both from above outside the building and from the side, inside the building. Has touch tank where you can pet the fish. Entrance DKK 85.
Touch tank at AQUA
• Silkeborg art museum Gudenåvej 7-9, tel:86825388, [3] houses the Asger Jorn collections. Open Apr-Oct: Tu-Su 10am-5pm, Nov-Mar: Tu-Fr noon-4pm, Sa-Su 10am-5pm. Entrance DKK 50.
• Paper museum at papirfabrikken.
• Kunstcentret Silkeborg Bad, Gjessøvej 40 A-D, 8600 Silkeborg, 86 81 63 29 (), [4]. varies. At a location of magnificent natural beauty by the Ørnsø lake surrounded by protected forests, the Art Centre Silkeborg Bad is located. The Art Centre has been established in the old spa facility that has undergone meticulous renovation. DKK 50. edit
• Bunker museum, (in the park by Kunstcentret Silkeborg Bad). sunday 13-16. dkk 10,-. edit
[edit][add listing] Do
Hjejlen
• Hjejlen [5] go on a boat ride on the oldest operative paddle steamer in the world.
• Himmelbjerget. Walk this 147 meter "mountain" (Himmelbjerget is literaly sky mountain) and the tower on top of it (DKK 7.50 entrance for the tower). There are kiosks, restaurants, toilets next to the top. You can get there by the river boats (stop: Himmelbjerget).
View From Himmelbjerget
Tower on Himmelbjerget
[edit][add listing] Buy
pedestrian shopping street
[edit][add listing] Eat
There are several restaurants at the paper mill:
• Michael D The restaurant and brasserie at the Radisson hotel at papirfabrikken. Tel +45 88822222. [6] Menus from 250DKK.
• Cafe Eval. Papirfabrikken 10. tel: 86803366, Good beers and tapas, pastas, steaks, and burgers. Tapas or pasta main course DKK 70.
There are also many restaurants around the main square and on the shopping streets radiating off of the main square. These restaurants meet all budget ranges. These include:
• Restaurant Gastronisk Institut on Søndergade 20. Fine food and wine. Three tables in front for streetside eating at lunch. Reasonably priced two-course lunches (105 DKK) and sandwiches. Dinners feature both ala carte and fixed price courses.
[edit][add listing] Drink
[edit][add listing] Sleep
• All kind of accommodation on a map cazzala.com - search for sleep
• Radisson SAS, Papirfabrikken 12, tel:88822222. Good hotel located at the Gudenå river in the former paper mill. from 895 DKK. Free internet, wireless at ground level, wired in rooms(get access code, RJ45 cable at the reception).
• Scandic, Udgaardsvej 2, 8600 Silkeborg, Denmark, tel +45 86 80 35 33, email silkeborg@scandic-hotels.com, nice hotel not far from the Silkeborg Langsø, 2 km or so out of town. Rooms from c. 990 DKK.
• Hotel Dania, [7]. Central location.
• Danhostel, [8] The youthhostel with a view of the river and in the center of town well kept and with good standards (very often outbooked).
[edit] Get out
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Seattle/Pioneer Square-International District
From Wikitravel
Puget Sound : King County : Seattle : Pioneer Square-International District
Revision as of 01:12, 28 September 2010 by 76.104.160.27 (Talk)
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Pioneer Square is Seattle's oldest neighborhood, showcasing a wealth of art galleries, bookstores, antique shops, cool restaurants, and buzzing nightclubs within easy walking (or free bus) distance of most downtown Seattle hotels. The cobblestone streets and horse-drawn carriages are a reminder of life a century ago. The classic red brick buildings give a warmth to the area not found in most sprawling US suburbias. Local lore holds that the term "skid row" originated in Pioneer Square -- when timber would be slid down Yesler Way to a steam powered mill on the Seattle waterfront. The area sits, from east to west, between 3rd Ave. and the waterfront; and between downtown proper to the north, and the sports stadiums to the south.
Just to its east, the International District is the name given to Seattle's Asian neighborhood. It is located southeast of downtown, loosely bounded by 4th Avenue S. and S. Dearborn Street. While the old Chinatown stops around the Interstate 5 freeway, the area to the east is called Little Saigon, centered on 12th and Jackson. From there, going south along Rainier Avenue, the stores transform from Vietnamese to Cambodian, beyond which it slowly merges into South Seattle.
Get In
It is easy to get here from the downtown hotels – the square is part of the Seattle Metro ride free zone; any bus traveling south from downtown will get you within a few blocks. There are a few pay parking lots, and limited street parking is available too. Often the best parking bet is the metered spaces under the viaduct – these parking spots are usually overlooked by all but the locals. Occidental St, which sits between 1st Avenue and 2nd Ave is closed to cars between Washington St. and Jackson St, and forms a pedestrian mall which backs up to many of the galleries and shops.
Most city buses that go to downtown Seattle from other parts terminate in or pass through Pioneer Square or the International District. From central downtown, it's about a five-minute walk due south toward the stadiums. One tourist-focused line is the Route 99 Waterfront Shuttle in distinctive yellow livery, which runs along Alaskan Way past the ferry terminal, aquariums, and Pike Place Market downtown. This route is always free.
Buses and trains in the Downtown Seattle Transit Tunnel make stops at Pioneer Square Station (a few blocks north of the main neighborhood) and International District Station. King Street Station, served by Amtrak and Sounder commuter rail, sits directly in the center of the area at 4th and Jackson.
See
• Smith Tower, 506 2nd Ave, +1 206 622-4004, [1]. Built in 1914, the Smith Tower was Seattle's first skyscraper and is probably the only tall building left in Seattle where uniformed attendants operate the elevators. Instead of stepping into a metal box with no view, you'll observe the different floors and peer into offices as you ascend or descend. How many people under the age of, say, 20 or so have ever had that experience? An outdoor observation deck on the 35th floor wraps completely around the four sides of the tower, providing panoramic views of the Olympic and Cascade mountain ranges, including Mt. Rainier, as well as of Elliott Bay, downtown Seattle, and Pioneer Square. The interior of the 35th floor contains the Chinese Room, with an ornate carved ceiling and a number of decorative flourishes imported from China in the early 20th century. $7.50 adults, $6 students and seniors, $5 children.
• Klondike Gold Rush National Historic Park - Seattle Unit, 319 2nd Ave S (at S Jackson St), [2]. Daily 9AM-5PM except Thanksgiving, Christmas, and New Year's Day. A key attraction in the Pioneer Square area. It is the Seattle branch of the Klondike Gold Rush National Historical Park, the remainder of which is in Alaska. Highlights the city's key role as the "Gateway to the Gold Fields" in supplying most of the Klondike stampeders of 1897 - 1898. National Park Service Rangers and volunteers staff the Seattle unit. They can provide information and perspective not only on the Gold Rush but also on Seattle's past and present. The Seattle unit contains many artifacts and historical photographs related to the Gold Rush. Movies about the Gold Rush (27 minutes), Seattle (15 minutes) and the Chilkoot Pass (15 minutes) are shown upon request except in summer when they're shown on a regular schedule. Rangers conduct free walking tours of the Pioneer Square area in the summer. They also demonstrate gold panning for school groups. Free.
• Wing Luke Asian Museum, 719 S King St, +1 206 623-5124, [3]. Tu-Su 10AM-5PM. The first Smithsonian affiliate in the Pacific Northwest, this museum features exhibits and programs related to pan-Asian American art, history, and culture as well as historic immersion and neighborhood walking tours. $12.95 adult, $9.95 students/seniors, $8.95 children.
• Seattle Buddhist Church, 1427 S Main St (south of Yesler Way), [4]. In the summer the community hosts a Japanese bon odori festival on the street out front.
Parks
• Pioneer Square. Pioneer Square proper is just a small corner park that's often occupied by homeless folks, but generally safe during the day.
• Occidental Park, (206)-684-4075. 6AM-10PM. This urban park is best known for its four totem poles carved by local artist Duane Pasco. Free.
• Hing Hay Park, 423 Maynard Ave S, [5]. A small park in the center of Chinatown. Though you're not too likely to see old folks doing tai chi or playing checkers, it still has character.
• Waterfall Garden, Second Ave at S Main St. This small, tranquil park features a 22-foot high waterfall cascading over natural granite boulders. The park occupies the site where two 19-year olds, James Casey and Claude Ryan, began a messenger service in 1907 in the basement of a tavern. That messenger service grew up to become United Parcel Service. The Annie E. Casey Foundation, started by James Casey and his siblings in honor of their mother, created the park and maintains it "in honor of the men and women of United Parcel Service."
Do
• Art Walk, [6]. The Art Walk is almost synonymous with Pioneer Square and takes place on the first Thursday of every month. Galleries are open until 9PM. Show up early for the free wine and hor d'hoevres.
• Underground Tour, 608 First Ave (at junction with James), +1 206 682-4646 (), [7]. Hourly, hours depending on season. The underground tour covers the area around Pioneer Square, and visits sites both above and below ground. On June 6, 1889, a great fire burned down most of downtown Seattle. City engineers rebuilt the city several feet above the high tide line to prevent flooding, giving rise to a complex underground tunnel system which housed the old downtown. Tours are insightful and humourous. $15.00 adults, $12.00 seniors and students, $7.00 children under 12.
• Venus Karaoke, 601 S King St, Ste 102. One of the few karaoke rooms in the city. Rented by the hour, a good selection of Cantonese, Mandarin, and English songs. Open late, with two bars upstairs. In the lobby, view the anime models with exceedingly unrealistic presentations of the female body.
Buy
• Uwajimaya Village, 600 5th Ave S, +1 206 624-6248, [8]. M-Sa 8AM-10PM, Su 9AM-9PM. The commercial, if not cultural, hub of the I.D. is Uwajimaya Village, a huge Japanese supermarket with many smaller eateries and a branch of the Kinokuniya bookstore. If you need anything at all from Japan while in Seattle, this is the place to find it.
Most of the older businesses in the I.D. are, of course, Chinese, and there are a few general stores where you can pick up good woks and other imported items. Over in Little Saigon, the Viet Wah supermarket has Asian foods for a lot cheaper than Uwajimaya.
Eat
True to its name, the International District has a great variety of ethnic cuisines. While tourists and most non-Asian Seattleites stick to the large Chinese restaurants, the smaller places serve mostly locals and offer quite authentic atmosphere as well as food. Chinese seafood restaurants are a Seattle institution popular with locals, many with "live tanks". Not particularly elegant, but the food is great (if a bit venturesome for some tastes). And while most of Seattle's immigrant Japanese population has long since moved out to the suburbs (as have the upscale sushi bars), a few restaurants still stick it out in the area.
Budget
Chinese
For a cheap eat, try dim sum lunch. Roving servers bring steam carts of exotic (e.g., chicken feet) but often delicious food, then stamp your meal ticket for each dish. When you're done, take your ticket up to the register and pay. If you aren't a complete master of chopsticks, bring your own fork for the slippery shrimp and rice noodles, because the staff will rarely get around to bringing one. If you're not getting what you want, or you don't see it, ask the staff - you may have to be a little aggressive.
• Canton Won Ton House, 608 S Weller St (at 6th Ave S), +1 206 682-5080. Su-Th 10AM-10PM, F-Sa 10AM-midnight. Hong Kong-style noodle soup and congee (jook); great with a side order of Chinese donuts (yau tiu). Very inexpensive.
• Jade Garden, 424 7th Ave S (at S King St), +1 206 622-8181. M-Th 9AM-2:30AM, F-Sa 9AM-3:30AM, Su 9AM-1AM. Authentic Dim Sum. While very popular, don't let the seemingly long wait for a table sway you -- it is usually less than 30 minutes.
• J & B Cafe (also confusingly called J & L), 670 S Weller St. Cheap, simple Hong Kong food, but don't expect dim sum (or English) here; it's Westernized dishes like curry and Portuguese baked fish. They even have Horlick's.
• House of Hong, 409 8th Ave S, (206) 622-7997, [9]. Su-Th 9:30AM-10PM, F-Sa 9:30AM-11PM. While more expensive, they do have parking on-site, which is a good clue that this is not very authentic. Their Lo Mai Gai is larger than other restaurants, as you are served only one bundle per order instead of the standard two or three. This makes sharing your Lo Mai gai awkward, and it tends to stick to the leaves in a glutenious unnatural manner.
• Mon Hei Chinese Bakery, 669 S King St. A one woman show with lots of variety at a reasonable price. Eat your sesame roll while chatting with the old timers sitting in the back.
• Purple Dot Cafe, 515 Maynard Ave S. This is not a fusion restaurant, but rather a Macau style restaurant. This explains why you can order your Hong Kong style dishes with spaghetti and cream sauce. Purple Dot is open really late on the weekends, where packs of 80lb. red-faced co-eds can be spotted stumbling around in their glittery halter tops. The restaurant's decor may remind one of a Hong Kong style Mickey Mouse Club, with its colorful curved soffits and fiesta patterned carpet. But at Purple Dot, the draw for authentic food overpowers the teeny bopper atmosphere, as during the day there are just as many families as there are clubbers at night. Wash down the cajun chicken wings with an iced lemon tea, or stick to Cantonese soul food like jook and wonton mein.
• Sichuanese Cuisine, 1048 S Jackson St. The name in Chinese is Lo Sichuan. Great dry-fried beans with chicken. Simpler hotpot than at Seven Stars Pepper, with tasty dumplings.
• Szechuan Noodle Bowl, 420 8th Ave S. The name of the shop in Chinese means "Great King of Beef Noodles".
• Vegetarian Bistro, 668 S King St. Vegetarian dim sum. Includes the use of faux meats.
• Henry's Taiwan, 502 S King St. Order the Locomotive Bento Box, cheap, large portion, and tasty.
Other cuisines
• Fort St. George, 601 S King St. A restaurant/bar that serves Japanese-style Western foods like spaghetti and curry rice. Popular with exchange students and occasional Seattle Mariners.
• Moonlight Cafe, 1919 S Jackson St (on the north edge of the International District), +1 206 322-3378. Serves excellent vegan mock-meat versions of Vietnamese and Chinese dishes such as noodle bowls and sesame beef. In fact they boast a full vegan menu with as many dishes as their separate carnivorous menu offers. $7-$10.
• Phnom Penh Noodle House, 414 Maynard Ave S. Cambodian noodles and rice dishes which are considerably more exciting than Al Gore, who appears in a photo with the owner.
• Pho Bac, 1240 S Jackson St. An oddly-located pink shack serving Vietnamese noodle soup. Don't ask for a menu; the only choices are regular or large, and what kind of beef you want.
• Green Leaf Vietnamese Restaurant, 418 8th Ave S. If celebrity chef Mario Batali and the Iron Chef America Chairman can eat here, so can (and will) you.
Mid-range
• Fuji Sushi, 520 S Main St. Open for lunch, just around the corner from Maneki. Smaller pieces, a bit pricer, but fresh and tasty.
• Grand Central Bakery, in the arcade between 1st Avenue and Occidental Park, just off South Jackson, [10]. One of the best sources for artisan bread in Seattle, this place offers an excellent lunch, cafeteria style (but stylish!). Not open on Sundays.
• Malay Satay Hut, 212 12th Ave S. Worth trying mango chicken.
• Maneki, 306 6th Ave S, [11]. Very good sushi, as well as many non-sushi Japanese dishes. The restaurant claims to be at least 100 years old, although it has moved since its estimated founding date in 1904, and is considerably smaller than the grand space it occupied prior to World War II. Their sushi pieces are very large, and their prices are very reasonable. Only open for dinner.
• The New Orleans, 114 1st Ave S, [12]. Great gumbo and jambalaya, but the real winner is the fried oyster po-boy sandwich. Great lunch spot on the cheap.
• Saigon Bistro, 1032 S Jackson St. The noodle soup with duck and plums is delicious. Also try the sea snails (or slugs?).
• Salumi, 309 3rd Ave S, [13]. This is the place to eat lunch in Pioneer Square. There is often a line that can take over an hour to get through. Salami sandwiches on artisan bread... can't beat it.
• Seven Stars Pepper, 1207 S Jackson St, Suite 211 (Ding How Plaza). Great hand-shaven dandan noodles, chonggin hot chicken, hotpot.
• Tamarind Tree, 1036 S Jackson St. It is worth the awkward crawl through Seattle's steepest and most congested parking lot to relax with a Tamarind Soda next cool contempo style fountain. Tamarind Tree is an anomoly in Little Saigon, to say the least. Three Vietnamese brothers created an atmosphere that feels like it should be located in a Belltown Hotel rather than a Vietnamese ghetto. Tamarind Tree packs in more flavors for under $9.00 than any other restaurant. Try the Fish Paste with Bacon, or the Seven Courses of Beef. Be amazed at how high quality service, sauces, and appetizers can be served up artfully for Little Saigon prices. Eat your spring rolls with a side of fresh peanut sauce.
• Uwajimaya, 600 5th Ave S. The food court at Uwajimaya, and the accompanying Uwajimaya grocery store, deserve special mention. The grocery store offers specialty items for almost all forms of Asian cooking. They have great produce, though not always the best prices. But most importantly, they have obscure items like Kafir lime leaves or entire lotus roots, labeled in English. The food court offers a wide variety of Asian cuisines, ranging from Hawaiian BBQ to Hong Kong style baked goods, and everything in-between, though the Thai offering is not so good. The Chinese steam tables offer reliable, western-style treats in large quantites for cheap. There is no real Japanese offering, but the grocery store deli has plenty of sushi and other Japanese lunch items available. The Korean establishment, Shilla Korean Bar-B-Q is probably the best out of the entire court, with very reasonable prices and large portions.
Drink
Bubble Tea
Bubbletea arrived in Seattle's ID around 1998. It was originally served in basic plastic cups with the signature dome lids. All the bubble tea cafes in the ID now vacuum seal the tops of each cup with a semi-permanent plastic covers.
• Ambrosia, 619 S King St, +1 206 623-9028. This was Seattle's first bubble tea establishment. Well known for its long lines and the curt Taiwanese "bubbletea nazi" that ran the cash register. Other bubble tea cafes followed suit, thus thinning out Ambrosia's clientele.
• Gossip Espresso & Tea, 651 S King St, +1 206 624-5402. This prime corner storefront used to be Seattle's oldest meat market. Gossip is now a popular hangout for bubbletea drinking neighborhood teens. A spiral staircase leads to a second level lounge where the original ornate ceiling panels still exist. Cash only, also has karaoke downstairs.
• Oasis Tea Zone, 519 6th Ave S, +1 206 447-8098. Pool tables, Ikea furniture, and music videos entertain a mostly younger crowd of bubbletea drinkers. Oasis is known for its more fragrant tasting bubbleteas.
• Pearl Cafe, 674 S Weller St, +1 206 287-9000. A basic, low overhead establishment that quietly competes with the jazzier neighborhood cafes. Older folks sit and watch whatever Hong Kong movie or gameshow that is constantly playing inside. Icecream, Lotto tickets, and public internet access available. Credit cards accepted.
• Maekawa Bar, 601 S King St, Suite 206. Seattle's only Izakaya. Serves Japanese pub grub, which is delicious. Generally busy, it is a good place to spend an evening eating and drinking. Have an award above the bar for being Seattle's best Izakaya. They do not appreciate you pointing out they are the only one. Go downstairs for Karaoke. Next to Ft. St. George.
Coffee
• All City Coffee, 4th Ave S, Prefontaine Pl S and S Washington St, [14]. A great artsy coffee/wine/beer shop together in a fabulous corner setting in an up and coming artist loft building.
• Elliott Bay Books Cafe, S Main St and 1st Ave S. Known for their generosity in allowing clients the ability to plunder the books in the store and proofread them before buying while sipping on a latte. It is a great experience surrounded by all the bookshelves in the basement of the store.
• Panama Hotel Tea & Coffee House, 607 S Main St, +1 206 515-4000. A unique renovation. Panama Hotel is both a teahouse and historical museum. Fine tea connoisseurs appreciate the wide selection of teas served with a high standard of quality. The Panama Hotel once housed the personal belongings of interned Japanese Americans who had to sell their homes and abandon their businesses. The belongings that were never claimed, including pieces of furniture and a piano are on display here.
• Trabant Coffee & Chai, 2nd Ave and James St, [15]. Trabant has won many accolates for their coffee, including Citysearch.com's "Best Coffee" award in 2005, 2007, and 2008. Modern design, great espresso and Clover coffee brewer, and competition-level baristas.
• Zeitgeist, 2nd Ave Extension and Jackson St, [16]. Elegant and arty.
Nightclubs
• The Last Supper Club, 124 S Washington St, [17]. One of the most popular nightclubs in Seattle. The sexual and erotic atmosphere is ideal for singles. The DJ's usally spin hip-hop on Friday nights, and dance/techno on Saturday nights.
Sleep
• Best Western Pioneer Square Hotel, 77 Yesler Way, +1 206 340-1234 (toll free: +1 800 800-5514). Close to Safeco Field, Qwest Field, and other Seattle attractions.
• Hostelling International Seattle (formerly the American Hotel), 520 S King St (at 6th Ave S), +1 206 622-5443 (, fax: +1 206 299-4141), [18]. checkin: 3PM; checkout: 11AM. Offers free breakfast, free wifi. Excellent common areas including a library, tv room, computer room and clean, spacious kitchen facilities. The location isn't the greatest, given the grit outside, but it is near everything and just a block from Union/King Street Stations. Starting at $29.
• Panama Hotel [19]. If you want a private old-fashioned room, modest but clean, with bathroom down the hall -- consider the historic Panama Hotel, in the Pioneer Square-International District. Very relaxing tea and coffee house, with free wireless internet connections, on the street level.
Contact
The City of Seattle provides free wi-fi access in Occidental Park. Use the SSID seattlewifi.
• International District/Chinatown Library, 713 8th Ave. S., [20]. M-Tu 1-8 PM, W-Th 10 AM-8 PM, F-Sa 10 AM-6 PM, Su closed. Public Internet terminals available.
This is a usable article. It has information for getting in as well as some complete entries for restaurants and hotels. An adventurous person could use this article, but please plunge forward and help it grow!
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m (Reverted edits by 41.6.174.136 (Talk) to last version by Wrh2)
m (Stay safe)
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Wild animals in many places pose little real threat to backpackers, but some – a human-fed bear in a national park, a cow moose protecting her calf, a hungry panther, or a venomous snake – may be quite dangerous. Check with local wildlife experts about what to be wary of, and how to protect yourself.
Wild animals in many places pose little real threat to backpackers, but some – a human-fed bear in a national park, a cow moose protecting her calf, a hungry panther, or a venomous snake – may be quite dangerous. Check with local wildlife experts about what to be wary of, and how to protect yourself.
+
+
It is very important to be well prepared for your wilderness travels and hikes. You should pack the correct cloths, sleeping gear, food and drinks, safety equipment and first aid kit in case something happens in the wild.
===Bear encounters===
===Bear encounters===
Revision as of 14:52, 7 January 2010
This article is a travel topic.
Back country heaven, Whistler
Wilderness backpacking is form of self-reliant travel that affords opportunities to see sights available no other way.
Contents
Understand
Carrying everything you'll need to survive for several days in the wilderness isn't everyone's idea of a "vacation", but if if you don't mind including some physical effort and additional inconvenience in your travel time, it's an ideal way to truly "get away from it all", and hopefully see some beautiful – or even spectacular – scenery.
Landscape
Before taking off on a backpacking trip, assess what kind of territory you'll be traveling through. Distances on a map never look that hard to cover, but once you find yourself staring up at a 400-foot ridge standing between you and tonight's camp, it's a different story. Topographic maps will give you a better idea of what you're getting yourself into, as well as being essential for navigation if you're going off-trail. Unless you have an uncanny sense of direction, you'll probably need a compass. GPS can be nifty, but many feel it takes the adventure out of hiking, and it may not always work as well in actual use as the sales pitch suggests.
Climate
Find out what kind of weather you can expect at the time of year you're planning to go. When's the rainy season? What's the temperature range? Keep in mind that going up in altitude is like going up in latitude. Daytime temperatures may be pleasant, but how cold does it get at night?
Fees/Permits
Check with the local authorities if you'll be using a state/provincial/national park to see what fees there are for use of the park, and for the trails and campsites, if any. In some parts of the world, right to access may give you permission to hike on privately-owned undeveloped land, but elsewhere – especially the highly-territorial United States – be sure to get permission (unless you want to risk prosecution – or gunshot – for trespassing).
Get around
Since "get around" means "walk", footwear is one of the most important aspects of backpacking. Traditional hiking boots could kill a small animal just by being dropped on them (empty) from a few feet up, but modern boots can be much lighter, reducing the drag on every step you take. You don't necessarily need to spend hundreds of dollars on state of the art boots, but odds are your favorite athletic shoes or street shoes will leave you very uncomfortable and hold up just as poorly. Stiff soles and plenty of ankle support are a good idea if you're going over any rocks.
But buying a new pair of boots just before your trip is an equally bad idea. Break the boots in, first with short walks, then longer ones. Wear them around for a week, and you'll know where they rub, if you want to put soft insoles in them, etc. They should conform to the shape of your foot, so by the time you're ready to hike, your boots are too. The break-in period also helps your feet get used to the boots, building up thin callouses in the spots where they rub a little.
If the terrain is especially challenging, or if your knees aren't what they used to be, you might benefit from using a hiking stick or a pair of trekking poles (like cross-country ski poles, but without the skis). They aren't just for the feeble; they can improve your balance and increase your pace by adding some power from your arms to your propulsion. A sturdy chest-high branch (not pulled from a standing tree) will do, or you can buy a telescoping staff or set of poles. Some of them can double as a camera monopod. And while this usage isn't recommended, you'd probably rather face an angry cougar with a pole in your hand than without one.
Wear
The kind and quantity of clothing to wear depends heavily on the location and season. The key strategy in all but the hottest climates is to layer your clothing. If the temperature is going to vary between night and day (and it probably will), carrying a set of clothing for the warm times and another set for the cool times will take up extra space and add extra weight. Instead bring clothes cool enough for daytime hiking, and bring extra layers to put on over them when it cools off after dark. "Convertible" slacks are handy in warmer weather, allowing you to zip off the legs and turn them into shorts when the day gets warm, or back into long pants for wading through prickly plants.
Packing at least one complete change of clothes ensures that if any item you're wearing gets soaked (by rain, a misstep crossing a stream, sweat, whatever) you'll have another to wear instead. This is especially important for socks, which are both the most likely item of clothing to get wet and the most important to keep dry. Spare boots aren't practical, but a pair of cheap flip-flops or loose-fitting light-weight shoes will give your feet a chance to breathe when you're not on the trail, and give you something to wear after you accidentally dunk your foot in a pond while collecting water.
Although cotton is normally comfy, park rangers call it "death cloth". It soaks up water many times its weight and hence its drying time is very slow, making it a less-than-ideal choice for undershirts and underwear you'll be wearing next to your sweaty skin; synthetic fabrics such as capilene will "wick" moisture away from your skin, and can better keep you both cool and dry. Many discount stores will also sell suitable shirts in their sports department if you don't want to drop the money on the specialty brands. Cotton also doesn't keep you warm when it gets wet; wool is a better material for your socks and outerwear. Cotton t-shirts as a middle layer or for sleeping in are fine.
Do with this information what you wish: Humans in many cultures across countless centuries have lived without freshly laundered underwear every morning. Also, keep in mind that the kind of underwear you normally wear may not be ideal for backpacking; women will probably prefer a "sport" bra that provides more support and no hooks in the back, and men may find that briefs provide less opportunity for skin-to-skin chafing and bunched up fabric than boxers.
Carry
There are two basic kinds of backpacks used in wilderness travel: internal frame and external frame.
The external frame is the more traditional variety, consisting of a metal frame that's strapped to your hips and shoulders, and which your sleeping bag, tent, and the fabric pack itself are strapped to. They're better for keeping your gear organized and accessible, and a bit cooler to wear, because they leave small gaps for air to move between you and the pack. They're the best option for the heaviest loads.
Internal frame packs have become very popular in the last couple decades. They use a flexible plastic frame built into the fabric of the pack itself, which allows you to carry more of the weight closer to your body, improving your balance. One trade-off is the lack of back ventilation. They also tend to have fewer internal compartments, with everything stuffed together inside, making it harder to get at things on the trail.
With either kind of pack, be sure to adjust the straps to put as much weight as possible on your hips, rather than your shoulders. The shoulder straps should mostly be keeping the pack from falling backward, not actually supporting its weight. This will save lots of wear and tear on your back and shoulders, making for a much less painful trip.
Some people prefer to bring along at least one of anything they might need, and others opt to travel more lightly, giving up convenience and comfort for mobility. But if your pack weighs more than a quarter of your body weight, it's too heavy.
Eat
You'll want "light" meals, not in the sense of fat or calorie content, but in terms of how much the food weighs in your pack. In fact, you may want to lay off a lot of your "healthy diet" habits for the duration of your trip, because you'll want those extra calories, and fats are a good compact source of all-day energy. Wilderness camping is the very kind of lifestyle that led homo sapiens to develop a fondness for that kind of food. Depending on the length of your trip, food could make up a substantial fraction of your pack weight (figure at least a pound per day). Since water makes up a large percentage of the weight of most foods we eat, and presumably can be found along the way, the obvious solution is to pack foods you can "just add water" to.
• Breakfast - Oatmeal is a good option: inexpensive, lightweight to carry, and easy to prepare. Measure portions ahead of time into zipper-sealed baggies for more convenience. Add a spoonful or two of brown sugar to make it more tasty.
• Lunch - You might welcome lunch as an excuse to stop to eat during the day, but preparing food on the trail can be a nuisance, so on-the-go foods like trail mix, granola or energy bars, or peanut butter are handy. For short trips, or for the first day or two of longer trips, you can bring semi-perishable foods such as fresh fruit or bagels.
• Supper - To restore your energy at the end of the day, freeze-dried foods are your most practical option. All sorts of pre-prepared dishes are available, mostly combinations of noodles, rice, chunks of veggies and meat, and sauce. Many can be prepared in the packaging they come in, making clean-up easier: just add boiling water, mix, and wait a few minutes. Especially with the sauce of hunger added, they can be quite tasty.
Some campsites have fire pits or grills available for cooking. If you use these, limit the wood you gather to small branches taken from the ground, not anything broken from trees (living or dead). It's not as folksy, but it's more considerate of the environment to bring a small gas-powered camp stove with you: they're safer, more efficient, and don't require scavenging firewood from the wilderness you're there to admire.
Other options include multifuel stoves. For longer trips, (where you would require more than one gas canister) provide better weight efficiency. They can also be refueled much more places, like a regular gas-station. If it is allowed to make backcountry fires in your area, skipping the stove may be an option. In general, there is plenty of wood in a forested backcountry area which is not heavily visited. A lot of food can be eaten without cooking also (like oatmeal and freezedrieds), if need be. When there has been rain, the only regular way of collecting dry wood for making the fire start is to break of dead branches on the bottom of pine trees. Birch bark is excellent to make the fire going, otherwise plastic that burns is usually better than paper.
Keep pots and pans to a minimum, both for weight and clean-up reasons. If camping with someone you're in the habit of kissing, sharing a pot of food instead of dishing it out onto plates isn't a hygiene issue (but may become a relationship issue if you don't share equitably). In fact, if you mix and eat your freeze-dried meals in the packages they came in, and your oatmeal in the baggies you packed it in, you can get away with just a single pan for heating water, which won't even have to be washed. Stick to stewy and spoon-able entrés, and you may not even need to bring a fork or dinner knife.
Drink
Be prepared to drink more fluids than you're used to. The reason overweight people sweat more than thinner people isn't just because they're well-insulated; it's because they're carrying around extra weight... just like a backpacker. If you're at your ideal body weight but carrying a 40-pound pack, expect to sweat like someone 40 pounds overweight. Walking for miles through the hills.
You might be able to pack all the water you'll need for short trips of a couple days, but not for anything longer. Some areas will have wells that you can pump to refill your water supply. In more remote areas, you'll have to collect water from lakes and streams. Check with the local authorities to find out which water supplies they recommend, and what precautions to use with them. Depending on what micro-organisms are common in the area's water supply, they may recommend using water purification tablets (a dose of poison strong enough to kill many bugs, but not affect humans), micropore water filters (usually pumped by hand), or boiling the water for several minutes. Boiling isn't usually a problem for cooking water, but filtration or chemical treatment are less hassle for water you'll want cool enough for refreshing drinks as you hike. Filtered water tastes best.
Sleep
Lightweight synthetic insulating materials have been developed for sleeping bags in the last few decades, but old-fashioned down remains a good option. Down still offers the most warmth for the least weight and it packs up more tightly than synthetic fill. However it loses its warmth-keeping ability when it gets wet and takes longer to dry. Down-filled bags last longer but are also more expensive. Mummy-style bags will keep you warmer than rectangular ones (less space for your body to heat up) and take up less room in a tent, but don't plan on moving around much if your sleep in one.
Sleeping bags are typically rated for the coldest temperature in which they'll keep you warm enough. There are standards for these ratings, but the scale itself is something of a guess, since they don't know what your metabolism is like, how sensitive to cold you are, or for that matter what you'll be wearing to sleep in. Select your bag based on the coldest temperature you can anticipate experiencing. If you can see yourself ever hiking in high altitudes, in high latitudes, or in spring or autumn, get a 3-season bag with a lower temperature rating. And if there's ever a chance you'll see snow when you camp, get something in the 0°F range. Additionaly inserting a simple "hut sleeping bag"- made of a single layer of silk(preferable) or other lightweight fabric can really raise the temperature in you sleeping bag.
The fluff in a sleeping bag is only to keep the air inside warm, not for softness. Cold ground can suck the heat out through the flattened underside of a bag as quickly as exposure to cold air would. For these reasons, a thin insulating foam pad will make your nights more comfortable. They won't come close to the softness of a mattress, however. (Inflatable pads compress smaller, but are susceptible to leaks.) Instead of a pillow, try wrapping the clothes you aren't wearing in a towel, or your sleeping bag's stuff sack, and rest your head on that. Or buy a travel pillow, which collapses into a tiny pouch.
Lodging
Some backpacking areas have shelters along the trails, spaced at intervals a typical hiker can cover in a day. If these are available, and the park authority lets you reserve them, you may be able to dispense with carrying a tent. This doesn't mean you can use a lightweight indoor "slumber party" sleeping bag, though; even if these shelters are fully enclosed, they probably won't offer much protection from cooler night-time temperatures.
Camping
Tents are available in many shapes, sizes, and levels of protection. Some models (especially domes) can be free-standing, requiring no stakes to hold them in shape. But they tend to be heavier, and trickier to set up. Unless you're sure you're never going to get rained on, a tent with a "rain fly" – a water resistant raincoat for your tent – is essential.
At the small end of the scale is the "bivy sack", which is little more than a raincoat for your sleeping bag; the most spacious ones are just big enough inside to carefully roll over. Important: a bivy bag is usually almost airtight and can cause suffocation if closed completely. Additionally, a bivy bag does not allow for drying anything, like a regular tent. Since it is so small condensation from your breath will build up. As a consequence humidity will build up if you don't get the chance to dry anything. Such as in the case of prolonged (2 days) rain. Bivy bags are therefore great for shorter trips or if you are comfortable that the weather or area will provide some opportunities for drying, and are significantly lighter than even the smallest tent.
A typical "1-person" tent might give you enough room inside to actually hunch over and maybe even scrunch up and turn around, but no more. A "2-person" tent is going to be big enough for just that: two people, lying right side-by-side. Depending on just how close you and your camping partner want to be, you might prefer a "2-to-3-person" tent (otherwise big enough for two adults and a child). If you're thinking of a larger tent so you can keep your gear with you (whether for easier access or to keep it out of the weather), a tent with a vestibule or an extended rain fly might be all you really need. By the time you get to a "4-person" tent, you're generally talking about something spacious enough that one or two people can sit upright in it, but heavy enough that you'll want to distribute the components among the people in your hiking party.
Although tents will keep most of the wind out, and usually trap air well enough to keep it warmer than outside, don't count on them to keep you warm; that's your sleeping bag's job. The difference between a 3-season tent and a 4-season tent isn't their warmth, but the latter's ability to stand up to stronger winds and snow. Using a gas- powered lamp can also help to warm up your tent, but beware of setting fire to your tent and/ or melting something as the lantern casings get extremely hot.
Backcountry
If you're travelling in an area without established campsites, you should always follow leave-no-trace camping principles for making and breaking camp, as well as your other activities in the wilderness.
Stay healthy
Take care of your feet: they're what's getting you home. If you start feeling "hot spots" on them, take care of them quickly before they develop into blisters. Moleskin offers the best protection, but if you don't have that, adhesive bandages or even tape will help protect these spots from friction.
Protect your exposed skin as well. You don't need to be sunbathing to need sunscreen. You'll be sweating, so apply waterproof "sport" sun lotion to anything that's going to be in the sun. A light-colored hat with a brim reduces the UV exposure further, and is essential if you have thin hair.
Mosquitoes, flies, and other insects can carry various unpleasant diseases; they can also be detrimental to your mental health. Mosquitoes in particular are most common around water (where they breed), in the evening twilight, and in heavy woods that resemble twilight. Liberal application of DEET-based insect repellent is your first, best line of defense. But even this won't stop them from swarming around you and in your face; a head net (best worn over a hat with a brim) provides a small DMZ that may help with your peace of mind, and is small and light enough to be packed "just in case".
You don't want to go overboard with medical supplies, but some first-aid gear is a worthwhile precaution. If you're lucky, it'll be the one thing you brought that you didn't "need", but if you're not, you'll definitely regret leaving the essentials behind. Adhesive bandages, moleskin, disinfectant, and aspirin/Ibuprofin are the bare essentials. As makeshift bandages (and dozens of other uses) hankies are worth the extra ounce in your pack.
Even if there are maintained outhouses along the trail (again: don't assume there will be), you shouldn't count on them having toilet paper; bring a partial roll from home. If you're unsure about the availability of facilities, bring a garden trowel so you can dig and then cover your own single-dump latrine (well off the trail and far away from any water supplies).
See also: Altitude sickness.
Stay safe
If there's mobile-phone service in the area you're hiking (and don't assume there will be), bringing the phone along (turned off, to preserve both the battery and the atmosphere) is a reasonable precaution in case of emergency. If you get a signal in a remote area, the dispatcher that happens to pick up your emergency call may have no idea where you are, so explain clearly.
Wild animals in many places pose little real threat to backpackers, but some – a human-fed bear in a national park, a cow moose protecting her calf, a hungry panther, or a venomous snake – may be quite dangerous. Check with local wildlife experts about what to be wary of, and how to protect yourself.
It is very important to be well prepared for your wilderness travels and hikes. You should pack the correct cloths, sleeping gear, food and drinks, safety equipment and first aid kit in case something happens in the wild.
Bear encounters
Here are some simple tips to remember before heading into areas of known bear activity:
• Research bears before departing on your journey. Learn about their behavior patterns and characteristics.
• Know your bears: Grizzly bears are identified the hump behind their neck. This is the highest point on their body. The area above the hind legs is the highest point on a black bear. Grizzly attacks on humans are mostly defensive, while black bear attacks on humans are often predatory (though they are rarer).
• Be aware of bear behavior. A bear standing on hind legs is usually doing so to get a better look. Swinging its head from side to side or turning its side to you usually implies it is seeking a way out. If a bear pops its jaws aggressively, it may charge. Bears often make several bluff charges, before actually trying to knock down the threat.
• Carry bear pepper spray and keep it on hand.
To avoid encounters:
• Do not cook near your camp.
• Wrap all food in plastic and store away from the camp.
• If you come across bear tracks, bear cubs or a partly eaten carcass, assume that an adult bear is not far away. Leave the area immediately.
• Make noise on the trail. The worst possible way to encounter a bear is to take it by surprise.
If you encounter a bear:
• Don't run. Bears are like dogs and will follow a running person.
• Do not stare into a bears eyes as this is sign of aggression.
• Talk to the creature in a calm voice so you can be identified as human, not prey. Do not imitate bear growls, shout or wave your arms around frantically.
• Slowly back away from the bear.
• If the bear follows, stand firm, but act in a calm non-threatening way.
• If there are several people, group together to present a single unit.
• If you're carrying bear spray, get it ready. Ensure that the the nozzle is pointed in the direction of the bear, and check that the wind direction will not carry the spray back onto you.
• Finally, if a bear attacks and you are sure it is defensive, play dead. Lay face down and place arms tightly over the neck. Keep legs together. The bear may still charge, but with a diminished threat it less likely to persist. Stay perfectly still until you are sure that the bear has left the area.
• If a bear makes a silent attack without first displaying signs of stress, assume it is a predatory attack. Immediately use a pepper spray, but if this fails, fight back aggressively using anything at hand, such as a stone, a sharp object, a pan or a stout piece of wood. For extra effect, target punches and strikes at the nose and eyes.
This is a usable article. It touches on all the major areas of the topic. An adventurous person could use this article, but please plunge forward and help it grow!
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Australian Bureau of Statistics
Celebrating the International Year of Statistics 2013
ABS Home > Statistics > By Catalogue Number
4921.0 - Participation in Selected Cultural Activities, Australia, 2010-11 Quality Declaration
Latest ISSUE Released at 11:30 AM (CANBERRA TIME) 21/02/2012 First Issue
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CHARACTERISTICS OF PARTICIPANTS
AGE AND SEX
People aged 15–24 years reported the highest participation rate in cultural activities in the 12 months before interview in 2010–11 (34%). Participation rates tended to decrease with age. For example, people aged 25–34 reported a participation rate of 28% and people aged 65 years and over had a participation rate of 23%. Overall, women had a higher participation rate (31%) than men (23%). Women were more likely than men to participate in cultural activities for all age groups, except those aged 25–34 years, for which the difference between men and women was not statistically significant (Table 1).
CULTURAL ACTIVITY PARTICIPATION RATE 2010–11, By age and sex
COUNTRY OF BIRTH
People born in Australia had a higher participation rate in cultural activities (28%) than people born overseas (23%). This rate varied depending on the type of country in which people were born. Those born in other than main English-speaking countries had a participation rate in cultural activities of 18%, whereas people born in main English-speaking countries had a similar participation rate in cultural activities (30%) to that for those born in Australia. (Table 1)
AREA OF USUAL RESIDENCE
Of the states and territories, the Australian Capital Territory (37%) had the highest participation rate in cultural activities, followed by Tasmania (32%). Other states and territories had participation rates in cultural activities of between 25% and 27%. (Table 2)
CULTURAL ACTIVITY PARTICIPATION RATE 2010–11, By state and territory
Across Australia the participation rate in cultural activities for residents in capital cities (27%) was similar to that for residents outside capital cities (26%) (Table 1).
LABOUR FORCE STATUS
Of the 11.5 million people employed in the week prior to interview, 27% (3.1 million people) participated in a cultural activity. People employed part-time had a higher participation rate in cultural activities (32%) than those employed full-time (25%). People who were unemployed had a participation rate in cultural activities of 32%, while those not in the labour force had a participation rate in cultural activities of 26%. (Table 1)
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Australian Bureau of Statistics
Celebrating the International Year of Statistics 2013
ABS Home > Statistics > By Release Date
1300.1.55.001 - Statistics News NSW, Sep 2000
Previous ISSUE Released at 11:30 AM (CANBERRA TIME) 30/09/2000
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PRODUCTION PRODUCER PRICE INDEXES
The first issue of a new quarterly publication, Stage of Production Producer Price Indexes, Australia (Cat. no. 6426.0) was released on July 24. It brings together existing producer price data for goods industries, including imports and exports, as well as incorporating newly developed indexes relating to a range of service industries. For further information contact David Collins on (02) 6252 6248, email david.collins@abs.gov.au.
© Commonwealth of Australia 2013
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Australian Bureau of Statistics
Celebrating the International Year of Statistics 2013
ABS Home > Statistics > By Catalogue Number
4715.0.55.006 - National Aboriginal and Torres Strait Islander Health Survey: Summary Booklet, 2004-05
Latest ISSUE Released at 11:30 AM (CANBERRA TIME) 20/02/2007 First Issue
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Vol 1, No 2 (2011)
Table of Contents
Articles
Repetition of Less Common Sound Patterns: A Unique Relationship to Young Children’s Phonological Awareness and Word Reading PDF
Jamie L Metsala p3
From Perceptions to Practice: Factors Affecting Recast PDF
Sajjad Sepehrinia, Alireza Zarea, Majid Soltani Moghaddam, Morteza Nasiri p18
Analyses of Move Structure and Verb Tense of Research Article Abstracts in Applied Linguistics PDF
Fan-ping Tseng p27
On Chinese EFL Learners’ Homonym Processing in Relation to Their Organization of L2 Mental Lexicon PDF
Xiumei Yu, Zhenyu Xu, Lan Sun p40
Parental Education and Social and Cultural Capital in Academic Achievement PDF
Reza Pishghadam, Reza Zabihi p50
How to Write Academically as a Postgraduate Student from Non-English Speaking Background: A Study from Teachers’ Perspective PDF
Nick Zhiwei Bi p58
Dyslexia in the United Arab Emirates University – A Study of Prevalence in English and Arabic Untitled () PDF
Rima Aboudan, Valsamma Eapen, Maryam Bayshak, Mouza Al-Mansouri, Marwa Al-Shamsi p64
A Phonological Contrastive Analysis of Kurdish and English PDF
Massoud Rahimpour, Majid Saedi Dovaise p73
The Pragmatics of English-Persian Dictionaries: Problems and Solutions PDF
Zohreh Gharaei, Abbas Eslamirasekh p83
The Acquisition of English be Auxiliary and Thematic Verb Constructions by Adult Arab ESL Learners PDF
Muneera Yahya Ali Muftah, Wong Bee Eng p91
An Evaluation of English Language Grammar for College Students 1&2: An EAP Coursebook Evaluation PDF
Hossein Hashemnezhad, Parviz Maftoon p106
Foreign Language Teacher Training in the Sudan: Past, Present and Strategies for Future Recruitment Policies PDF
Ahmed Gumaa Siddiek p115
The Semantic Structures of Chinese Verb-resultatives PDF
Hongling Yin p126
The Tragic Sense of Passivity, Docility and Marriage Conventionality in Hardy’s The Woodlanders PDF
Noorbakhsh Hooti, Masoud Ahmadi Mousaabad p134
Translation versus Transliteration of Religious Terms in Contemporary Islamic Discourse in Western Communities PDF
Ahmed Abdel Azim ElShiekh, Mona Ahmed Saleh p141
Assessment of Grammatical Competence Based on Authentic Texts PDF
Yonca Ozkan p148
Self-expressions, Socialization and Learning in Dialogue Journals: Features of Beginner Writers in Second Language Writing PDF
Mahani Mansor, Latisha Asmaak Shafie, Anis Maesin, Surina Nayan, Nazira Osman p155
Pragmatic Transfer in Iraqi EFL Learners' Refusals PDF
Ahmed Qadoury Abed p166
Word Choice and Symbolic Language: A Case Study of Persian Translations of THE SCARLET LETTER PDF
Hossein Vahid Dastjerdi, Elahe Madah Shoorche p186
Evaluation of the Simple View of Reading in an EFL Context: An Additive or Product Model? PDF
Atefeh Ghaedsharafi, Mortaza Yamini p196
The Relationship between Language Learning Motivation and the Choice of Language Learning Strategies among Chinese Graduates PDF
Xiuyan Xu p203
Gabriel Okara’s The Voice as Social Discourse: A Lexico-Semantic Perspective PDF
Ebi Yeibo p213
SMS Texting and Its Potential Impacts on Students’ Written Communication Skills PDF
Solomon Ali Dansieh p222
Performance of Mediation and Situational Constraints of China’s Secondary School EFL Teachers PDF
Xiongyong Cheng p230
Beyond Method: The Rise of Reflective Teaching PDF
Jalil Fat’hi, Fouad Behzadpour p241
Error Recognition Tests as a Predictor of EFL Learners' Writing Ability PDF
Adel Dastgoshadeh, Parviz Birjandi, Kaveh Jalilzadeh p252
Some Recommendations for Integrating Literature into EFL/ESL Classrooms PDF
Mohammad Khatib, Saeed Nourzadeh p258
On the Bilingual Teaching Reform in China: A Look into Sino-U.S Bilingual Education PDF
Baoren Su p264
The Changing Role of Nation-state PDF
Yongxiu Zhou p269
The Effects of On-line and Pre-task Planning on Descriptive Writing of Iranian EFL Learners PDF
Massoud Rahimpour, Mohsen Safarie p274
Investigating Language-Related Episodes during Mechanical and Meaningful Output Activities PDF
Shirin Abadikhah p281
Technology as an Assessment Tool in Language Learning PDF
Taher Bahrani p295
A Study on Strategy Instruction and EFL Learners’ Writing Skill PDF
Giti Mousapour Negari p299
This work is licensed under a Creative Commons Attribution 3.0 License.
International Journal of English Linguistics ISSN 1923-869X (Print) ISSN 1923-8703 (Online)
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Eagle (1950 series) (Hulton Press) #v8#10
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American Comics Group, 1943 Series
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Format:
Standard Golden Age U.S; Later Standard Silver Age U.S.; Full Color; Glossy Cover; Newsprint Interior; Saddle-Stitched; was On-Going Series
Issue Notes
Parts of this issue are reprinted:
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Issues in this series have been indexed by:
• Jerry Hillegas
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• Matthew Torrance
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Case Report
Basaloid carcinoma of the lung associated with central cavitation: a unique surgical case focusing on cytological and immunohistochemical findings
Sohsuke Yamada1*, Hirotsugu Noguchi1, Atsunori Nabeshima1, Takashi Tasaki1, Shohei Kitada1, Tetsuro Baba2, Hidetaka Uramoto2, Takeshi Hanagiri2 and Yasuyuki Sasaguri1
Author Affiliations
1 Departments Of Pathology And Cell Biology, School Of Medicine, University Of Occupational And Environmental Health, Kitakyushu, Japan
2 Departments Of Surgery II, School Of Medicine, University Of Occupational And Environmental Health, Kitakyushu, Japan
For all author emails, please log on.
Diagnostic Pathology 2012, 7:175 doi:10.1186/1746-1596-7-175
The electronic version of this article is the complete one and can be found online at: http://www.diagnosticpathology.org/content/7/1/175
Received:26 November 2012
Accepted:5 December 2012
Published:11 December 2012
© 2012 Yamada et al.; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
A history of an increase in pulmonary mass was presented in the right upper lobe of a 72-year-old male. The bronchial brushing cytology specimens contained many sheet-like or three-dimensional clusters of malignant cells having small to medium-sized, uniform oval to round, and hyperchromatic nuclei, inconspicuous nucleoli, and scanty cytoplasm, admixed with mitotic figures. A coarsely granular chromatin pattern was predominantly noted. We first interpreted it as suspicious of malignancy, such as atypical carcinoid. A right upper lobectomy was performed, and gross examination revealed a centrally cavity-formed tumor lesion, containing asymmetrically thinned wall and looking grayish to whitish, partly adjacent to the bronchiolar wall. On microscopic examination, the tumor was predominantly composed of a solid proliferation of atypical epithelial cells without apparent glandular or squamous differentiation, often arranged in an alveolar growth pattern with peripheral palisading. Immunohistochemically, these atypical cells are negative for all three neuroendocrine markers and thyroid transcription factor 1, whereas positive for 34βE12, p63 and S-100 protein. Therefore, we finally made a diagnosis of basaloid carcinoma with cavity formation. We should be aware that, owing to its characteristic features, cytopathologists might be able to raise basaloid carcinoma of the lung as one of differential diagnoses, based on careful cytological examination.
Virtual slides
The virtual slide(s) for this article can be found here: http://www.dianosticpathology.diagnomx.eu/vs/1519986488570234 webcite
Keywords:
Basaloid carcinoma; Lung; Cytology; Cavitation
Background
Although basaloid carcinoma (BC) of the lung is a rare subtype of nonsmall cell lung cancer, one original paper described that up to 32% tumors were reclassified as BCs among a large series of surgically resected lung cancers with retrospective review, originally classified as poorly or undifferentiated carcinoma [1]. In 1975, Spencer first reported the histopathologic, immunohistochemical, ultrastructural, and clinical features of BC of the lung [2]. Subsequently, this entity was established based on the following criteria, as previously described by Brambilla et al. in 1992 [3]: (1) A solid lobular or anastomotic trabecular pattern growing invasively in a finger-like fashion from the bronchial and/or glandular duct lining; (2) Small cuboidal to fusiform cells of mean diameter 12 to 15 μm, with moderately hyperchromatic nuclei and without prominent nucleoli. There was a scant but visible cytoplasm, and no nuclear molding; (3) Peripheral palisading with radially arranged cells at the periphery of lobules; (4) A high rate of mitosis, between 15 and 44 per 10 high-power fields. The World Health Organization (WHO) classification of tumours of the lung now records carcinoma with basaloid pattern, either as a pure BC, a variant of large cell carcinoma with above typical histopathologic patterns, or as a basaloid variant of squamous cell carcinoma when coexisted with areas of squamous differentiation [4]. BC of the lung often poses a diagnostic challenge to clinicians and cytopathologists, since its entity is difficult to diagnose pre-operatively [5,6]. In fact, one old paper reported that the cytologic differentiation of BC extensively overlap with those of small cell carcinoma [5]. Although another group demonstrated that patients with BC of the lung did not have a poor prognosis than the other nonsmall cell lung cancers [7], Brambilla et al. recently have confirmed that lung carcinoma with a basaloid pattern is a unique entity with a significantly worse outcome [8], similar to BCs in organs other than the lungs [3]. Thus, it would be critical to establish an accurate preoperative diagnosis by bronchial brushing and washing cytology.
Indeed, pulmonary BC could be a relatively uncommon disease, but not as compared with some recently published case reports of extremely rare tumor cell types in the lung [9,10]. Despite of that, we report a unique surgical case of BC of the lung, associated with central cavitation. Based on the cytology specimens, we preoperatively interpreted it merely as suspicious of carcinoma.
Materials and methods
The patient was a 72-year-old Japanese man. Bronchial brushing and washing cytology, and transbronchial lung biopsy from the pulmonary mass were performed, followed by a right upper lobectomy. The tumor specimens after fixation in 10% neutral buffered formalin were embedded in paraffin for histological or immunohistochemical examinations. All immunohistochemical stainings were carried out using Dako Envision kit (Dako Cytomation Co., Glostrup, Denmark) according to the manufacturer’s instructions, and using commercially available prediluted monoclonal antibodies against the following antigens: synaptophysin (Dako, diluted 1:20), chromogranin A (Dako, diluted 1:200), CD56 (NICHIREI, diluted 1:1), cytokeratins (34βE12; Leica Microsystems, Wetzlar, Germany, diluted 1:200, CK7; Dako, diluted 1:50, and CK20; Dako, diluted 1:60), p63 (Dako, diluted 1:30), S-100 protein (Dako, diluted 1:900), thyroid transcription factor 1 (TTF-1; Dako, diluted 1:100), α-smooth muscle actin (α-SMA; Dako, diluted 1:150), h-caldesmon (Dako, diluted 1:50), calponin (Dako, diluted 1:50), CD10 (NOVOCASTRA laboratories Ltd., Newcastle, United Kingdom, diluted 1:20), CEA (Dako, diluted 1:50), and Ki-67 (MIB-1; Dako, diluted 1:50). The profile of all these antigens is summarized in Table 1. Since all tumor specimens were fixed in formalin, transmission electron microscopy could not be performed.
Table 1. The profile of all immunohistochemical antigens
Case presentation
The patient had a history of cerebral infarction 10 years ago. He was a heavy smoker over 50 years. There was no history of malignancy, immunosuppressive disorders, use of immunosuppressive medications, or unusual infections.
During a follow-up of his infarction, a chest X-ray showed a mass shadow with central cavity area in the middle region of the right lung 1 and half years before the surgery. The sputum culture examined detected colonies of Mycobacterium Gordonae, however, following that, a recent increase of pulmonary mass was presented. Laboratory data, including blood cell count and chemistry, were almost within normal limits, except for high levels of blood urea nitrogen (BUN; 38 mg/dL) and creatinine (Cr; 1.87 mg/dL), manifesting as mild renal dysfunction. Carcinoembryonic antigen (CEA; 4.3 ng/mL), squamous cell carcinoma antigen (SCC; 5.3 ng/mL), cytokeratin 19 fragment (CYFRA; 5.3 ng/mL), neuron specific enolase (NSE; 13.5 ng/mL), and pro-gastrin-releasing peptide (pro-GRP; 78.8 pg/mL) levels as tumor markers were modestly increased up, but carbohydrate antigen (CA) 19–9 and sialyl Lewis X-i antigen (SLX) levels were within normal limits. A chest CT scan revealed a relatively well-demarcated mass, measuring approximately 37 x 30 x 23 mm, associated with central and variably thin-walled cavity formation, in the right upper lobe, S2. CT scans of the head and abdomen disclosed no definite evidence of metastases in the lymph nodes or other organs. The patient had neither recurrence nor metastases of the lung cancer, respectively, however, was dead due to bronchopneumonia at 3 years after the operation.
Pathological findings
The first bronchial brushing cytology specimens were consisted of many clusters of cohesive and sheet-like or three-dimensional tumor cells and a small number of individual tumor cells without necrotic or hemorrhagic backgrounds (Figure 1A). The bronchial washing cytology specimens were relatively inadequate, but very similar to the findings of brushing one. The malignant cells showed small to medium-sized (12 to 20 μm in diameter), relatively uniform, and round to oval with mild pleomorphism and had relatively scanty cytoplasm (Figure 1B). Additionally, the nuclei were hyperchromatic, predominantly in a coarsely granular chromatin pattern, and often had inconspicuous nucleoli, but occasionally mitotic figures (Figure 1B). Rosettes were absent, whereas a very small number of malignant squamoid cells was rarely seen. Based on that, we first interpreted it as suspicious of carcinoma, such as atypical carcinoid, and an ordinary right upper lobectomy was performed. On the other hand, the transbronchial lung biopsy specimens from the pulmonary mass were too small to be diagnostic.
Figure 1. Cytomorphologic examination of the bronchial brushing cytology specimens. (A) The cytology specimens were consisted of many clusters of cohesive and sheet-like or three-dimensional tumor cells and a small number of individual tumor cells without necrotic or hemorrhagic backgrounds (Papanicolaou stains). Bar = 25 μm. (B) Those malignant cells showed small to medium-sized (12 to 20 μm in diameter), relatively uniform, and round to oval with mild pleomorphism and had relatively scanty cytoplasm. Additionally, the nuclei were hyperchromatic, predominantly in a coarsely granular chromatin pattern, and had inconspicuous nucleoli but mitotic figures (arrowhead) (Papanicolaou stains). Rosettes were absent. Bar = 25 μm.
On gross examination, the cut surface revealed a centrally cavity-formed, relatively poorly-demarcated, and solid firm mass, measuring 35 x 27 x 25 mm, which looked from grayish to whitish in color, partially adjacent to the bronchiole (Figure 2A). This central cavity measured approximately 30 x 10 mm, but filled with no necrobiotic materials. The background of the lung had no remarkable change, i.e., not emphysematous (Figure 2A). A scanning magnification of it showed that the cancer components, less than 30% in volume, were surrounded by the cavity and irregularly grew up along the asymmetrically thickened but relatively thin cavity wall, together with extension to the peripheral alveolar wall in a sheet-like fashion (Figure 2B). This tumor lesion was partly adjacent to the bronchiolo-vascular bundle (Figure 2B). These features might indicate a sequential progression from the bronchiole to the surrounding alveolar space. There were no carcinoma in situ components within our thorough investigation.
Figure 2. Gross and microscopic examination of the resected specimen. (A) On gross examination, the cut surface revealed a centrally cavity-formed, relatively poorly-demarcated, and solid firm mass, measuring 35 x 27 x 25 mm, which looked from grayish to whitish in color, partially adjacent to the bronchiole (lower side, inset). This central cavity measured approximately 30 x 10 mm, but filled with no necrobiotic materials. Bar = 10 mm. (B) A scanning magnification of it (H&E stains) showed that the cancer components were surrounded by the cavity and irregularly grew up along the asymmetrically thickened but relatively thin cavity wall, together with extension to the peripheral alveolar wall in a sheet-like fashion (lt. side). This tumor lesion was partly adjacent to the bronchiolo-vascular bundle (rt. lower side). There were no carcinoma in situ components in our case. Bar = 5 mm.
Microscopic findings showed a solid and sheet-like proliferation of relatively uniform and small to medium-sized atypical epithelial cells having hyperchromatic nuclei and scant eosinophilic cytoplasm, often arranged in an alveolar fashion with peripheral palisading, typical of BC of the lung (Figure 3A). By contrast, rosettes structures were absent. Apparent keratinization, intercellular bridge, or glandular differentiation was also not evident, and there was not intracytoplasmic mucin with Alcian-Blue staining. On high-power view, mitotic counts were high (more than 15 per 2 mm2) (Figure 3B). The carcinoma cells partly involved the adjacent bronchiolar wall but without evidence of vessel permeation. Moreover, although foci of comedo-type tumor necrosis were not recognized within the cancer nests and the central cavity, the cancer-cavity junction sometimes contained coagulative necrosis of pre-existing alveolar wall (Figure 3C). Immunohistochemically, these carcinoma cells were negative for all three neuroendocrine markers, i.e., synaptophysin, chromogranin A and CD56, TTF-1, CEA, CK20, h-caldesmon, α-SMA, calponin, and CD10, but specifically positive for 34βE12 (Figure 4A), CK7 and p63 (Figure 4B). Additionally, one part of tumor nests was positive for S-100 protein (Figure 4C). On the other hand, MIB-1 labeling index was approximately 5% in the proliferating atypical cells of the cancer nests. All immunohistochemical profile of the carcinoma cells is summarized in Table 2.
Figure 3. Microscopic examination of the BC of the lung. (A) Low power view showed a solid and sheet-like proliferation of relatively uniform and small to medium-sized atypical epithelial cells having hyperchromatic nuclei and scant eosinophilic cytoplasm, often arranged in an alveolar fashion with peripheral palisading. However, rosettes structures were absent. Apparent keratinization, intercellular bridge, or glandular differentiation was also not evident (H&E stains). Bar = 100 μm. (B) On high-power view, mitotic counts (arrowheads) were high (more than 15 per 2 mm2) (H&E stains). Bar = 25 μm. (C) Although foci of comedo-type tumor necrosis were not recognized within the cancer nests and the central cavity, the cancer-cavity junction contained coagulative necrosis of pre-existing alveolar wall (inset) (H&E stains). Bar = 1 mm.
Figure 4. Immunohistochemical examination of the BC of the lung. (A, B, C) The carcinoma cells of BC were specifically positive for 34βE12 (A) and p63 (B). Additionally, one part of tumor nests was positive for S-100 protein (C). Bars = 50 μm.
Table 2. Immunohistochemical profile of the carcinoma components in our case of BC of the lung
Based on all these features, we suggested that these carcinoma cells were not characteristic of neuroendocrine, squamous, glandular, or transitional differentiation, and finally made a diagnosis of BC of the lung associated with central cavitation. Final pathological stage was determined as pT2aN0M0, stage IB, according to the International Association for Study of Lung Cancer (IASLC) classification [11].
Discussion
Unlike the current BC case, frequent carcinoma in situ components should cause advanced clinical treatment, including more aggressive surgery or adjuvant chemotherapy, even in the early stage for BC of the lung [8]. It would lead to confer a significantly poor prognosis of BC amongst nonsmall cell lung cancer in stage I to II patients [8]. Thus, it could be critical to establish an accurate preoperative diagnosis by bronchial brushing and/or washing cytology, the clinical utility of which in diagnosing pulmonary tumors has been generalized. The cytological characteristic of BC of the lung would partly reflect the histopathological ones, showing cohesive, three-dimensional and/or sheet-like clusters of relatively small and uniform malignant cells, often having finely granular chromatin, inconspicuous nucleoli, high mitotic rate and scanty cytoplasm, arranged occasionally in a rosette-like pattern, as well as single cells formation in the background of possible necrosis [4-6]. However, in fact, the features of this relatively new and rare entity have not been well described or reviewed more recently. As in the present case, the cytology findings (Figure 1) showed almost similar to those as described above, even though neither rosette-like fashion nor necrotic backgrounds were evident. In spite of that, a confident and accurate diagnosis of BC of the lung might be impossible only on cytology specimens, likely due to lack of experience, cytomorphologic variety, misinterpretation and/or sampling errors. Nevertheless, in cases without evidence of neuroendocrine or squamous or glandular differentiation, such as ours, cytopathologists should raise possibility of BC as one of differential diagnoses, other than large cell neuroendocrine carcinoma, atypical carcinoid, small cell carcinoma, poorly differentiated squamous cell carcinoma or adenocarcinoma, or basaloid variant of squamous cell carcinoma, at the very least. Future studies will be further required after collecting and examining a larger number of pulmonary BC cases.
It is very likely that our case report is histopathologically remarkable for two reasons at least: first, central cavitation accompanied uniquely within the tissue of BC (Figure 2). Actually, to date, the number of ‘true’ cases reported as BC of the lung in the English literatures is not large, and most recent reference is from 2008 within our thorough investigation [8]. According to those papers, all BC tumors have exhibited nodular or mass lesions without cavity formation, not similar to our case. Furthermore, this case peculiarly showed coagulative necrotic foci of pre-existing alveolar wall in the cancer-cavity junction (Figure 3C), indicating ischemic change of the pulmonary tissue surrounded by the BC areas. Xue et al. have very recently proposed that the solitary thin-walled cavity of lung adenocarcinoma would be formed via multiple processes: adenocarcinoma cells initially develop in alveolar wall and grow toward bronchiole, and next formed a unidirectional check-valve owing to lack of cartilage in bronchiole; the accumulations of gases enter alveoli; the alveoli rupture and fuse into cavity with separation; and finally, the cavity gradually gets larger and larger with the increased inner pressure [12]. As in our BC case, it was suggested that the carcinoma cells firstly developed in the bronchiolar wall and subsequently grew extensively toward alveolar wall, and vice versa, since BC of the lung could originate from a basal bronchial or bronchiolar epithelial stem cell, as described by Brambilla et al.[3]. In this scenario, the above peculiar histopathological findings (Figure 3C) might confirm their above hypotheses with regard to the pathogenetic mechanisms of solitary thin-walled cavitation in lung cancer [12]. It would be intriguing to study this topic after investigating many cases of it. Second, immunohistochemical expression of not merely p63 but S-100 protein was positively seen in the tumor nests (Figure 4). Although there have been no large, detailed immunohistochemical studies of BC of the lung until now, the results indicate that those tumor cells have potential myoepithelial phenotypes, as well. We could provide the possible evidence for the first time that BC of the lung might arise from a ductal epithelial-myoepithelial cell, as a result of neoplastic transformation of outer supporting myoepithelial cells, as well as inner ductal epithelial cells [13]. However, since other myoepithelial markers examined, such as α-SMA, calponin, and CD10, were negative (Table 2), this suggestion may be highly speculative and partly unsupported. Despite of that, future convincing data will be further required to determine whether our hypothesis is significant or not.
Conclusion
We herein reported a rare case of BC of the lung associated with central cavitation. The present case was tentatively diagnosed as suspicious of carcinoma, not otherwise specified, on the cytology specimens, since its features showed unclear differentiation. All cytopathologists should be aware that its cytomorphologically characteristic findings from extensively careful examination might induce one of differential diagnoses, and possibly a correct diagnosis. BC of the lung may be more common than generally considered.
Consent
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
SY and HN participated in conception of the idea and writing of the manuscript. SY, HN, TT, AN, SK, TB, HU, TH and YS performed the cytohistological and immunohistochemical interpretation of the tumor tissue. All authors have read and approved the final manuscript.
References
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Eur Respir J 2008, 31:854-859. PubMed Abstract | Publisher Full Text
9. Bohn OL, León EA, Lezama O, Rios-Luna NP, Sánchez-Sosa S, Llombart-Bosch A: Pulmonary artery sarcoma with angiosarcoma phenotype mimicking pleomorphic malignant fibrous histiocytoma: a case report.
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11. Groome PA, Bolejack V, Crowley JJ, Kennedy C, Krasnik M, Sobin LH, Goldstraw P, IASLC International Staging Committee; Cancer Research and Biostatistics; Observers to the Committee; Participating Institutions: The IASLC lung cancer staging project: validation of the proposals for revision of the T, N, and M descriptors and consequent stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours.
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13. Yamada S, Nabeshima A, Tabata T, Guo X, Tasaki T, Wang KY, Shimajiri S, Sasaguri Y: Invasive salivary duct carcinoma ex pleomorphic adenoma of the parotid gland: a teaching case giving rise to the genuine diagnostic difficulty on an inadequate cytology specimen.
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You are here: Home / Publications / Environmental Risk Assessment - Approaches, Experiences and Information Sources / Introduction to Risk Assessment Concepts
Introduction to Risk Assessment Concepts
Last modified : Apr 13, 2011 06:54 PM
Chapter 1: Introduction to Risk Assessment Concepts
This chapter is a general introduction to environmental risk assessment and examines its basic concepts - hazard, risk, risk assessment, risk management, risk perception and risk communication.
The technique of risk assessment is used in a wide range of professions and academic subjects. Engineers "risk assess" bridges to determine the likelihood and effect of failure of components, and social welfare workers "risk assess" their clients to determine the likelihood of the reoccurrence of anti-social behaviour. Risk assessment has become a commonly used approach in examining environmental problems. It is used to examine risks of very different natures. For instance, the approach is used to assess the environmental risks posed by Genetically Modified Organisms (GMOs), chemicals, ionising radiation and specific industrial plants. Definitions in risk assessment are all-important because of the wide range of uses of the approach, and different meanings of terms used by different groups of experts and practitioners.
In this introductory chapter some basic definitions are necessary.
Hazard is commonly defined as "the potential to cause harm". A hazard can be defined as "a property or situation that in particular circumstances could lead to harm" (Royal Society, 1992). Risk is a more difficult concept to define. The term risk is used in everyday language to mean "chance of disaster". When used in the process of risk assessment it has specific definitions, the most commonly accepted being "The combination of the probability, or frequency, of occurrence of a defined hazard and the magnitude of the consequences of the occurrence" (Royal Society, 1992).
The distinction between hazard and risk can be made clearer by the use of a simple example. A large number of chemicals have hazardous properties. Acids may be corrosive or irritant to human beings for example. The same acid is only a risk to human health if humans are exposed to it. The degree of harm caused by the exposure will depend on the specific exposure scenario. If a human only comes into contact with the acid after it has been heavily diluted, the risk of harm will be minimal but the hazardous property of the chemical will remain unchanged.
There has been a gradual move in environmental policy and regulation from hazard-based to risk-based approaches. This is partly due to the recognition that for many environmental issues a level of zero risk is unobtainable or simply not necessary for human and environmental protection and that a certain level of risk in a given scenario is deemed "acceptable" after considering the benefits.
Risk assessment is the procedure in which the risks posed by inherent hazards involved in processes or situations are estimated either quantitatively or qualitatively. In the life cycle of a chemical for instance, risks can arise during manufacture, distribution, in use, or the disposal process. Risk assessment of the chemical involves the identification of the inherent hazards at every stage and an estimation of the risks posed by these hazards. Risk is estimated by incorporating a measure of the likelihood of the hazard actually causing harm and a measure of the severity of harm in terms of the consequences to people or the environment.
Risk assessments vary widely in scope and application. Some look at single risks in a range of exposure scenarios such as the IPCS Environmental Health Criteria Document series, others are site-specific and look at the range of risks posed by an installation.
In broad terms risk assessments are carried out to examine the effects of an agent on humans (Health Risk Assessment) and ecosystems (Ecological Risk Assessment). Environmental Risk Assessment (ERA) is the examination of risks resulting from technology that threaten ecosystems, animals and people. It includes human health risk assessments, ecological or ecotoxicological risk assessments, and specific industrial applications of risk assessment that examine end-points in people, biota or ecosystems.
Many organisations are now actively involved in ERA, developing methodologies and techniques to improve this environmental management tool. Such organisations include OECD, WHO and ECETOC. One of the major difficulties concerning the use of risk assessment is the availability of data and the data that is available is often loaded with uncertainty.
The risk assessment may include an evaluation of what the risks mean in practice to those effected. This will depend heavily on how the risk is perceived. Risk perception involves people's beliefs, attitudes, judgements and feelings, as well as the wider social or cultural values that people adopt towards hazards and their benefits. The way in which people perceive risk is vital in the process of assessing and managing risk. Risk perception will be a major determinant in whether a risk is deemed to be "acceptable" and whether the risk management measures imposed are seen to resolve the problem.
Risk assessment is carried out to enable a risk management decision to be made. It has been argued that the scientific risk assessment process should be separated from the policy risk management process but it is now widely recognised that this is not possible. The two are intimately linked.
Risk management is the decision-making process through which choices can be made between a range of options which achieve the "required outcome". The "required outcome" may be specified by legislation by way of environmental standards, may be determined by a formalised risk-cost-benefit analysis or may be determined by another process for instance "industry norms" or "good practice". It should result in risks being reduced to an "acceptable" level within the constraints of the available resources.
Risks can be managed in many ways. They can be eliminated, transferred, retained or reduced. Risk reduction activities reduce the risk to an "acceptable" level, derived after taking into account a selection of factors such as government policy, industry norms, and economic, social and cultural factors.
It is important to note that although risk assessment is used extensively in environmental policy and regulation it is not without controversy. This is also true for risk management.
Reference list for this chapter
European Environment Agency (EEA)
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Denmark
Phone: +45 3336 7100
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• Cundall, Frank. The Governors of Jamaica in the Seventeenth Century. London: The West India Committee, 1936. Digital version at DLOC - free.
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About this Journal Submit a Manuscript Table of Contents
International Journal of Alzheimer's Disease
Volume 2011 (2011), Article ID 539762, 15 pages
doi:10.4061/2011/539762
Research Article
On the Involvement of Copper Binding to the N-Terminus of the Amyloid Beta Peptide of Alzheimer's Disease: A Computational Study on Model Systems
Department of Chemistry, The University of Calgary, Calgary AB, T2N 1N4, Canada
Received 25 May 2011; Revised 4 August 2011; Accepted 16 August 2011
Academic Editor: Rosanna Squitti
Copyright © 2011 Samira Azimi and Arvi Rauk. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Density functional and second order Moller-Plesset perturbation theoretical methods, coupled with a polarizable continuum model of water, were applied to determine the structures, binding affinities, and reduction potentials of Cu(II) and Cu(I) bound to models of the Asp1, Ala2, His6, and His13His14 regions of the amyloid beta peptide of Alzheimer's disease. The results indicate that the N-terminal Asp binds to Cu(II) together with His6 and either His13 or His14 to form the lower pH Component I of Aβ. Component II of Aβ is the complex between Cu(II) and His6, His13, and His14, to which an amide O (of Ala2) is also coordinated. Asp1 does not bind to Cu(II) if three His residues are attached nor to any Cu(I) species to which one or more His residues are bound. The most stable Cu(I) species is one in which Cu(I) bridges the Nδ of His13 and His14 in a linear fashion. Cu(I) binds more strongly to Aβ than does Cu(II). The computed reduction potential that closely matches the experimental value for Cu(II)/Aβ corresponds to reduction of Component II (without Ala2) to the Cu(I) complex after endergonic attachment of His6.
1. Introduction
The sequence of the human amyloid beta peptide, Aβ(1-42), in single-letter code, is:
D1AGFRH6DSGY10EVH13H14QKLVFFAED-VGSNKGAIIGLM35VGGVVIA42
Cupric ion (Cu2+) forms a 1 : 1 complex with Aβ(1-40) or Aβ(1-42) [1] with approximately picomolar or nanomolar affinity ( M for Aβ(1-42); [1] M for Aβ(1-40) [2]). The presence of added or in vivo buffers may lower the effective affinity to a considerable extent [1, 3]. The Cu(II) is bound as type 2, that is, distorted square planar arrangements of ligands with possibly one or two additional axial ligands. EPR measurements indicate a 3N1O equatorial coordination pattern [4]. At room temperature, two [3, 57] or three [8] forms whose populations are dependent on pH are observed. The lower pH component is referred to as component I (or Ia and Ib) [9] while the higher pH component is Component II, all with 3N1O coordination. It is likely that the three N ligands are due to a combination of the imidazole groups of His6, His13, His14, a deprotonated amide N, and the N-terminus since these are the most common ligands for copper bound in proteins. Indeed, there is direct evidence, obtained by ESR experiments on Aβ(1-16) in which the histidines were isotopically enriched with 15N, that all three His residues bind to Cu(II) at physiological pH = 7.4 [1012]. The origin of the O ligand is a subject of some debate, although Tyr10, Glu3, Asp7, and Glu11 have been ruled out, as has water [13]. On the basis of hyperfine sublevel correlation (HYSCORE) spectroscopy applied to site-specific 13C and 15N labeled Aβ(1-16), the carbonyl of Ala2 is implicated as the O ligand in the coordination mode at higher pH = 8.0 (Component II), along with all three His residues [12]. This result is supported by computational modeling of Aβ(1-16) [14]. At higher pH (pH = 8.7–9), studies by both EPR [6] and NMR [7] on labeled compounds seem to indicate that deprotonation and coordination of the amide N of Ala2 occurs, together with the N-terminal NH2 and one or two His side chains. Hureau and Faller and coworkers [6, 7] assigned this high pH structure as “Component II,” but it is at odds with the structure deduced by others at physiological pH that does not involve the N-terminus and was designated Component II.
There is general but not universal agreement that the N-terminus is also part of the native Aβ/Cu binding site, although the nature of its involvement is still unclear. In an earlier study, Karr and coworkers found that copper binding to Aβ was sensitive to changes in the N-terminus, including deletion [4], but, in a subsequent study, they note that removal or mutation of Asp1 does not disrupt the equatorial coordination sphere [13]. They propose that the N-terminus participates via hydrogen bonding to an axial ligand [13]. Kowalik-Jankowska et al. carried out potentiometric and spectroscopic measurements on both human and mouse Aβ(1-16) and Aβ(1-28) over a wide pH range, 2.5–10.5, and noted a significant shift in the coordination pattern upon acetylation of the N-terminus in all cases [15]. Barnham and coworkers used multifrequency CW-EPR spectroscopy applied to site-specific 15N-labeling at Asp1, His6, His13, and His14 of Aβ(1-16) to deduce the presence at pH = 6-7 of two independent 3N1O Cu2+ coordination modes both of which incorporated the N-terminal NH2 group, an O atom, His6, but only one of His13 (Component Ia) or His14 (Component Ib) [9]. On the other hand, Hong et al., propose that the 3N1O coordination arises from an equilibrium between three structures at pH = 6.5–7.4 that all incorporate, beside an “O” atom, the N-terminal NH2 group, His6, and either a deprotonated backbone amide residue or one of His13 or His14, but not simultaneously His13 and His14 [8]. Both low pH results are in qualitative agreement with the structure assigned to Component I at pH = 6 by Hureau and Faller and coworkers who proved coordination of the NH2 and carbonyl groups of Asp1 together with His6 and one of His13 and His14.
Besides being highly pH dependent, indications are that copper coordination is probably size dependent as well. NMR studies of Cu2+(aq) interacting with full-length uniformly 15N-labelled Aβ(1-40) at pH = 7.3 found that the Asp1 signals were not shifted upon addition of Cu2+ and seem to indicate that the N-terminus is not involved in copper binding at all [16].
On the basis of ab initio computations on model systems, we have previously proposed that the primary binding site of Cu(II) to Aβ is His13His14 which provide two of the three observed N ligands through Nδ of the imidazole groups. By our procedures, we could not verify the presence or absence of the carbonyl O atom of Ala2 as has been proposed experimentally. However, in the computations, the O of the intervening amide group (O of His13) inevitably became coordinated to the Cu(II) [17]. We proposed that this amide oxygen corresponds to the mysterious “O” of the 3N1O coordination pattern and that the third “N” was probably that of His6 or Asp1. Possibly because of the excessively high affinity constant calculated in that study, , this suggestion has not been taken seriously by any of the experimental groups that have examined Cu coordination to Aβ. We have since reevaluated the binding by the procedures employed in the present work and found a substantially lower value, , [18] that is more in accordance with the accepted data for Cu(II) binding to Aβ [2]. We note that isothermal calorimetry experiments by Hong et al. found that Cu2+ binding to His13His14 is most favored by the enthalpic contribution to the free energy change but that the enthalpic preference was overwhelmed by an unfavorable entropic term [8].
Less is known experimentally about the coordination of Cu(I) to Aβ. We have previously [19, 20] modeled the attachment of Cu(I) to the His13His14 region of Aβ by computational methodology similar to that employed in the present work. The computations suggest that Cu(I) is dicoordinated and bound to the two His sidechains via the proximal N atoms (Nδ) in a linear fashion. Himes et al. have demonstrated such binding experimentally by EXAFS and XANES data and results carried out on copper(I) complexes of small HisHis peptides [21], and fragments of Aβ [22]. Such a structure was also found by XAS spectroscopy on Aβ(1-40) [23]. Apparently, Cu(I) binds to Aβ(1-16) with femtomolar affinity [24], much higher than does Cu(II). The linear two-coordinate complexes were also able to add a third imidazole ligand in a T-shaped configuration in a dynamic process that interchanges all three His residues [25]. Interestingly, the two-coordinate complexes were resistant to oxidation, but the three-coordinate complexes were redox active [26]. However, the Cu(I) complexes with HisHis containing fragments were able to produce H2O2 in the presence of O2 but without added reducing agents. The amount of H2O2 produced was independent of the presence of Tyr10 (a potential source of electrons) or other residues such as Asp1 or His6 which are potential binding sites for the copper [22].
The reduction potential of Cu(II)/Aβ has been investigated by several groups. Aqueous Cu2+ has a one-electron reduction potential V versus the standard hydrogen electrode (SHE). An early report that monomeric Cu(II)/Aβ(1-42) had an exceptionally high reduction potential V versus SHE [27] has been discounted as due to oligomer formation. The consensus value is (“Cu(II)/Aβ”/“Cu(I)/Aβ”) 0.30 V–0.34 V [28, 29] which represents a modest elevation of the oxidizing power of the Cu(II) upon complexation to Aβ. Brzyska et al., find a concentration- and buffer-dependent reduction of the reduction potential upon addition of Cu(II) to monomeric Aβ(1-40), although, in the absence of buffer, their value is similar to the others [30]. As noted above, there is uncertainty as to the actual nature of the oxidized and reduced species involved. Guilloreau et al. report a wide difference between the reduction potential and oxidation potential of copper bound to Aβ(1-28), 0.33 V and 0.63 V, respectively [29]. This is taken as an indication of different geometries at the Cu(II) and Cu(I) binding sites [30].
We have undertaken the present study in order to examine the role of Asp1 in the coordination of Cu(II) as well as Cu(I) in Aβ. We employ a higher level of theoretical treatment than was previously applied in order to estimate the binding affinities of complexes containing all combinations of Asp1, modeled by the N-methyl amide derivative, 1 (Figure 2), His6, modeled by imidazole (Im), an amide carbonyl, modeled by N-methylacetamide (NMA), and His13His14, modeled as previously [17, 20] by N-α-dihydrourocanylhistamine, 5 (Figure 3). Simultaneous involvement of both Asp1 and Ala2 were modeled by the N-methyl amide derivative of Asp1Ala2, 3 (Figure 1). Reduction potentials for various Cu(II)/Cu(I) couples were also derived and compared with experimental values in order to elucidate the nature of the species involved.
Figure 1: Structures with Cu(II), Asp1, and imidazole Im. Ball colors: Cu: large yellow; C: orange; N: blue; O: red; H: white.
Figure 2: Structures with Cu(II), Asp1Ala2 3, and imidazole Im. Ball colors: Cu: large yellow; C: orange; N: blue; O: red; H: white.
Figure 3: Structures with Cu(II), HisHis 5, Asp1, and Imidazole Im. Ball colors: Cu = large yellow; C = orange; N = blue; O = red; H = white.
2. Computational Methods
All calculations were carried out with Gaussian 03 and 09 [31, 32] using the hybrid density functional method, B3LYP [33], and second-order Moller-Plesset perturbation theory. Gaseous-phase geometry optimization, harmonic frequency calculation, and thermochemical parameters were determined at the B3LYP/6-31 + G(d) basis set, which is henceforth referred to as the small basis set (SB). The frequency calculation confirmed that the optimized structures were at local minima on the potential energy hypersurface. The zero point energies were scaled by 0.9806 [34]. However, this was not done for the thermal correction of enthalpy or entropies. In the case of the zwitterionic Asp1, 1 (Figure 1) and Asp1Ala2, 3 (Figure 2), it was necessary to optimize the structure and carry out frequency analysis in the presence of the solvent reaction field (SCRF = IEFPCM), where IEFPCM is the integral equation following polarizable continuum model [35, 36] with the default parameters for water. Some structures had a great deal of conformational flexibility. Chemical intuition was used to seek the most stable structures, and no attempt was made to do a comprehensive search of conformational space. Instead, account was taken of conformational flexibility by the addition of an approximate entropy of mixing term, , where is an estimate of the number of conformers derived by simple rotamer counting [37]. Values of are listed in Table S2 in Supplementary Materials available online at doi: 10.4061/2011/539762. Entropies were also converted to a state of 1 M by addition of the term for volume change, , where 24.46 litres is the volume of 1 mol of ideal gas at 298 K. For more accurate enthalpies and to compensate for the lack of long-range dispersion energy in B3LYP, single-point energies were calculated at an approximation for the MP2/LB level, where LB is the large basis set, 6-311+(2df,2p).
Details of all computed quantities and structural information, are provided in Tables and , respectively. Molden 4.0 was used as a visualization tool [38].
2.1. Free Energies of Solvation, , and Empirical Corrections
In order to calculate the free energy change in water, , the change in the free energy of solvation, , was added to the free energy change in the gaseous phase, , corrected for a standard state of 1 M. was determined using IEFPCM [35, 36] as implemented in G03, and the B3LYP/SB density. In our experience, charged species are undersolvated by the IEFPCM with standard scaling of the united atom Hartree-Fock (UAHF) radii, so selective scaling was applied as follows: the radii of the metal ion and all atoms directly attached to it were scaled by a factor of 1.1; all other atoms were scaled by the default value, 1.2. Experimental rather than calculated relative free energies of solvation were applied where available in order to reduce errors further. For the proton, (H+) = −1107 kJ mol−1 was adopted [39]. The experimental value of was adopted for H2O, −16.2 kJ mol−1, where the value reflects the fact that water is 55.6 M. For all other species, free energies of solvation were taken as calculated by the procedure described above.
2.2. Calculation of Reduction Potentials for “Cu(II)”/“Cu(I)” Redox Couples
The mechanisms proposed below involve only intermolecular single-electron transfer processes. The standard reduction potential of a “Cu(II)”/“Cu(I)” couple, relative to the standard hydrogen electrode (SHE), (“Cu(II)”/“Cu(I)”), is defined by where F is the Faraday constant, F = 96.485 kJ mol−1 V−1, is the free energy change for the standard hydrogen cell half reaction, (1/2)H2(g) + e → H+(aq), ( = −418 kJ mol−1, ignoring the electron) [40], and is the calculated free energy change for reaction (3), again ignoring the electron In (3), “Cu(II)” and “Cu(I)” represent species containing oxidized and reduced copper, respectively. The symbol aL recognizes the fact that a number of ligands may be shed in the reduction process and that the associated entropy change may be an important component of the free energy change. The actual potential, , of the half reaction under ambient conditions is related to the standard potential, , through the Nernst equation, where is the reaction quotient specifying concentrations of oxidized and reduced components and other species associated with the chemical change. In the special case that n protons are consumed in solution buffered at pH = 7 under otherwise standard conditions, the reaction quotient reduces to , and the symbol, , denotes the potential at pH 7 (nV).
For most of the energy differences calculated in the following sections, errors inherent in the calculation of absolute values could be expected to cancel yielding reliable relative energies. However, this is less likely to be the case for the calculation of aqueous free energy changes for reactions such as (3). Since a transition element is involved and the number of electrons changes, the enthalpy change will be less accurately described at this theoretical level than expected for lighter elements. An extreme case is illustrated by the difference between the calculated (at the B3LYP/LB level) and experimental second ionization potential of atomic copper (IE2 (calc) = 2008 kJ mol−1; IE2 (exp) = 1958 kJ mol−1 [41]). The discrepancy is most likely due to the unequal treatment of electron correlation (an enthalpic term). As in a previous publication [42], we assume that the error in the ionization potential of Cu+ will be present in the reduction potentials, (/), irrespective of the metal environment since they all involve the change in copper oxidation state from +2 to +1. Without correcting for the error in the enthalpy change, the calculated value for the reduction of aqueous cupric ion is (/) = 0.42 V versus SHE, compared to the experimental value, (/) = 0.17 V [41]. An empirical correction of +57 kJ mol−1 brings the calculated and experimental numbers into agreement. Thus for addition of an electron to any Cu2+ species, the correction to the calculated ΔH is taken as +57 kJ mol−1.
With the procedures described above, we expect that aqueous free energy changes, , will be accurate to ±15 kJ mol−1 for all of the reactions considered.
3. Results and Discussion
The B3LYP/SB-optimized structures and all calculated energies and thermochemical properties are provided in Tables S1 and S2 and shown in Figures 13. Chemical transformations and aqueous free energy changes are given in the following in the form of numbered equations which are repeated in Table 1 along with a complete breakdown of the components at the MP2/LB level. The corresponding data at the B3LYP/LB level are given in Table S3.
Table 1: Relative energies at 298 K of species discussed in the text: enthalpies based on MP2/LB energiesa.
4. Interaction of Cu2+(aq) with the N-Terminal Asp1 1
The N-terminal Asp1 of Aβ is modeled by 1 (Figure 1), where the C-terminus is derivatized by NHCH3. The most stable form of 1 in water is zwitterionic. The most stable form of the aqueous cupric ion is the pentaaqua structure, . Reaction with 1 yielded numerous aquated structures 2 with different patterns of chelation:where , , and , have been adjusted to pH = 7. Structures of 2a(H2O)2, 2b(H2O)2, and 2c(H2O)2 are shown in Figure 1. It should be noted from Table 1 that the release of multiple water molecules in processes such as (5a)–(5c) endows a large entropic component favoring complex formation. In addition, release of a proton into a solution buffered to pH = 7 provides an additional 40 kJ mol−1 (=) as a driving force for the forward direction.
Of the three 1 : 1 complexes, only the most stable, 2a(H2O)2, is formed exergonically at physiological pH. This structure has a square pyramidal configuration with three-point coordination of the Asp residue to the cupric ion. The amino and carboxylate groups form adjacent corners of the square, and the carbonyl of the amide occupies the axial position. Two water molecules complete the square base. Structure 2b(H2O)2, which is lacking the axial carbonyl oxygen coordination, is less stable than 2a(H2O)2 by 32 kJ mol−1. The primary reason for the lower stability of 2b(H2O)2 is enthalpic. The Cu–O bond strength of the coordinated carbonyl oxygen of Asp1 is about 50 kJ mol−1 (Table 1). The most stable structure with a deprotonated amide N coordinated to the Cu(II) is 2c(H2O)2, which is 47 kJ mol−1 less stable than 2a(H2O)2. The missing proton is on the carboxylate group. Its p is predicted to be 13. In 2c(H2O)2, the amide N and the N-terminal NH2 groups occupy adjacent corners of the square pyramidal base with two waters in the other two corners. The neutral carboxylic acid group of 2c is attached to the axial position with a long bond (2.43 Å, compared to the average Cu-OH2 distance, 2.08 Å) [43].
4.1. Interaction of Cu2+(aq) with the N-Terminal Asp1Ala2 3
The amide-deprotonated structure, 2c(H2O)2, is not predicted to be stable in water. However, such a structure permits additional chelation by the carbonyl of the same residue, Ala2 in the present model system. Thus, 3 (i.e., Asp1Ala2) (Figure 2) may provide three ligands for Cu2+(aq) if the amide group is deprotonated. The bicyclic structure, 4(H2O) (Figure 2), is the most stable structure that has coordination by the N-terminal NH2 of Asp1 and the deprotonated amide N and carbonyl O of Ala2 to the Cu2+. All three groups occupy sites in the equatorial coordination plane, the last site being occupied by a water molecule. A second water H bonds to the first and the carboxylic acid group rather than to the copper. The carboxylate group of Asp1 is protonated and interacting with the copper only through H-bonding to the bound water. Equation (6) examines the stability of 4(H2O) relative to the dissociated species: where has been adjusted to pH = 7. Thus, compared to (5c), coordination by the O of Ala2 provides an additional 19 kJ mol−1 of stabilization but is not enough to render the complex stable in water at physiological pH. The predicted of the carboxylate proton of 4(H2O) is 10, indicating that the deprotonated form of 4(H2O) would be stable at pH = 9.
4.2. Interaction of Cu2+/Asp1 Complex, 2a(H2O)2, with Imidazole (Im)
The side chain of His6 is modeled by imidazole (Im). Interaction of Cu2+(aq) with one and two His is represented by:The structures of the two Im/Cu(II) complexes are shown in Figure 1. Displacement of a water ligand by Im is predicted to be isoergonic, kJ mol−1. This result derives from the near cancellation of a highly exergonic change in the gaseous phase by a correspondingly large loss of free energy of solvation (the and terms in Table 1). It is in disagreement with results derived from early pH measurements which found log10β1 = 3.76 or = −21 kJ mol−1 [44]. Addition of the second Im was found experimentally to have log10β2 = 3.39 or = −19 kJ mol−1 [44]. The displacement of a second water is calculated to be more favored, by 10 kJ mol−1. The computed results suggest that a monoadduct will disproportionate to form the bisadduct and aqueous Cu(II). The preferred orientation of the imidazole rings in Cu(Im)2(H2O)3 is perpendicular to the basal square plane. In the bis(Im) complex, both cis- and trans-diastereomers are stable and are nearly isoergonic. In the cis-structure, only one of the imidazole rings is almost perpendicular to the basal plane. The single Im in Cu(Im) is intended to represent His6 or one of His13 or His14. The second Im of Cu(Im)2 may be one of His13 or His14, or a His6 from a second Aβ. Thus, the 1 : 1 interaction of Cu2+(aq) with Im is less favorable than with Asp1 by 18 kJ mol−1 and the 1 : 2 interaction is comparable.
The most stable structures, 2a(Im)(H2O) and 2a(Im)2, for the 1 : 1 : 1 and 1 : 1 : 2 complexes, respectively, between Cu2+(aq), Asp1, and Im are shown in Figure 1. Structure 2a(Im)(H2O) is related to 2a(H2O)2 by the substitution of the water that is anti to the carboxylate group by Im. The basal plane with the axially coordinated amide carbonyl is preserved. Substitution in 2a(H2O)2 of the water anti to the amino group yielding 2b(Im)(H2O) results in loss of the axial ligand and distortion of the basal plane. Structure 2a(Im)(H2O) is more stable than 2b(Im)(H2O) by 38 kJ mol−1 (from data in Table ).
Substitution of both waters of 2a(H2O)2 by Im yields 2a(Im)2. A second structure, 2b(Im)2, in which the Im residues are opposite the NH2 and amide carbonyl groups, and the carboxylate group occupies the axial position, is also stable. In 2b(Im)2, the carboxylate group is coordinated through one of the oxygen atoms but perpendicular to the CO2 plane. Structure 2a(Im)2 is more stable than 2b(Im)2 (Figure 1) by 11 kJ mol−1. Equations (8a) and (8b) explore the possible reactions that may yield the 1 : 1 : 1 Cu2+(aq), Asp1, and Im adduct, 2a(Im)(H2O):where has been adjusted to pH = 7. Thus, 2a(Im)(H2O) is stable with respect to dissociation either by releasing an imidazole ligand or the N-terminal Asp. In the context to Aβ, these results imply that Asp1 1 and any of the His residues may form a stable complex with Cu(II) in water at physiological pH.
The possible formation of the 1 : 1 : 2 complex, 2a(Im)2, is explored in reactions (9a) and (9b):where has been adjusted to pH = 7. Thus, as with 2a(Im)(H2O), the 1 : 1 : 2 complex, 2a(Im)2, is also stable toward dissociation, and, in the context to Aβ, these results imply that Asp1, His6, and either of His13 or His14 may form stable complexes in water at physiological pH.
By (6), it was apparent that deprotonation of the amide N (of Ala2) required coordination of the O of Ala2 in order to afford a complex, 4(H2O), that could be formed at pH = 9 but was not stable at pH = 7. Equations (10a) and (10b) examine the possibility that the water of 4(H2O) may be displaced by Im: where has been adjusted to pH = 7. Thus, the additional stabilization afforded by replacing water by Im (10a), is sufficient to render the product, 4(Im) (Figure 2), stable in water at physiological pH (10b), but would have only marginal stability at lower pH, kJ mol−1 at pH = 6. Structure 4(Im) has a tetracoordinate square planar configuration. The carboxylate group of Asp1 is H-bonded to the NH2 group and not interacting with the copper. Deprotonation of 4(Im) affords 4(Im)() (Figure 2) with p = 11. 4(Im) is pentacoordinated with the carboxylate group occupying the fifth site. In the context of Aβ, (10a) and (10b) imply that a 3N1O complex incorporating the N-terminal NH2 group, the carbonyl O, and the deprotonated amide N of Ala2, and one of His6, His13 or H14, should be observed at physiological pH: By (11), coordination of a second Im to the vacant axial coordination site of 4(Im) to yield 4(Im)2 (Figure 2) is unfavorable by 7 kJ mol−1. Such a structure may be an intermediate for the interchange of the His residues of Aβ.
But is a deprotonated amide structure like 4(Im) stable compared to a form like 2a(Im)2 in which the amide is protonated and Ala2 is not involved? Equation (12) compares the stability of the most stable copper-coordinated structure that uses both Asp1 and Ala2, 4(Im), with one that does not involve Ala2, namely, 2a(Im)2: The relatively large exergonicity of (12), kJ mol−1, strongly suggests that Ala2 is not involved in the bonding in the N-terminal copper-bound species. The principal reason, from Table 1, is enthalpic ( = −84 kJ mol−1 and is a consequence of the greater acidity of the carboxylate group than of the amide group. Thus, 2a(Im)2 is the closest model for Component I of Aβ, but raising the pH, at least in the physiological range, does not lead to Component II as proposed by Faller and Hureau and coworkers [6, 7]. In the following section, we propose another structure for Component II and discuss the nature of the pH dependence.
4.3. Interaction of Cu2+ with His13His14 5
We explore below the special case of His13His14 where the Im groups of the two His residues are tethered by an intervening amide link. The tethering has an important consequence. As with 3, this configuration permits three-point chelation to the copper, a favorable contribution to the free energy of binding, but without the penalty of amide deprotonation.
The His13His14 sequence of Aβ is modeled by 5 (Figure 3), in which only the two side chains and the intervening amide link are preserved [17]. The interaction between 5 and Cu2+(aq) yielding 6(H2O)2 was recently studied experimentally and reexamined theoretically by the procedures employed in the present paper [18]. The calculated association constant, for (13), was in good agreement with the experimental value, log10 = 5.6 [18]: Structure 6(H2O)2, which models the mode of attachment of Cu(II) to His13His14, has the two Im groups in the trans-positions of a distorted square plane. The backbone amide carbonyl oxygen and a water molecule occupy the other two opposing sites. A second water occupies the apical site of the square pyramid. The trans-orientation of the two Im groups is the favored mode of attachment as seen in trans-Cu(Im)2(H2O)3 (Figure 1). It has been argued that the copper does not attach to a HisHis sequence through the Nδ atoms in a trans-arrangement as in 6(H2O)2, but rather through the Nε atoms in a cis-arrangement [1]. The latter is the configuration seen in the crystal structure of bis(cyclo-L-histidyl-L-histidyl)copper(II), the cyclic anhydride of histidine [45]. In this compound, Cu2+ chelates to the Nε atom of the imidazole rings in a cis-arrangement. In the present system, the most stable structure in which Cu(II) is attached to 5 with the cis coordination pattern, is (H2O)3 (Tables S1 and S2)). Structure (H2O)3 is predicted to be less stable relative to 6(H2O)2 + H2O by 36 kJ mol−1. The constraint imposed by the framework of the cyclic anhydride of histidine does not permit bridging of the copper ion through one or both Nδ atoms of the Im groups. In 5, or in monomeric Aβ, there are no such constraints. We also found structures, (H2O)2 and (H2O)2 (Tables S1 and S2)), in which coordination is through one Nδ and one Nε nitrogen of 5. These also have the cis orientation and are even less stable, 46 and 51 kJ mol−1 (data in Table S2). We do not consider these structures to be relevant to the chemistry of Cu/Aβ in Alzheimer’s disease and do not discuss them further.
Species 6(H2O)2 may add an additional Im residue yielding, 6(Im)(H2O). The results are presented in: The remaining water is in an axial orientation with a long Cu-O separation, 2.40 Å. Exchange of the water by an O of an amide carbonyl group (of NMA = N-methylacetamide) yields 7 (Figure 3). In 7, the two carbonyl groups occupy equivalent positions in the equatorial plane of a trigonal bipyramidal configuration about the Cu(II) ion. Attempts to optimize square planar structures with the O of His13 or NMA in an axial position converged to similar trigonal bipyramidal structures. The reaction is described in: Reaction (15) is moderately exergonic in water, indicating that the Cu(II) environment could consist of the three His residues and an additional carbonyl group. In the context of Cu/Aβ, the experimental results of Barnham and coworkers [12], and the theoretical modeling of Sodupe and coworkers [14], on Cu(II)/Aβ(1-16), the obvious candidate for the additional carbonyl O is Ala2. We note however that displacement of water by NMA is strongly endothermic in the gaseous phase, kJ mol−1 (Table 1). This is a consequence of the steric crowding about the Cu(II) site that forces the unusual trigonal bipyramidal geometry. The exergonicity of reaction (15) in water ensues from an even larger favorable change in the free energy of solvation, = −84 kJ mol−1 (Table 1). Solvation was also found to favor the coordination of the O of Ala2 in the work of Sodupe and coworkers [14].
4.4. Interaction of Cu2+/Asp1Complex, 2a(H2O), with His13His14 5
The most stable structures corresponding to the 1 : 1 : 1 complex between Cu2+(aq), Asp1, and His13His14 (5), namely, 8a and 8b, are shown in Figure 2. The more stable of the two, 8a, has a square pyramidal coordination sphere about the copper, with bidentate coordination of the –NH2 and – groups of the Asp in the basal square. One of the Im groups (formally of His13) and the backbone amide carbonyl group of 5 form the other two corners. The other Im group (formally of His14) has moved into the apical site. The second structure, 8b, which is less stable by 18 kJ mol−1, has the same square pyramidal 3N1O basal configuration as 8a, but the apical Im group has released. Possible routes for the formation of the more stable isomer 8a are examined in:where has been adjusted to pH = 7. The negative free energy change of (16b), = −15 kJ mol−1, indicates that if the cupric ion was already attached to 2a(H2O)2, that is, the N-terminus, it can also associate with 5, that is, His13His14. However, the small positive value, = +3 kJ mol−1, indicates that 8a would be partially dissociated, releasing the N-terminal Asp. Equation (17a) addresses the question of whether the N-terminus can be coordinated if there are already three His residues coordinated to the copper ion. Such a structure, 9, is shown in Figure 3:where and have been adjusted to pH = 7. The moderately high value, kJ mol−1, indicates that simultaneous attachment of all four potential ligands to Cu(II), the N-terminal Asp and the three histidines, is not likely at physiological pH. Equations (17b) and (17c) indicate that such an arrangement would be unstable with respect to loss of one histidine but not two.
In the context of Aβ, the overall picture that emerges from the above considerations is that the N-terminus and all three His residues may not be simultaneously associated with the cupric ion. However, such a structure could be a transitional form connecting more stable structures in which the Cu2+(aq) is attached to His6, His13, and His14 (6(Im)(H2O) or 7) (Figure 3) or to the N-terminus and two of the three His residues, His6 and His13, or His6 and His14 (both modeled by 2a(Im)2) (Figure 1) but not His13 and His14 (8a is unstable by (16a)) (Figure 3). Thus, structure 2a(Im)2, with 3N1O equatorial coordination to Cu(II), serves as a model for Components Ia and Ib. In each case the equatorial O ligand is one of the carboxylate O atoms of Asp1. Structures 6(Im)(H2O) or 7 serve as models for Component II. 6(Im)(H2O) has the observed 3N1O coordination pattern. Structure 7 is preferred because it is more stable, but it formally has a 3N2O coordination pattern in a trigonal bipyramid. The computed results for Cu(II) species agree in most respects with experimental expectations, except possibly for the nature of the O ligand, which would be the carbonyl O atom of His13 if 6(Im)(H2O) proves to be the better model for Component II. However, favoring 7 in this respect also is the experimental [12] and other computational [14] evidence that the “O” should be the O atom of Ala2 provided the approximately equivalent equatorial O atoms of the trigonal bipyramidal geometry would manifest as 3N1O coordination in EPR experiments. Attempts on our part to completely displace the O of His13 in Cu(II) complexes by any other ligand always failed.
If Component I is modeled by 2a(Im)2 and Component II is modeled by 7, what then is the nature of the pH dependence that shifts the equilibrium from one to the other in the narrow physiological pH range? We suggest that, since the p of His residues is in this range, one or more of the His residues would be protonated. The presence of the Cu2+ ion sets up a delicate balance: in Component I, either His13 or His14 is protonated, permitting the other to bind to the copper together with His6 and Asp1 (but not Ala2); at a slightly higher pH, the remaining His is deprotonated and all three can bind to the copper, displacing Asp1 but leaving the nearby O of Ala2 attached.
5. Interaction of Cu+(aq) with the N-Terminal Asp1 1
The most stable form of the aqueous cuprous ion at the present theoretical level is the T-shaped triaqua structure, Cu(H2O)3+ (Figure 4), Reaction with Asp1 1 yielded several aquated structures with different patterns of chelation. The most stable of these is the 1 : 1 Cu(I) : Asp1 complex, (H2O) (Figure 4, see the following equation): where has been adjusted to pH = 7. We denote structures containing the cuprous ion by the superscript I on the structure number of the Cu(II) equivalent. As with and , the cuprous form of a complex will generally have fewer ligands than the equivalent cupric form. Some or all of the attached H2O will be lost upon reduction of the copper. If there is no attached water, then one or more of the coordinated ligands will be released upon reduction. The structures of all complexes containing Cu(I) are shown in Figure 4.
Figure 4: Stable structures with Cu(I). Ball colors: Cu = large yellow; C = orange; N = blue; O = red; H = white.
The small endergonic free energy change for reaction (18) in water, kJ mol−1 at pH = 7, suggests that there is a small amount of 1 : 1 complex formed between Cu+(aq) and Asp1 under physiological conditions. We examine whether complexation of Asp1 is feasible if the cuprous ion is already attached to one or more imidazoles. The reactions for the 1 : 1 complex between Cu+(aq) and Im, Cu(Im)(H2O)+, is given in: Thus, Cu(Im)(H2O)+ is stable in water and the free energy of complexation is higher than for the equivalent Cu(II) complex (7a). The following reactions explore the addition of a second imidazole group to Cu(Im)(H2O)+, either as free Im or as His13 or His14 of 5, yielding products (20a), Cu(Im)(H13H14)+ (20b), and Cu(Im)(H14H13)+ (20c), respectively:Thus, addition of His14 of 5 is approximately equivalent energetically to the addition of a free Im group and both are more exergonic than addition of a single Im (19). Addition of His13 (20b) is more exergonic still due to a higher free energy of solvation (Table 1) which ensues as a consequence of the higher dipole moment of Cu(Im)(H13H14)+, μ = 15.4 D compared to μ = 13.2 D for Cu(Im)(H14H13)+.
Both 1 : 1 : 1 and 1 : 1 : 2 complexes between Cu(I), Asp1 1, and Im, namely, and (Im)2 (Figure 4), are stable in the gaseous phase. Formation of the 1 : 1 : 1 complex, (Im) (Figure 4), is essentially isoergonic at pH = 7 if one Im is already attached to Cu(I): where has been adjusted to pH = 7. Addition of a second Im to form the 1 : 1 : 2 complex, (Im)2 (Figure 4), is endergonic, kJ mol−1: Because of the high affinity of Cu(I) for two imidazoles, addition of Asp1 1 to the bis(imidazole)Cu(I) complex will not occur: where has been adjusted to pH = 7. On the basis of this result, we have not attempted to add Asp1 to Cu(Im)(H13H14)+ or Cu(Im)(H14H12)+.
5.1. Interaction of Cu+ and/Asp1 1, with His13His14 5
Cu(I) binds to the HisHis region 5 yielding the 1 : 1 complex, (Figure 4), with high affinity, Coordination of additional waters to is endergonic, for example, ΔG ≥ 15 kJ mol−1 for the addition of one water (data not shown). The calculated affinity constant, log10K(23) = 12.7, is in very good agreement with that found for the Cu(I)/Aβ(1-16) complex, log10 [24]. The value is substantially higher than for the addition of two free imidazoles to Cu+(aq) (20a), or a free Im and one of the two imidazoles of 5 ((20b) and (20c)), thus highlighting the importance of chelation. It is also higher than for the addition of Cu2+(aq) to HisHis (13). The calculations clearly confirm [30] that Cu(I) will bind more strongly than Cu(II) to Aβ and that the preferred site of binding of Cu(I) is His13His14. The linear geometry and a Cu-N distance of 1.877 Å in Cu(I)/Aβ(1-40) was deduced from fitted EXAFS data by Shearer and Szalai [23]. Our calculated value for , 1.894 Å, is in good agreement.
Addition of Asp1 1 to the linear Cu(I)/HisHis complex, , in the gaseous phase yields two stable structures, and (Figure 4), of equal energy in water. However, the formation of either by addition of Asp1 1 to in water is highly endergonic ((25a) and (25b)) due to the high stability of :where and have been adjusted to pH = 7. Equations (16a), (16b), and (17a) indicate that the N-terminus will be weakly associated with Cu(II) complexes of two of the His residues. However, upon reduction of the copper to Cu(I), the N-terminus will be released leaving only the linear Cu(I)/HisHis structure. Equation (15) indicates that an amide carbonyl will be weakly associated with Cu(II) complexes of all three His residues. Equation (26) examines whether the carbonyl would remain attached to the reduced copper species, : The complex with NMA (N-methylacetamide), (Figure 3), is strongly bound in the gaseous phase, kJ mol−1, but is formed endergonically in water due to a combination of loss of solvation free energy and an unfavorable entropic term (Table 1). Addition of Im to to yield (Im) (Figure 4) is slightly endergonic, As with NMA, the addition reaction is endergonic principally by virtue of loss of free energy of solvation, but also in part due to the unfavorable change in entropy (Table 1).
In the context of a reduced copper/Aβ complex, there is ample experimental evidence that Cu(I) is bound to His13His14 precisely as depicted in , in a linear fashion through the Nδ of both Im groups (Figure 4) [21, 22, 46]. All other ligands, including the third Im, are released upon reduction. The Im (His6) is tethered to the Cu(I) binding region at His13His14, and the loss of entropy may be less, reducing the endergonicity of (27). There is experimental evidence that a third Im can associate transiently with Cu(I)/Aβ [26].
6. Reduction Potentials for Cu(II) Complexes with the N-Terminal Asp1 1
Computed reduction potentials for various combinations of Cu(II)/Aβ and Cu(I)/Aβ coordination patterns, when compared with the experimental value for Cu/Aβ, V–0.34 V, [28, 29, 47] may serve to distinguish among the different possibilities that have been suggested in the literature and discussed in the Introduction. Since all experimental indications suggest that Aβ and Cu/Aβ are highly fluxional species, the most stable structures should be most populated. We assume that electrochemical reduction is an equilibrium process. Logically then, reduction of the (predicted) most stable Cu(II) species, yielding the most stable Cu(I) species, should yield the most representative value of or . As a second point of reference, the experimental value for the reduction of aqueous cupric ion is (Cu2+(aq)/Cu+(aq)) = 0.17 V [41]. We now examine possible redox scenarios in the Cu/Aβ context.
Equation (28) describes the reduction process if the copper was attached only to the N-terminal Asp1: The calculated standard reduction potential (2a(H2O)2/) = −0.07 V, is lower than the value for aqueous copper. Therefore, Cu(II) cannot be attached only to the N-terminus since the lower is incompatible with the experimental observation that the reduction potential is elevated. A lower value is expected since a negatively charged group is attached to the Cu(II), thereby lowering the net charge of the oxidized species.
Equation (29) describes reduction of copper attached in a 1 : 1 ratio to Asp1 and Im The Cu(II) species, 2a(Im)(H2O), was found to be stable in water ((8a) and (8b)), but the Cu(I) species, , had only transient stability (21): The result, (2a(Im)(H2O)/)) = −0.07 V, indicates that the presence of the Im moiety has little effect on the predicted reduction potential.
With respect to the possibility that Cu(II) may be coordinated to Asp1 and two of the Im moieties, the Cu(II) species, 2a(Im)2, was found to be stable at pH = 7 ((9a) and (9b)). Structure 2a(Im)2 corresponds to Component I, the low pH species, in which Cu(II) is attached to His6 and either His13 or His14 as well as the N-terminus. The corresponding reduced species, (Im)2 was found to release the Asp (23). Equations (30a) and (30b) describe the appropriate reduction process if the Cu(I) of Component I remains attached to the same two His residues: If, during the reduction process, the most stable Cu(I) product, , is formed, the process may be modeled by (31) in which His6 is retained or by (32) in which His6 is released: In summary, the reduction potentials of Cu(II) attached to the N-terminus and one or two independent His residues ((30a) and (30b)) in which the Cu(I) remains attached to the same two His residues are predicted to be slightly lower than the experimental value for Cu(II)/Aβ complexes, 0.30 V–0.34 V. However, if the Cu(I) rearranges to include both His13 and His14, with or without loss of His6 ((31) and (32), resp.), values are predicted to be close to the experimental value. Therefore, it is possible that Component I is the species that is observed to undergo reduction.
Component II, modeled by 6(Im)(H2O) or 7, does not involve the N-terminal Asp1. Reduction of either species in which Cu(II) is coordinated to His13His4 will yield the Cu(I)/HisHis species, , with the release of all other coordinating ligands. In the instance that Cu(II) is only attached to HisHis except for waters (33), an elevated value of is obtained: The high result confirms that 6(H2O)2 is also an incomplete description of the bonding in Cu(II)/Aβ. A more representative species is 6(Im)(H2O), which models all three His residues coordinated to Aβ with a coordinated water: The value (34) is close to but higher than the experimental range. The species, 6(Im)(H2O), has a coordinated water molecule which may be exchanged for another ligand. On the basis of the experimental finding that the O atom of Ala2 is in the Cu(II) coordination sphere of Component II, we consider here structure 7, in which the water is replaced by an amide carbonyl, using N-methylacetamide (NMA) as a model. The substrate, 7, is shown in Figure 3. The reduction of 7 is described in: The value (35) is substantially higher than the experimental range.
Thus, it appears that none of mechanisms that involve reduction and spontaneous loss of ligands provides a satisfactory description of the reduction process. Balland et al., have recently carried out a detailed study of the kinetics of the reduction/oxidation of Cu/Aβ(1-16) complexes by cyclic voltametry and homogeneous transfer from osmium complexes [47]. The electron transfer rate was found to be extremely slow and required a preorganization by 22 and 16 kJ mol−1 to geometries of the Cu(II) and Cu(I) species, respectively, between which the actual electron transfer takes place. In the present model systems, the preorganization of the oxidized species is to release the bound carbonyl oxygen, that is, the reverse of (15) for which = 20 kJ mol−1. The preorganization of the reduced species prior to oxidation is to gain the Im residue, that is, (27) for which kJ mol−1. Thus, in the Balland et al. scheme, the actual reduction is described by: The calculated reduction potential, (6(Im)(H2O)/(Im),H2O) = 0.31 V, is in excellent agreement with that measured by Balland et al., = 0.30 V, and the calculated free energy changes for the preorganization steps are also in good agreement.
7. Conclusions
High-level ab initio electronic structure calculations were applied to models of the N-terminus of Aβ, as well as Ala2, His6, and His13His14, to predict structures of the complexes of Cu(II) and Cu(I) in water at physiological pH. The calculated binding affinities of both Cu(II) and Cu(I) to the His13His14 model, log10 = 6.3 (13) and log10 = 12.7 (24), respectively, are in good agreement with experimental values, 5.6 [18] and 14 [24], respectively which lends confidence to other calculated free energy changes.
At the present level of theory, Cu(II) species are predicted to be pentacoordinated in a square pyramidal configuration. The one exception we found is in the case of 7 (Figure 3), the proposed model for Component II of Aβ. In 7, two carbonyl oxygen atoms, of Ala2 and His13, occupy nearly equivalent sites in the equatorial plane of a trigonal bipyramid. On the other hand, the predominant configuration at Cu(I) in water is linear dicoordination, with the exception of and the possible exception of Cu(I) with all three His residues attached (modeled by (Im) (Figure 4)) which are T-shaped structures.
It was found that Asp1 forms stable complexes with Cu(II) and two His residues, either the pair His6, His13, or the pair His6, His14, but not His13His14, both modeled by 2a(Im)2 (Figure 1). Complexes involving the deprotonated amide of Ala2 are substantially less stable. The complex, 2a(Im)2, represents the bonding configuration of Cu(II) in Component Ia and Component Ib of Aβ. Each has 3N1O square planar coordination with tridentate attachment of Asp1. The –NH2 and groups contribute one of the N ligands and the O ligand in the equatorial plane, while the carbonyl O of Asp1 occupies the axial position.
The N-terminus does not attach to Cu(II) if His6 and His13His14 are already attached. Structure 7 is the best candidate for Component II. The assignment of 7 as a model for Component II is in agreement with the findings of Barnham and coworkers [12]. Hureau and Faller and coworkers suggested that the amide NH of Ala2 is deprotonated at higher pH and proposed a structure for Component II that is modeled by 4(Im) (Figure 2) in our study [6, 7]. Our results suggest that the presence of the carboxylate group of Asp1 makes deprotonation of the amide group very improbable near physiological pH. Rather, we propose that deprotonation of a protonated His residue of either His13 or His14 facilitates the formation of Component II at the expense of Component I.
The binding configuration of Cu(I) to Aβ is modeled by (Figure 4). The Cu(I) is linearly dicoordinated to His13His14 through the Nδ nitrogen atoms of the imidazole groups. Weak coordination of His6, as in (Im), is possible in water as an endergonic process.
Our calculations support in full the redox scheme for Cu/Aβ(1-16) proposed by Balland et al., which requires preorganization steps for both oxidized and reduced species [47]. The sequence of steps for reduction is described by the reverse of (15) and (27), and (36), which we repeat here for clarity: The experimental values derived from the data of Balland et al. are given in square parentheses. The reoxidation occurs by the exact reverse sequence.
Acknowledgments
The work was supported by an Individual Discovery Grant from the Natural Sciences and Engineering Council of Canada (NSERC). Generous access to the computational facilities of WestGrid is gratefully acknowledged.
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Publication Listing
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• Title: Science Fiction Monthly, March 1974 (View All Issues) (View Issue Grid)
• Editors: Patricia Hornsey
• Year: 1974-03-00
• Publisher: New English Library
• Price: £0.25
• Pages: 28
• Binding: tabloid
• Type: MAGAZINE
• Title Reference: Science Fiction Monthly, 1974
• Cover: Ray Feibush
• ISFDB Record Number: 290835
• Notes: Volume 1, Number 3.
Note that _Swords of Mars_ is presented as by E. M. Clifton-Dey.
Note that Eddie Jones' illustration on page 6 is bizarely signed "FS 7 Antoni" (sic) but looks like Jones' work.
Whaites' essay is a cross between an essay and an interview.
Note that Mike Ashley is mispelled Michael Ashby on essay's title page but that primary verifier choose to use the canonical name.
• Bibliographic Comments: Add new Publication comment (SCNCFCTNMF1971)
Cover art hosted by ISFDB
Contents (view Concise Listing)
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Primary Verified by Hauck on 2011-03-27 01:01:45
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Copyright (c) 1995-2011 Al von Ruff.
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Bibliography: Not Fade Away
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Title: Not Fade Away
Author: Spider Robinson
Year: 1982
Type: SHORTFICTION
Storylen: shortstory
ISFDB Record Number: 42931
User Rating: This title has fewer than 5 votes. VOTE
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Copyright (c) 1995-2011 Al von Ruff.
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Genes 2012, 3(4), 615-633; doi:10.3390/genes3040615
Article
Assessment of Fecundity and Germ Line Transmission in Two Transgenic Pig Lines Produced by Sleeping Beauty Transposition
1 Friedrich-Loeffler-Institut, Institute of Farm Animal Genetics, Höltystraße 10, 31535 Neustadt, Germany 2 Paul-Ehrlich-Institute, Paul-Ehrlich-Straße 51-59, 63225 Langen, Germany
* Author to whom correspondence should be addressed.
Received: 9 August 2012; in revised form: 10 September 2012 / Accepted: 14 September 2012 / Published: 12 October 2012
(This article belongs to the Special Issue Transgenic Technology: Benefits or Dangers?)
Download PDF Full-Text [751 KB, uploaded 12 October 2012 09:32 CEST]
Abstract: Recently, we described a simplified injection method for producing transgenic pigs using a non-autonomous Sleeping Beauty transposon system. The founder animals showed ubiquitous expression of the Venus fluorophore in almost all cell types. To assess, whether expression of the reporter fluorophore affects animal welfare or fecundity, we analyzed reproductive parameters of two founder boars, germ line transmission, and organ and cell specific transgene expression in animals of the F1 and F2 generation. Molecular analysis of ejaculated sperm cells suggested three monomeric integrations of the Venus transposon in both founders. To test germ line transmission of the three monomeric transposon integrations, wild-type sows were artificially inseminated. The offspring were nursed to sexual maturity and hemizygous lines were established. A clear segregation of the monomeric transposons following the Mendelian rules was observed in the F1 and F2 offspring. Apparently, almost all somatic cells, as well as oocytes and spermatozoa, expressed the Venus fluorophore at cell-type specific levels. No detrimental effects of Venus expression on animal health or fecundity were found. Importantly, all hemizygous lines expressed the fluorophore in comparable levels, and no case of transgene silencing or variegated expression was found after germ line transmission, suggesting that the insertions occurred at transcriptionally permissive loci. The results show that Sleeping Beauty transposase-catalyzed transposition is a promising approach for stable genetic modification of the pig genome.
Keywords: transgenic animal; germ line transmission; active transgenesis; hyperactive transposase; humanized pig model; livestock, cytoplasmic plasmid injection; gene silencing; permissive locus
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Cite This Article
MDPI and ACS Style
Garrels, W.; Holler, S.; Cleve, N.; Niemann, H.; Ivics, Z.; Kues, W.A. Assessment of Fecundity and Germ Line Transmission in Two Transgenic Pig Lines Produced by Sleeping Beauty Transposition. Genes 2012, 3, 615-633.
AMA Style
Garrels W, Holler S, Cleve N, Niemann H, Ivics Z, Kues WA. Assessment of Fecundity and Germ Line Transmission in Two Transgenic Pig Lines Produced by Sleeping Beauty Transposition. Genes. 2012; 3(4):615-633.
Chicago/Turabian Style
Garrels, Wiebke; Holler, Stephanie; Cleve, Nicole; Niemann, Heiner; Ivics, Zoltan; Kues, Wilfried A. 2012. "Assessment of Fecundity and Germ Line Transmission in Two Transgenic Pig Lines Produced by Sleeping Beauty Transposition." Genes 3, no. 4: 615-633.
Genes EISSN 2073-4425 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
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And they say that Osiris, when he was king of Egypt, drew them off from a beggarly and bestial way of living, by showing them the use of grain, and by making them laws, and teaching them to honor the Gods; and that afterwards he travelled all the world over, and made it civil, having but little need of arms, for he drew the most to him, alluring them by persuasion and oratory, intermixed with all sorts of poetry and music; whence it is that the Greeks look upon him as the very same with Bacchus. They further add that Typhon, while he was from home, [p. 76] attempted nothing against him; for Isis was very watchful, and guarded him closely from harm. But when he came home, he formed a plot against him, taking seventy-two men for accomplices of his conspiracy, and being also abetted by a certain Queen of Ethiopia, whose name they say was Aso. Having therefore privately taken the measure of Osiris's body, and framed a curious ark, very finely beautified and just of the size of his body, he brought it to a certain banquet. And as all were wonderfully delighted with so rare a sight and admired it greatly, Typhon in a sporting manner promised that whichsoever of the company should by lying in it find it to be of the size of his body, should have it for a present. And as every one of them was forward to try, and none fitted it, Osiris at last got into it himself, and lay along in it; whereupon they that were there present immediately ran to it, and clapped down the cover upon it, and when they had fastened it down with nails, and soldered it with melted lead, they carried it forth to the river side, and let it swim into the sea at the Tanaitic mouth, which the Egyptians therefore to this day detest, and abominate the very naming of it. These things happened (as they say) upon the seventeenth of the month Athyr, when the sun enters into the Scorpion, and that was upon the eight and twentieth year of the reign of Osiris. But there are some that say that was the time of his life, and not of his reign.
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This work is licensed under a Creative Commons Attribution-ShareAlike 3.0 United States License.
An XML version of this text is available for download, with the additional restriction that you offer Perseus any modifications you make. Perseus provides credit for all accepted changes, storing new additions in a versioning system.
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1answer
98 views
How and how much does it cost to I register my startup logo (International)
This may sound as a duplicate of other questions, but the enphasis is International. I've found it neccesary to have a logo at the stage of looking for VC's, among other things. But currently I do ...
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Constraints to Integrated and Non – Integrated Fish Farming Activities in Ogun State, Nigeria
B. G. Abiona, E. O Fakoya, W.O. Alegbeleye, E.O. Fapojuwo, S.O S.O Adeogun, A. A. Idowu, A.K. Aromolaran
Abstract
The study examined constraints to integrated and non- integrated fish farming activities in Ogun State, Nigeria. Random sampling techniques was used to select 133 non - integrated fish farmers (NIFF) and 216 integrated fish farmers (IFF) (n = 349) from the study area. Data were analysed using chi-square and Pearson Product moment correlation. Results showed that 92.5% of NIFF was male compared to IFF (90.7%). Also, 96.8% of IFF and 79.7% of NIFF were married. The mean ages of sampled farmers were 44 years (NIFF) and 46 years (IFF) while the mean fish farming experiences were 4 years (NIFF) and 5 years (IFF). However, respondents’ major constraints to fish farming were exploitation by middlemen (88.9%), price fluctuation (92.8%), inadequate capital (87.9%) and epileptic power supply (77.4%). The chi-square analyses showed that knowledge of fish farming had significant association with respondents sex (?2 = 9.44, df = 2, p = 0.00), occupation (?2 = 25.5, df = 8, p = 0.01), Pearson correlation analyses showed significant relationship between farmers knowledge and age (r = 0.20, p = 0.00), fish farming experience (r = 0.17, p = 0.00), level of cosmopoliteness (r = 0.16, p = 0.00) and production constraints (r = -0.00, p = 0.00).
Full Text: PDF
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Journal of Agricultural Science ISSN 1916-9752 (Print) ISSN 1916-9760 (Online)
Copyright © Canadian Center of Science and Education
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Connexions
Sections
You are here: Home » Content » Water Pollution
About: Water Pollution
Module by: Steve Altaner. E-mail the author
View the content: Water Pollution
Metadata
Name: Water Pollution
ID: m41441
Language: English (en)
Summary: In this module, the following topics will be covered: 1) water pollutants and how they degrade water quality, 2) the lack of safe drinking water in some parts of the world , 3) sewage treatment 4) the difficult process to remediate groundwater pollution, and 5) solutions for the crisis involving water pollution
Subject: Science and Technology
Keywords: Arsenic, Biochemical oxygen demand, Bioremediation, Bottled water, Combined sewer systems, Constructed wetland, Contaminant plume, Cultural eutrophication, Excessive plant nutrient, Hard water, Heat, Heavy metal, Hypoxia, Mercury, Nonpoint source (of water pollution), Oil spill, Oxygen-demanding waste, Pathogens, Persistent organic pollutant, Point source (of water pollution), Sediment, Septic tank system, Sewage treatment plant, Sludge, Solvent, Total dissolved solids, Toxic chemical, Underground fuel storage tank, Water pollution
License: Creative Commons Attribution License CC-BY 3.0
Authors: Steve Altaner (tgilles@uillinois.edu)
Copyright Holders: U of I Open Source Textbook Initiative (tgilles@uillinois.edu)
Maintainers: U of I Open Source Textbook Initiative (tgilles@uillinois.edu)
Latest version: 1.7 (history)
First publication date: Oct 19, 2011 6:51 pm -0500
Last revision to module: Mar 23, 2012 11:20 pm -0500
Downloads
PDF: m41441_1.7.pdf PDF file, for viewing content offline and printing. Learn more.
EPUB: m41441_1.7.epub Electronic publication file, for viewing in handheld devices. Learn more.
XML: m41441_1.7.cnxml XML that defines the structure and contents of the module, minus any included media files. Can be reimported in the editing interface. Learn more.
Source Export ZIP: m41441_1.7.zip ZIP containing the module XML plus any included media files. Can be reimported in the editing interface. Learn more.
Version History
Version: 1.7 Mar 23, 2012 11:20 pm -0500 by U of I Open Source Textbook Initiative
Changes:
1) Fix links to Figures, 2) Fix printed size of images (MWL)
Version: 1.6 Mar 21, 2012 10:52 pm -0500 by U of I Open Source Textbook Initiative
Changes:
1) Bold Module title in "The Module Water Cycle and Fresh Water Supply (Section 5.2) described one aspect" 2) AND As discussed in Module Climate Processes; External and Internal Controls (Section 3.2) 3) fix capitalization of glossary terms. (MWL)
Version: 1.5 Jan 18, 2012 8:39 am -0600 by U of I Open Source Textbook Initiative
Changes:
Add Google Analytics tracking code
Version: 1.4 Jan 16, 2012 3:11 pm -0600 by U of I Open Source Textbook Initiative
Changes:
add summary and key terms; Remove number from title; fix headings; Remove numbers from Figure Captions; bold "Figure" in content. (mwl)
Version: 1.3 Nov 15, 2011 2:44 pm -0600 by U of I Open Source Textbook Initiative
Changes:
fixed Aquatic Dead Zones image (mwl)
Version: 1.2 Oct 31, 2011 10:43 am -0500 by U of I Open Source Textbook Initiative
Changes:
added Altaner as author (mwl)
Version: 1.1 Oct 24, 2011 4:07 pm -0500 by U of I Open Source Textbook Initiative
Changes:
Created module (mwl)
How to Reuse and Attribute This Content
If you derive a copy of this content using a Connexions account and publish your version, proper attribution of the original work will be automatically done for you.
If you reuse this work elsewhere, in order to comply with the attribution requirements of the license (CC-BY 3.0), you must include
• the authors' names: Steve Altaner
• the title of the work: Water Pollution
• the Connexions URL where the work can be found: http://cnx.org/content/m41441/1.7/
See the citation section below for examples you can copy.
How to Cite and Attribute This Content
The following citation styles comply with the attribution requirements for the license (CC-BY 3.0) of this work:
American Chemical Society (ACS) Style Guide:
Altaner, S. Water Pollution, Connexions Web site. http://cnx.org/content/m41441/1.7/, Mar 23, 2012.
American Medical Assocation (AMA) Manual of Style:
Altaner S. Water Pollution [Connexions Web site]. March 23, 2012. Available at: http://cnx.org/content/m41441/1.7/.
American Psychological Assocation (APA) Publication Manual:
Altaner, S. (2012, March 23). Water Pollution. Retrieved from the Connexions Web site: http://cnx.org/content/m41441/1.7/
Chicago Manual of Style (Bibliography):
Altaner, Steve. "Water Pollution." Connexions. March 23, 2012. http://cnx.org/content/m41441/1.7/.
Chicago Manual of Style (Note):
Steve Altaner, "Water Pollution," Connexions, March 23, 2012, http://cnx.org/content/m41441/1.7/.
Chicago Manual of Style (Reference, in Author-Date style):
Altaner, S. 2012. Water Pollution. Connexions, March 23, 2012. http://cnx.org/content/m41441/1.7/.
Modern Languages Association (MLA) Style Manual:
Altaner, Steve. Water Pollution. Connexions. 23 Mar. 2012 <http://cnx.org/content/m41441/1.7/>.
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Information for "Didj MP3 Streaming"
Jump to: navigation, search
Basic information
Display titleDidj MP3 Streaming
Default sort keyDidj MP3 Streaming
Page length (in bytes)2,851
Page ID4867
Page content languageEnglish (en)
Search engine statusIndexable
Number of views3,331
Redirects to this page0
Counted as a content pageYes
Page protection
EditAllow all users
MoveAllow all users
Edit history
Page creatorNirvous (Talk | contribs)
Date of page creation20:49, 23 April 2010
Latest editorReggie (Talk | contribs)
Date of latest edit16:52, 14 July 2011
Total number of edits10
Total number of distinct authors4
Recent number of edits (within past 91 days)0
Recent number of distinct authors0
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Maryland NewspapersEdit This Page
From FamilySearch Wiki
Revision as of 20:36, 28 July 2011 by Larry0011 (Talk | contribs)
United States U.S. Newspapers Maryland Newspapers
Contents
History
Newspaper publication in Maryland began in 1727 with the release of the Maryland Gazette in Annapolis.
Resources for Maryland Newspapers
Libraries and Archives
The following libraries have Maryland newspaper collections on site.
Digital Issues Online
Wikipedia has more about this subject: List of online newspaper archives
Historical newspapers
• NewspaperArchive.com ($) has a large collection of Maryland newspapers online. This database is free at some libraries. It may be under the name Access NewspaperArchive.
• Ancestry.com ($) has over 20 historical Maryland newspapers.
• University of Pennsylvania (free) has links to a handful of free historical Maryland newspapers online.
Current newspapers
Indexes
• Barnes, Robert W. Gleanings from Maryland Newspapers. Four Volumes. Lutherville, Maryland: Bettie Carothers, 1975-76. (ISBN: none) (OCLC;8196057) (FHL book 975.2 V2ba v. 2; film 928166 item 7) This work covers 1727 to 1795.
• Barnes, Robert W. Marriages and Deaths from the Maryland Gazette, 1727-1839. Baltimore, Maryland: Genealogical Publishing Company, 1973. (ISBN 0806305800) (ISBN 0806305800);(OCLC;28916982) (FHL book 975.2 V2b)
• Green, Karen Mauer. The Maryland Gazette, 1727- 1761: Genealogical and Historical Abstracts. Galveston, Texas: Frontier, 1989. (ISBN 0932231071); (FHL book 975.2 D2g)
Guides
Family History Library
To locate newspapers in the Family History Library's collection which pertain to a large part of Maryland, click here The Family History Library is not actively collecting newspapers of the United States.[1]
.
Web Sites
Reference
1. Telephone interview of Ken Nelson by Michael Ritchey. Salt Lake City, 8 December 2008. Ken is a member of the Family History Library's Collection Management team. He said that although the library would not turn down a free microfilm of a U.S. newspaper, newspaper collections are not currently part of the acquisition profile for U.S. places, and haven't been for some years.
Need additional research help? Contact our research help specialists.
Need wiki, indexing, or website help? Contact our product teams.
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GlobalVoices in Learn more »
Iran: Netizens Reflect on Four More Years for Obama
This post also available in:
Malagasy · Iran: Fakafaka Ataon'ny Mpiserasera Momba ny Efa-taona Fanampiny Ho an'i Obama
Français · Iran : Paroles d'internautes sur l'élection d'Obama
Español · Irán: Internautas opinan sobre los "cuatro años más" para Obama
Originally published at Arseh Sevom by Peyman Majidzadeh
The confetti has settled and the US elections are quickly fading into the background. Americans voted for President Barack Obama on Tuesday November 6, 2012 sealing his re-election. In the most expensive election campaign in the history of United States, as the Center for Responsive Politics [en] reported, Obama won 332 electoral votes against 206 of the same for Romney. Although only American citizens were eligible to vote, people around the world followed the results closely. With Iran featuring as one of the main topics of US foreign policy, it's no surprise that Iranians took a great interest in the election. The majority of Iranians wanted Obama to win to avoid what they saw as a probable war, despite the fact that many see the crippling economic sanctions as no less than a silent war against ordinary people in Iran.
There was a lot of discussion on Facebook among Iranians. Among the many Iranians who closely followed the elections results, Soroush posted [en]:
“The world moved a step farther from insanity of war, I hope.”
In another status update, he posted a map of the results with the following caption:
“I strongly believe this was a milestone in the history of Iran, too. Future will show us how!”
In response to one of the commenters professing a preference for Romney due to unbearable inflation and the skyrocketing cost of living in Iran, Soroush replied [fa]:
“I would rather pay double for electricity than not have it at all. I highly doubt that after a probable war Iran would be any better off than Afghanistan (which is beyond imagination). Eight years of war was enough for me. In fact, it was more than enough. There is at least hope now [for no war]…”
Ali Abdi posted a note on his Facebook [fa] prior to elections saying:
“Neither Obama nor Romney are appropriate candidates for the Iranian people. Both are in favor of the crippling sanctions against the Iranian people and allies of the apartheid government in Israel at the cost of harming Iranians… Obama has a relatively better understanding of the history and the political, social, cultural, and geographical situation of Iran and our region. He is against an attack by Israel on Iran and less likely to initiate a military attack against Iran. He is not the best choice but the only one that can be elected with the least harm for Iranians. I do not have a right to vote in this country, but if I did and resided in one of the swing states, I would have voted for Barack Hussein Obama.”
Ahmad republished a headline from Al-Alam on his blog [fa], writing that the possibility of a military attack against Iran or Syria is close to zero now. Referring to Obama’s foreign policy in the second term he writes:
“There won’t be any war against Iran.”
In a post called “The Victory of Barack Obama and its Effects on Iranian Society”, Inspiration from within [fa] recalled the results of a poll done in 2009 and highlighted that according to that poll, only 15% of Iranians could differentiate between Bush and Obama. The author writes:
“After Obama’s victory, implicit congratulatory messages could be found on various websites.”
He then asked what had changed in political understanding over the past four years.
Nargess congratulated Obama by reposting a part of his acceptance speech on her blog:
” … I believe we can keep the promise of our founders, the idea that if you're willing to work hard, it doesn't matter who you are or where you come from or what you look like or where you love. It doesn't matter whether you're black or white or Hispanic or Asian or Native American or young or old or rich or poor, able, disabled, gay or straight, you can make it here in America if you're willing to try…”
World regions
Countries
Languages
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[maemo-developers] What's wrong with folder browsing?
From: Laurent GUERBY laurent at guerby.net
Date: Sun May 20 22:03:31 EEST 2007
On Sun, 2007-05-20 at 20:45 +0300, Daniel Stone wrote:
> On Sun, May 20, 2007 at 04:25:04PM +0200, ext Laurent GUERBY wrote:
> > Folder approach is intuitive, shared by all reasonable apps on all
> > platforms
>
> Except for more or less every media player ever made (cf. iTunes).
Amarok is frequently cited as a free software iTunes equivalent and it
works *exactly* as I describe: if you want it to index you can choose
what folder(s) to index, if you don't want to index you just use "open"
and it works just like any UI standard conforming software.
Intuitive, reactive and powerful.
It's quite easy to find people complaining about iTunes being
a ressource hog and taking forever to scan stuff.
However biased it is, google "itunes amarok".
And I still can't honestly believe that the developpers of media
software want to tell their user: oh you have a 2GB card fully
of media and you want to play it on your N800? No problem! Insert
it then .... please wait two hours ... and no sorry you can't use your
N800 because it's dog slow ... then there you go! How great and easy!
Spot the problem.
Laurent
More information about the maemo-developers mailing list
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Alm:Protoplasting
From OpenWetWare
(Difference between revisions)
Jump to: navigation, search
(Strip outer membrane)
(Permeabilize cell wall)
Line 49: Line 49:
===Permeabilize cell wall===
===Permeabilize cell wall===
-
#Step 1
+
#Pellet, rinse with SMM, resuspend in SMM + lysozyme
-
#Step 2
+
#Shake and incubate
-
#*Step 2 has some additional information that goes with it. i.e. Keep at 4°C.
+
*No current step to stop lysozyme
-
#Step 3
+
*Should have protoplasts now
-
##Step 3 has multiple sub-steps within it.
+
-
##Enumerate each of those.
+
===Optional: Fuse protoplasts===
===Optional: Fuse protoplasts===
Revision as of 16:22, 2 April 2007
Contents
Materials for 1 round
• sucrose, 0.5M
• SMM, divided
• SMM + lysozyme
Regeneration:
soft agar (0.8%) plates containing
In some cases, protoplasts were resus- pended in LB medium containing 0.5 M sucrose and spread onto soft agar plates containing LB medium and 0.5 M sucrose with autoclaved plastic spreaders. The plates were subsequently incubated at either 25 or 37 1C.
In other cases, the protoplasts were diluted into molten soft agar at 45 1C containing either LB medium and 0.5 M sucrose or M9 medium, 0.5 M sucrose, and either Leu (100 mg/ml) or Arg (100 mg/ml), depending on the nutritional requirements of the auxotrophic strains used, and then poured onto soft agar plates of the same composition.
Overview
Replace this sentence with a brief description of the protocol and its goal.
Materials
List reagents, supplies and equipment necessary to perform the protocol here. For those materials which have their own OWW pages, link to that page. Alternatively, links to the suppliers' page on that material are also appropriate.
• supply 1 (i.e. tubes of a certain size? spreaders?)
• reagent 1
• X μL reagent 2
• component A (reagent 2 is made up of multiple components)
• component B
• equipment 1
• equipment 2
Procedure
Strip outer membrane
1. Pellet cells
2. Pour off supernatant
3. Resuspend in Tris-HCl
4. Add EDTA slowly
5. Shake
6. Pellet and rinse
Permeabilize cell wall
1. Pellet, rinse with SMM, resuspend in SMM + lysozyme
2. Shake and incubate
• No current step to stop lysozyme
• Should have protoplasts now
Optional: Fuse protoplasts
1. Mix aliquots of protoplasts of each parent strain
2. Add PEG
3. Step 3
Regenerate protoplasts
1. Step 1
2. Step 2
• Step 2 has some additional information that goes with it. i.e. Keep at 4°C.
3. Step 3
1. Step 3 has multiple sub-steps within it.
2. Enumerate each of those.
Notes
1. List troubleshooting tips here.
2. You can also link to FAQs/tips provided by other sources such as the manufacturer or other websites.
3. Anecdotal observations that might be of use to others can also be posted here.
Please sign your name to your note by adding '''*~~~~''': to the beginning of your tip.
References
Relevant papers and books
1. [--]
2. Goldbeter A and Koshland DE Jr. . pmid:6947258. PubMed HubMed [Goldbeter-PNAS-1981]
3. JACOB F and MONOD J. . pmid:13718526. PubMed HubMed [Jacob-JMB-1961]
4. Mark Ptashne. A genetic switch. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press, 2004. isbn:0879697164. [Ptashne-Genetic-Switch]
All Medline abstracts: PubMed HubMed
Contact
or instead, discuss this protocol.
Personal tools
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User:Shayan Doroudi
From OpenWetWare
Revision as of 13:26, 16 June 2011 by Shayan Doroudi (Talk | contribs)
(diff) ←Older revision | Current revision (diff) | Newer revision→ (diff)
Jump to: navigation, search
I am a new member of OpenWetWare!
Contents
Contact Info
Shayan Doroudi (an artistic interpretation)
I work in the Your Lab at XYZ University. I learned about OpenWetWare from BIOMOD, and I've joined because I want to edit the Caltech BIOMOD page..
Education
• Year, PhD, Institute
• Year, MS, Institute
• Year, BS, Institute
Research interests
1. Interest 1
2. Interest 2
3. Interest 3
Publications
1. Goldbeter A and Koshland DE Jr. . pmid:6947258. PubMed HubMed [Paper1]
2. JACOB F and MONOD J. . pmid:13718526. PubMed HubMed [Paper2]
leave a comment about a paper here
3. Mark Ptashne. A genetic switch. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press, 2004. isbn:0879697164. [Book1]
All Medline abstracts: PubMed HubMed
Useful links
Personal tools
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eye55's bookmarks
"There is nothing so disobedient as an undisciplined mind, and there is nothing so obedient as a disciplined mind."
Buddha on mind
5 fans of this quote
"You yourself, as much as anybody in the entire universe, deserve your love and affection."
Buddha on war
11 fans of this quote
"Money is the most egalitarian force in society. It confers power on whoever holds it."
Starr, Roger on money
"In the domain of Political Economy, free scientific inquiry meets not merely the same enemies as in all other domains. The peculiar nature of the material it deals with, summons as foes into the field of battle the most violent, mean and malignant passions of the human breast, the Furies of private interest."
Marx, Karl on politics
"The human being is in the most literal sense a political animal, not merely a gregarious animal, but an animal which can individuate itself only in the midst of society."
Marx, Karl on politics
"The philosophers have only interpreted the world in various ways; the point, however, is to change it."
Marx, Karl on philosophers and philosophy
"All social rules and all relations between individuals are eroded by a cash economy, avarice drags Pluto himself out of the bowels of the earth."
Marx, Karl on money
"Machines were, it may be said, the weapon employed by the capitalists to quell the revolt of specialized labor."
Marx, Karl on machinery
"The history of all hitherto existing society is the history of class struggles."
Marx, Karl on history and historians
3 fans of this quote
"Religion is the opium of the masses."
Marx, Karl on religion
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"Religion is the sigh of the oppressed creature, the heart of a heartless world, and the soul of soulless conditions. It is the opium of the people."
Marx, Karl on religion
"In bourgeois society capital is independent and has individuality, while the living person is dependent and has no individuality."
Marx, Karl on individuality
"In a higher phase of communist society... only then can the narrow horizon of bourgeois right be fully left behind and society inscribe on its banners: from each according to his ability, to each according to his needs."
Marx, Karl on communism and socialism
"The production of too many useful things results in too many useless people."
Marx, Karl on unemployment
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"We should not say that one man's hour is worth another man's hour, but rather that one man during an hour is worth just as much as another man during an hour. Time is everything, man is nothing: he is at the most time's carcass."
Marx, Karl on time
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"Society does not consist of individuals but expresses the sum of interrelations, the relations within which these individuals stand."
Marx, Karl on society
"The product of mental labor -- science -- always stands far below its value, because the labor-time necessary to reproduce it has no relation at all to the labor-time required for its original production."
Marx, Karl on science
"The rich will do anything for the poor but get off their backs."
Marx, Karl on riches
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"Let the ruling classes tremble at a Communist revolution. The proletarians have nothing to lose, but their chains. .Workers of the world unite!"
Marx, Karl on evolution
"We should consider every day lost in which we have not danced at least once."
Nietzsche, Friedrich on dance and dancing
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"[Dancing is] A perpendicular expression of a horizontal desire."
Shaw, George Bernard on dance and dancing
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"Remember, Ginger Rogers did everything Fred Astaire did, but she did it backwards and in high heels."
Thaves, Bob on dance and dancing
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"Never shall I forget the time I spent with you. Please continue to be my friend, as you will always find me yours."
Beethoven, Ludwig Van on friends and friendship
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"The stupidity of men always invites the insolence of power."
Emerson, Ralph Waldo on power
"The gambling known as business looks with severe disfavor on the business known as gambling."
Bierce, Ambrose on gambling
"Edible. Good to eat and wholesome to digest, as a worm to a toad, a toad to a snake, a snake to a pig, a pig to a man, and a man to a worm."
Bierce, Ambrose on food and eating
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"Knowledge is the small part of ignorance that we arrange and classify."
Bierce, Ambrose on knowledge
"Laughter -- An interior convulsion, producing a distortion of the features and accompanied by inarticulate noises. It is infectious and, though intermittent, incurable."
Bierce, Ambrose on laughter
"Marriage. The state or condition of a community consisting of a master, a mistress and two slaves, making in all, two."
Bierce, Ambrose on marriage
"A body of water occupying about two-thirds of a world made for man, who has no gills."
Bierce, Ambrose on oceans
"A prejudice is a vagrant opinion without visible means of support."
Bierce, Ambrose on prejudice
"Religion. A daughter of Hope and Fear, explaining to Ignorance the nature of the Unknowable."
Bierce, Ambrose on religion
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"Corporation. An ingenious device for obtaining individual profit without individual responsibility."
Bierce, Ambrose on business
"To be positive: to be mistaken at the top of one's voice."
Bierce, Ambrose on certainty
"Heaven lies about us in our infancy and the world begins lying about us pretty soon afterward."
Bierce, Ambrose on childhood
"Bride. A woman with a fine prospect of happiness behind her."
Bierce, Ambrose on weddings
"Creditor. One of a tribe of savages dwelling beyond the Financial Straits and dreaded for their desolating incursions."
Bierce, Ambrose on credit
"A cynic is a blackguard whose faulty vision sees things as they are, and not as they ought to be."
Bierce, Ambrose on cynics and cynicism
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But wait... my book has more: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 next
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I'm male and made my book on 28th April 2010.
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From principles is derived probability, but truth or certainty is obtained only from facts. Hawthorne, Nathaniel
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A bit about Hawthorne, Nathaniel ...
Nathaniel Hawthorne (July 4, 1804 May 19, 1864) was a 19th century American novelist and short story writer. He is seen as a key figure in the development of American literature.
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I think the best way of doing good to the poor, is not making them easy in poverty, but leading or driving them out of it. In my youth I travelled much, and I observed in different countries, that the more public provisions were made for the poor the less they provided for themselves, and of course became poorer. And, on the contrary, the less was done for them, the more they did for themselves, and became richer. Franklin, Benjamin
This quote is about poor · Search on Google Books to find all references and sources for this quotation.
A bit about Franklin, Benjamin ...
Benjamin Franklin (January 17, 1706 April 17, 1790) was one of the most prominent of Founders and early political figures and statesmen of the United States. Considered the earliest of the Founders, Franklin was noted for his curiosity, ingenuity and diversity of interests. His wit and wisdom is proverbial to this day. More than anyone he shaped the American Revolution despite never holding national elective office. As a leader of the Enlightenment he had the attention of scientists and intellectuals all across Europe. As agent in London before the Revolution, and Minister to France during, he more than anyone defined the new nation in the minds of Europe. His success in securing French military and financial aid was decisive for American victory over Britain. He invented the lightning rod; he invented the notion of colonial unity; he invented the idea of America; historians hail him as the "First American". The city of Philadelphia, Pennsylvania will mark Franklin's 300th Birthday in January 2006, with a wide array of exhibitions, and events citing Franklin's extraordinary accomplishments throughout his illustrious career.
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It's easy! Just pick the product you like and click-through to buy it from trusted partners of Quotations Book. We hope you like these personalized gifts as much as we do.
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No duty is more urgent than that of returning thanks. Ambrose, St.
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212 - The Extra Degree
The one extra degree makes the difference. This simple analogy reflects the ultimate definition of excellence. Because it's the one extra degree of effort, in business and life, that can separate the good from the great. This powerful book by S.L. Parker and Mac Anderson gives great examples, great quotes and great stories to illustrate the 212° concept. A warning - once you read it, it will be hard to forget. Your company will have a target for everything you do ... 212°
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Quotes by Lin-Chi
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"The real being, with no status, is always going in and out through the doors of your face."
Lin-Chi on life
"If you love the sacred and despise the ordinary, you are still bobbing in the ocean of delusion."
Lin-Chi on worth
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Australian Bureau of Statistics
Celebrating the International Year of Statistics 2013
ABS Home > Statistics > By Release Date
8301.0 - Production of Selected Construction Materials, Jan 2011
Previous ISSUE Released at 11:30 AM (CANBERRA TIME) 23/02/2011
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Australian Bureau of Statistics
Celebrating the International Year of Statistics 2013
ABS Home > Statistics > By Catalogue Number
8699.0 - Zoos, Parks and Gardens Industry, Australia, 1996-97
Latest ISSUE Released at 11:30 AM (CANBERRA TIME) 09/11/1998
© Commonwealth of Australia 2013
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Research article
Human papillomavirus (HPV) prevalence and types among Turkish women at a gynecology outpatient unit
Polat Dursun1*, Süheyla S Senger1,2, Hande Arslan1,2, Esra Kuşçu1 and Ali Ayhan1
Author Affiliations
1 Baskent University School of Medicine, Departments of Obstetrics & Gynecology, Ankara, Turkey
2 Departments of Infectious Disease, Ankara, Turkey
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BMC Infectious Diseases 2009, 9:191 doi:10.1186/1471-2334-9-191
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2334/9/191
Received:13 November 2008
Accepted:30 November 2009
Published:30 November 2009
© 2009 Dursun et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background
Human Papillomavirus (HPV) is a well-known pathogen for lower genital tract neoplasias, yet little is known regarding HPV prevalence in Turkey. The aim of this study was to investigate the prevalence of HPV DNA and to determine HPV types distribution among women with normal and abnormal cytology.
Methods
A total of five hundred seven (n = 507) women were retrospectively evaluated between 2004-2008. Conventional polymerase chain reaction was used to detect the presence of HPV types in cervicovaginal samples obtained from patients during gynecologic examination.
Results
One hundred four (n = 104) of the women were excluded from the study because of the incomplete data and a total of 403 women were used for the final analysis. There were, 93 (23%) women with cytologic abnormality and 310 (77%) women with normal cytology. Overall, 23% of the women was HPV positive. The overall prevalence of HPV in women with abnormal Pap smears was 36% (93/403), of which in ASCUS 22%, LSIL 51% and HSIL 60%. Also, HPV DNA was positive in 20% of the women with normal cervical cytology. The most common HPV types in cytologically normal women were as follows; HPV 16 (36%), HPV 6 (22%) and HPV 18 (13%). The rate of other HPV types were as follows; HPV11 4.4%, HPV45 4.4%, HPV90 4.4%, HPV35 2.2%, HPV67 2.2%, HPV81 2.2%, and multiple type HPVs 8.9%. The most common HPV types in cytologically abnormal women were HPV 16 (35%), HPV6 (19%) and HPV18 (8%). The rate of multiple HPV infections in women with normal Pap test was 2.2%.
Conclusion
HPV prevalence and type distribution in this study were similar to that reported worldwide at least in our study population. Hovewer, HPV prevalence was more common compared with previous studies reported from Turkey. This might be related with methodology and hospital based patient accrual and high rate of women with abnormal cytology. Further population based prospective studies are needed to eliminate the drawbacks of our study and to determine nonhospital based HPV prevalence in Turkish women.
Background
Cervical cancer is the one of the leading cause of cancer-related deaths among women worldwide. It is e estimated 500,000 cases occurring annually and a 50% case fatality rate [1].
According to statistics of Ministry of Health and GLOBOCAN 2002, cervical cancer is the 9th most common cancer among women in Turkey and ranks 13th among cancer-related deaths, with an estimated 1364 cases occurring annually and more than 50% of fatality rate [2].
Today, it is widely accepted that Human papillomavirus virus (HPV) is the main causal factor of cervical carcinoma. More than 100 HPV genotypes have been described and nearly 20 of them have been associated with cervical carcinoma. It has been reported that HPV prevalence range between 1.4% to 25.6% in the world [3]. Previous studies reported that HPV prevalence between 2% to 6% among the low risk women in Turkey [4-8]. However, these studies generally included small number of cases or performed by using Hybrid Capture I or II. The aim of this study is to investigate the HPV prevalence by using PCR method and to report the rate of HPV infection in women with normal and abnormal cervical cytology.
Methods
Between January 2004 and August 2008, 503 consecutive sample of women attending gynecological outpatient clinics for regular gynecologic control in Baskent university School of Medicine, Departments of Obstetrics and Gynecology were included to this retrospective analysis. Women were eligible if they had no previous diagnosis or treatment for cervical, vulvar or vaginal cancer and ever sexually active. Also, patients with previous history of chemoradiotherapy for cervical carcinoma were excluded from the analysis. Information on sociodemographic characteristics, medical history and sexual and reproductive behaviour was obtained at the time of the gynecological visit which was filled during the gynecological visit. Samples of exfoliated cervical cells were obtained using a cytobrush. After the preparation of a standard cervical smear, the remaining cells were placed in tubes with 0.9% saline and stored at - 201C until shipment to the our microbiology laboratory. Pap smears were classified according to the Bethesda system by pathology department. HPV DNA detection and genotyping performed by PCR in our microbiology labaratory as described previously [9]. The data were analysed by of the t test, continuity-corrected chi-square method or Fisher's exact test, One way Anova, calculation of prevalence ratio and descriptive statistics as required, and the probability type I error was set at 0.05 (two-tailed). Prevalence ratio for each decads (2th, 4th and 5th) calculated by comparing with 3rd decad using poisson regression with robust variance estimates as described previously [10,11] Statistical analysis performed by SPSS v.11.5.
HPV DNA detection and genotyping
HPV DNA detection in cervical swabs was conducted by using real-time polymerase chain reaction (PCR) with a commercial kit (Fluorion, Iontek, Turkey). For DNA extraction the QIAamp DNA Mini Kit (Qiagen, Hilden, Germany) was used in accordance with the instructions of the manufacturer. A 150 bp fragment of the L1 gene was amplified using GP5 and GP6 primers. An amplified gene product was identified via melting curve analysis and visualized by incorporation of Sybr Green dye during amplification. HPV genotyping was performed with DYEnamic ET Terminator Cycle Sequencing Kit (Amersham Biosciences Corp., NJ, USA) and ABI PRISM 310 Genetic Analyzer at Iontek Ltd, Turkey.
The study protocol was approved by at Ethical Board of Baskent University, School of Medicine.
Results
During the four year period, 503 women who attend for regular gynecological examination were analyzed for HPV in our departments. One hundred four of these women were excluded from the analysis because of the incomplete data and a total of 403 women were used for the final analysis.
Mean age of the patients was 37.5 ± 9.3 (range 19-67 y). Ninety percent of the population was premenaposal while 10% was menopausal. There were significant differences with respect to HPV positivity between women under 30 years old and women older than 30 years old (34% vs.20%, p = 0.005) but, there was no significant differences with respect to decads of life and HPV positivity. Also, menopausal status has no effect on HPV positivity. HPV was positive in 24% of the premenopausal women and 17% of the menopausal women (p = 0.323).
There were, 93 (23%) women with cytologic abnormality and 310 (77%) women with normal cytology. Cervical cytologic abnormalities were diagnosed as follows; 42% atypical squamous cell of undetermined significance (ASCUS), 46% low-grade squamous intraepithelial lesion (LSIL), and 11% high-grade SIL (HSIL). Overall, 23% of the women was HPV positive. On the other hand, HPV was positive in the 36% of the women with cytologic abnormalities and this figure was 20% in women without cytologic abnomality. HPV was positive in 22%, 51%, 60% of the ASCUS, LSIL and HSIL respectively (Table 1). The most common HPV types in cytologically normal women were as follows; HPV 16 (36%), HPV 6 (22%) and HPV 18 (13%). The rate of other HPV types were as follows; HPV 11 4.4%, HPV 90 4.4%, HPV 45 4.4%, HPV 67 2.2%, HPV 81 2.2%, HPV 35 2.2%, and mixed type HPVs 8.9%. The most common HPV types in cytologically abnormal women were HPV 16 (35%), HPV 6 (19%) and HPV 18 (8.8%) (Table 2). The prevalence ratio for 2nd, 4th, 5th and 6th decads of life comparing the 3rd decads of life were 1.78, 1.12, 1.14 and 2.07, respectively (Table 3).
Table 1. Distribution of cervical cytology and HPV in the study population
Table 2. HPV type distribution in cases with normal and abnormal cytology
Table 3. HPV prevalence by age in women with normal cervical cytology (n = 310)
Discussion
Today, it is well known that some kind of cancers are closely related with persistent infection of oncogenic types HPV. On the basis of epidemiological and virological studies, HPV is estimated to cause 100% of cases of cervical cancer, 90% of anal cancer, 40% of cancers of the external genitalia (vulva, vagina and penis), at least 12% of oropharyngeal cancers and 3% of oral cancers [12]. It has been estimated that HPV is responsible for 5.2% of all cancers worldwide [13]. Furthermore, Human papillomavirus (HPV) has been established as a necessary cause of cervical cancer and its precursors, including cervical intraepithelial neoplasias grades 2 and 3 (CIN 2-3). Therefore, detection of high-risk HPV is becoming increasingly attractive as a primary screening tool. Also, data for HPV-type distribution is sine qua non to development of new HPV-screening tests and to assessment of the effect of future vaccination on HPV infections of differing severity, but published data about the HPV prevalence in Turkey limited [3-8].
Although Turkey has historically had low incidence rates of invasive cervical cancer, cervical cancer ranks among the 9th most common female malignancies with an age-standardized incidence rate of 4.5 per 100.000. Our country has a more than 70 million population, but, unfortunately, there is no population based studies which investigating HPV prevalence in Turkish women. Previous studies reported that HPV prevalence between 2%-6% among the low risk women in Turkey (Table 4). In contrast, HPV prevalence and type distribution in our study was similar to that reported worldwide. Our HPV prevalence is the highest rate reported from our country so far and probably just reflect the HPV profile of our patients population. We believe this high prevalence may arise from the high rate of women with abnormal cervical cytology, the higher educational status of our patient population [14,15]. hospital based patient accrual and usage of more sensitive HPV evaluation method. As it can be seen in Table 4, prevalence of HPV in Turkey was found 2 times higher in PCR studies compared with hybrid capture studies. Interestingly, Bao et al. reported that HPV prevalence increased with the dates of study publication due to the technological improvement of the HPV measuring methods. This situation may also be generalized to our study as well [16].
Table 4. HPV studies reported from Turkey
In 2007, Sanjosé et al. reported that overall HPV prevalence in 157.879 women with normal cervical cytology was estimated to be 10.4% in a meta-analysis of 78 studies [17]. In 2008, Bao et al. reported that overall HPV prevalence was 14.4% in Asia in a meta-analysis of 79 studies which including 25,368 women [16]. In this study, for women with normal cytology/histology, HPV prevalence had a smaller range of 14.0% in southeastern Asia to 14.4% in south central Asia. On the other hand, in an another meta-analysis including the results of 15.613 women, overall HPV prevalence was 8.7%,14.3% and 5.2% for Asia, South America and Europe, respectively [3]. In our study, the rate of HPV positivity in women with normal cervical cytology was 20%. Variations between studies most likely reflect differences in the population studied with respect to risk factors for exposure to HPV and methods of evaluations.
In women with abnormal cytology results, the presence of HPV infection has been reported in 28.8%-61.3% of cases [18-22]. In our study, HPV was positive in 36% of women with abnormal cytology. This low rate of HPV in women with abnormal cytology could be explained by the false evaluation of the Pap test of women which was referred to our instution. HPV infection by multiple genotypes has been reported to occur in 10% to 20% of HPV-positive cases and to show dependence on HPV type, age of the patient, and the presence of cytologic abnormalities [23]. Interestingly, we also found that 8.9% of HPV-infected women has more than one HPV genotype in women with normal cervical cytology while this percentage was 11.8 in women with abnormal cervical cytology (p > 0.05). In other studies, this figures varies between 7% and 23% depending on the cytological diagnosis. Double infection with HPV 16 and 18 was found 6.6% in women with normal cervical cytology. Arora et al. reported the 6.7% of the women with normal cytology had double infection with HPV 16 and 18 [24]. Therefore, Arora et al suggested that the cases who are HPV positive for any of the high risk types but have concurrently negative Pap smear or no visible lesions should be followed up more frequently than the HPV negative cases as they have a substantially greater risk of developing an abnormal smear [24,25]
Some epidemiologic studies reported that a significant reduction in HPV prevalence throughout the third decade of life [26]. It has also been reported that HPV prevalence is between 32-64% in women under 25 years-old women while this figure between 2-4% in women older than 45 years old [27]. Similarly, in our study the rate of HPV infection was 34% in women under 30 years old and this rate was significantly higher than women older than 30 years old. Hovewer, there was no significant differences in HPV prevalence by decads of life in patients with normal cervical cytology (Table 3). This situation also needs to be explanation. On the other hand, it is weel known, HPV-16 is the most prevalent type worldwide. However, the second most prevalent one is HPV-18 in Western countries, whereas it is HPV-58 in Asia [6]. HPV 16, 6 and 18 were the most common three type in our study population as in western countries [23]. On the other hand, HPV prevalence was reported to be 81.0% in women with HSIL. The ten most common HPV types were 16, 58, 52, 18, 33, 51, 31, 56, 35, and 45 in HSIL [16]. Onan et al from Turkey reported that 45% of the women with cervical intraepithelial neoplasia (CIN) had high risk HPV [28]. Inal et al. performed HC-II study in 1353 women from Izmir region which has the highest cervical cancer incidence in Turkey, and reported 2.1% women had positive for HPV. Hovewer, all the women with cytological abnormalities had positive for HPV DNA. Therefore, the authors concluded that "In spite of low general frequency of cervical HPV colonization, there was a strong correlation between HPV and CIN" [4]. In our study, HPV was positive in 36% of the cases with cytological abnormalities.
Conlusion
In conclusion, although geographicly Turkey is located between Europe and Asia, HPV prevalence and genotypes are similar to those reported from western countries in Turkish women with normal and abnormal cytology. Hovewer, HPV prevalence was more common compared with previous studies reported from Turkey. This might be related with methodology and hospital based patient accrual and high rate of women with abnormal cytology. Further population based prospective studies are needed to eliminate the drawbacks of our study and to determine nonhospital based HPV prevalence in Turkish women.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
PD, conceived of the study, performed analysis and interpretation of data, drafted the manuscript and revised the manuscript. SSS performed the data analysis, revised the manuscript. HA, performed the data analysis, revised the manuscript. EK supervised the study, revised the manuscript. AA, supervised the study and revised the manuscript. All authors read and approved the final manuscript.
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Pre-publication history
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http://www.biomedcentral.com/1471-2334/9/191/prepub
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Research article
Prof-in-a-Box: using internet-videoconferencing to assist students in the gross anatomy laboratory
Stephen J Moorman
Author Affiliations
Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, 675 Hoes Lane West, Piscataway, NJ 08854 USA
BMC Medical Education 2006, 6:55 doi:10.1186/1472-6920-6-55
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1472-6920/6/55
Received:5 September 2006
Accepted:15 November 2006
Published:15 November 2006
© 2006 Moorman; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background
The optimal learning environment for gross anatomy is the dissection laboratory. The Prof-in-a-Box (PiB) system has been developed where an anatomist using distance-learning technologies 'helps' students in a dissection laboratory at a different site.
Methods
The PiB system consists of: (1) an anatomist in his/her office with a computer and video camera; (2) a computer and 2 video cameras in the lab; (3) iChat AV software; (4) a secure server to host the PiB-student 'consultation'. The PiB system allows the students and faculty to interact via audio and video providing an environment where questions can be asked and answered and anatomical structures can be identified 'at a distance' in real-time. The PiB system was set up at a prosected cadaver and made available for student use during 'office hours'.
Results
25–30% of the students used the PiB system. Anatomical structures were identified, questions answered and demonstrations given 'at a distance' using the system. Students completed an optional questionnaire about the PiB system at the end of the semester. Results of the questionnaire indicate that the students were enthusiastic about the PiB system and wanted its use to be expanded in the future.
Conclusion
Many of the functions of a faculty member in the gross anatomy dissection laboratory can be performed 'at a distance' using the PiB system. This suggests that a geographically dispersed faculty could assist in providing instruction in the dissection labs at multiple medical schools without needing to be physically present.
Background
We have a problem in gross anatomy: Within the next decade there will be a critical national shortage of PhD-level faculty trained to teach gross anatomy [1]-the way we teach will have to change. Effective use of educational theory and distance-learning technologies to provide lectures (delivered by geographically dispersed faculty) to students at numerous schools is one way to continue to provide medical students with instruction in gross anatomy when this shortage becomes reality. However, the optimal learning environment for gross anatomy is the dissection laboratory [2-6] where students learn to recognize anatomical structures and their relationships in situ. To date, no one has demonstrated that it is possible to use distance-learning technologies to provide instruction in a dissection laboratory setting. Historically, this laboratory dissection experience has been supervised and guided by trained faculty in a setting with a significantly lower faculty-student ratio (1:20 at the home school) than that for the lectures (1:170 at the same school). In the dissection lab, the faculty serve as a resource to (1) answer questions, (2) help students identify structures, and (3) perform aspects of the dissections for the students when warranted. When the faculty shortage materializes, the quality of the laboratory experience will suffer as the faculty-student ratio in the dissection laboratory shifts toward that of the lecture.
This problem might be avoided by the development of a system where a trained anatomist using distance-learning technologies 'helps' students in a dissection laboratory at a different site. At least two of the three functions (1 & 2) of a faculty member in the dissection laboratory might be performed 'at a distance' using currently available distance-learning technologies. If this system is successful, the number of faculty needed "on-site" would be reduced to the number needed to perform the third function in the dissection lab. This could result in a geographically dispersed faculty able to provide both the lecture and laboratory experience for the students at numerous medical schools.
A Prof-in-a-Box system (PiB) has been developed that consists of three components: (1) a secure server to 'host' a videoconference; (2) a trained anatomist in his/her office with a computer and video camera; (3) a computer with two video cameras adjacent to a cadaver in the dissection lab. This system used iChat-AV software to allow the anatomist to see the students and the dissection via the cameras in the lab. The camera in the faculty office allowed the students to see the faculty member, providing a more personal aspect to the interaction. The software allowed the students and faculty to interact via live audio and video providing an environment where questions could be asked and answered and anatomical structures could be identified 'at a distance'.
Methods
Prior to choosing computers for the PiB system, the following requirements were established (see Discussion):
Secure (encrypted) transmission
Built-in, cross-platform videoconference capability
No additional software to buy.
Cross-platform control of the computer in the laboratory from the office.
Sufficient camera resolution to identify anatomical structures
Server
Since none of the commercial (free) instant messaging servers (MSN®, AOL®, and Yahoo®) that support videoconferences are secure, an in-house, secure server was set up to host the PiB videoconferences. The iChat server is a Jabber® server that supports SSL Certificates and encryption and is an integral part of the Apple OSX v10.4 server software. The server consisted of the following hardware/software combination:
Dual Processor G5 computer (Apple Computers)
Dual 2.7 GHz PowerPC G5 processors, 2 GB SDRAM, 380 GB Hard Drive
OS-X 10.4 Server Software
Unlimited client license
iChat/Jabber® server enabled
21" LCD Display (Apple Computers)
100 Mb Ethernet connection
The Information Services and Technology (IST) office at the university granted permission to connect this computer to the local network and have it function as a server provided it did not distribute IP addresses. IST also agreed to provide a 'static' IP address and domain name for the server. In order to facilitate future collaborations, IST also enabled data throughput on the university firewall for the ports specified in the iChat server documentation.
Office Equipment
To avoid the need to find a Jabber® client for a Windows operating system that supports secure videoconferences, an iMac computer was used. The most recent version of the Apple OS (v10.4) supports secure videoconferences through the iChat software included with the computer. Therefore, the following in the office:
20" iMac (Apple Computers)
1.8 GHz PowerPC G5 processor, 1 GB SDRAM, WIFI 802.11b/g card, 150 GB Hard Drive
iSight FireWire video camera (Apple Computers)
FireWire cable
OS-X v10.4
iChat-AV software (included as part of OS-X v10.4)
Apple Remote Desktop software v2.2
100 Mb Ethernet connection
The iSight camera and Apple Remote Desktop software were not included in the standard purchase of an iMac computer. The iSight camera is 'plug-and-play' and fully compatible with iChat. The Apple Remote Desktop (ARD) software was purchased to control the computer in the laboratory using the computer in the office (see discussion).
Dissection Laboratory Equipment
Prior to setting up a system in the lab, a standard video camera (e.g., the iSight) was evaluated to determine if it had sufficient resolution to identify anatomical structures remotely. In a preliminary test using just bones, the resolution using the iSight camera was good enough to identify small structures such as tubercles. However, the working distance for the camera was 4–6 inches to give the necessary magnification. An inexpensive miniDV camera with FireWire output had higher resolution and a longer working distance than the iSight camera making the miniDV camera a better choice. The boom arm of a fluorescent drafting light was modified to hold the miniDV camera. This allowed the camera to be mounted either directly to the dissecting table or to the laboratory bench top adjacent to the dissecting table.
In the gross anatomy course, one cadaver is dissected by a faculty member. This prosected cadaver is available for the students to inspect and study outside of scheduled class hours. The following computer and peripheral equipment were set up at the prosected cadaver in the gross anatomy dissection lab.
Mac-Mini (Apple Computers)
1.42 GHz PowerPC G4 processor, 512 MB SDRAM, Bluetooth card, WIFI 802.11b/g card, 80 GB Hard Drive
17" monitor (Dell Computers)
iSight FireWire video camera (Apple Computers)
FireWire Cable
Optura-30 miniDV camera
FireWire Cable
Drafting light boom arm
FireWire (IEEE 1394) 3-port hub
USB Speakers
OS-X v10.4
iChat AV software (included as part of OS-X v10.4)
100 Mb Ethernet connection
This system, nicknamed Dr. PiB, sat on the laboratory bench at one end of the dissection table. The iSight camera, mounted on the monitor, was fixed in place and allowed the students at the prosected cadaver to be seen. The boom arm for the miniDV camera was mounted at the 'head' of the dissection table using the standard drafting light screw-mount. From this location, the students could position the miniDV camera on the boom arm over the cranial half of the prosected cadaver. By moving the boom arm to the 'foot' of the table, the camera could be positioned over the caudal half of the cadaver. Using the ARD software, remotely switching between the two cameras was possible. The Mac-Mini has only one FireWire port and only a very small internal speaker. Using the FireWire hub enabled both cameras to be connected to the computer simultaneously. The USB speakers allowed the student to hear the faculty member without leaving the dissection table.
General Methods
In preparation for the project, the prosected cadaver was not inspected by the faculty member prior to any PiB session. In that way, the only information the faculty member had about the identity of a structure was limited to what could be 'seen' through the camera.
The same faculty member (the author) was available for 'consultation' via the PiB system one afternoon (1:30–4:30) a week on an afternoon when there were no other scheduled classes. Dr. PiB turned itself on and logged in to the iChat server automatically. The iChat software on Dr. PiB was configured to automatically accept invitations for videoconferences by running the 'Terminal' application, typing "defaults write com.apple.ichat AutoAcceptVCInvitations 1" and restarting the computer. A videoconference was initiated with Dr. PiB from the office and the conference was kept active for the entire 3-hour period. The iChat window on Dr. PiB was minimized when there was no one actively engaged in a consultation. When a student indicated that s/he had a question (usually by saying "Dr. PiB?"), the iChat window was made visible using the ARD software. Whenever a new student came to the cadaver, s/he was reminded that the faculty member was available through Dr. PiB to answer any questions s/he had.
The number of students who used the prosected cadaver was tracked, as were the times they arrived at the cadaver and the times they left. The questions they asked were logged, as were and the structures identified or assisted in identifying using the PiB system. In addition, any system problems that were encountered were logged. At the end of the gross anatomy course, all students in the course were provided with the opportunity to answer a brief, on-line, optional questionnaire about the PiB system.
Results
The PiB system was deployed in the laboratory for 12 weeks of the 17-week semester that gross anatomy was in session. During this time, 60 students (out of 160 enrolled in the course) used the PiB system to 'consult' with the professor in the box. The identity of 30 structures was confirmed, 26 structures were identified and 14 questions were answered for the students using the PiB system. In addition, one demonstration of the movements of the digits of the hand was done using the PiB system.
The structures identified included the following:
Gemelli muscles
Obturator internus muscle
Dorsal Root Ganglion
Dorsal ramus
Ventral ramus
Common interosseous artery
Obturator nerve
Adductor muscles
Saphenous nerve
Coronary arteries
Coronary sinus
Lymph node on hilum of lung
Internal thoracic artery and vein
Umbilical ligaments
Left and middle colic arteries
Subcostal nerve
Ilioinguinal nerve
Branches of the internal iliac artery
Branches of external carotid artery
Medial pterygoid muscle
63 students completed the optional evaluation. The follow is a summary of the responses to the questions.
Question #1 – How often did you use the PiB?
a) Hardly at all 22
b) A couple of times 13
c) Often 1
d) Frequently 2
e) Almost every week 0
f) Not applicable 22
Question #2 – Was the PiB useful?
a) Hardly at all 18
b) To a small degree 7
c) To a moderate degree 10
d) To a considerable degree 6
e) To a very high degree 15
Question #3 – What should we do with the PiB next year?
a) Make it available next year 32
b) Use it in the laboratory in general 18
c) Discontinue its use 6
Students were also given the opportunity to comment on the PiB system. The following is a summary of the germane comments:
• I think the resource is a good idea. However I am still a fan of having a professor in the lab.
• I used PiB system just about every Friday in the 2nd block. I really found it helpful. I was impressed that it worked so well and that Dr. Moorman was really able to see what we wanted to show him with the camera. It was a really helpful addition to my studying mechanisms because sometimes a group of us would have a discrepancy about what something was/where something was and Dr. Moorman could give us a definitive answer in less than a minute on something that might have never been resolved if we all kept fighting about it together.
• It would be really great it you could have it on the prosected cadaver for a block and then maybe have it on another body (the best body for the internal ab structures, for example...) for another block. I don't know if moving the camera is just too hard, but I think that would be helpful so that at least people wont always just rely on the prosected cadaver.
• I also think that PIB is something that we should try to do with the other universities. I think it would be VERY helpful to be able to speak with profs from other places if that could get set up.
• As far as I'm concerned, the only bad thing about Prof-In-The-Box was that the Internet connection was terrible and it kept cutting out.
• I thought it was very nice of instructors to give up their free time to sit in front of the screen and help us with the cadavers like that. I think it was generally an OK idea. It was better than nothing when you were really unsure about something on the cadaver.
• Very useful and helpful to clarify information.
• Prof-in-the-box was good for checking whether or not your understanding of the location of structures was right.
• I thought the Prof in the Box was a great tool to use. Highly recommended using it again.
• Good for when you have questions.
• It was a good resource
• First of all its fun. Second of all it promotes peer teaching with the reassurance that there is a teacher there just in case there's a real problem.
Discussion
Four requirements had to be met prior to starting the project and choosing computers for the PiB system: (1) All videoconference transmissions had to be secure (encrypted); (2) The computers had to have built-in, cross-platform videoconference capability so that there was no additional software to buy; (3) cross-platform control of the computer in the laboratory from the office; and (4) The camera in the laboratory had to have sufficient resolution to identify anatomical structures in a video image.
The videoconference transmissions had to be secure to assure the university of compliance with HIPAA (The Health Insurance Portability and Accountability Act of 1996) and to preserve the confidentiality of our donors. This requirement precluded using any of the free commercial instant messaging/videoconference servers such as AIM®, MSN®, or Yahoo®. During the initial development of this project, Apple Computers announced that the next version of OS-X would include an iChat server as an integral part of the OS-X server software. The iChat server is a Jabber® based server and can host both secure and non-secure videoconferences. Jabber® is an open-source cross-platform set of streaming XML protocols and technologies that enable any two computers on the Internet to exchange messages, audio, video, and files in close to real time.
Apple's iChat software is preinstalled on all Apple computers. Microsoft's MSN Messenger is preinstalled on all PCs with the Windows® operating system. However, MSN Messenger can only communicate with the public IM servers and with Microsoft's Live Communications Server software. There are commercial implementations of a Jabber® client for the PC that allow secure videoconferences, but these software packages are not free. The conclusion was that Apple computers had the only built-in software that met the requirements.
In this initial project, it was desirable to have Dr. PiB be as user friendly as possible in the dissection laboratory. This meant the students should not have to be concerned with turning on the system, contacting the faculty member, or switching the cameras to allow the faculty member to see the cadaver. The student should only be concerned with aiming the camera over the cadaver. This meant that Dr. PiB in the dissection laboratory needed to be controlled using the computer in the office. Within the university's intranet, this can be easily accomplished using Apple Remote Desktop (ARD) software. To accomplish this through the university's firewall, the target computer needs a fixed IP address and the appropriate ports need to be enabled on the firewall to allow data throughput to the target computer. With Virtual Network Computing enabled on a Windows based PC, it is also possible to use ARD software to control a PC.
One of the most important aspects of the PiB system is the requirement that the camera in the laboratory have sufficient resolution to identify structures remotely. The iSight camera has 640 × 480 resolution. The iSight camera appeared to have sufficient resolution necessary to identify anatomical structures. However, in order to fill the field of view with an anatomical specimen at a magnification that allows structures to be identified, the working distance of the camera is so short that it precludes the student and camera making simultaneous observations. Although miniDV format cameras have the same resolution as the iSight camera, the way the image is handled results in a higher effective resolution. This means the videoconference image originating from a miniDV camera can be enlarged on the computer screen without loss of resolution making anatomical structures easier to identify. The miniDV camera also had the advantage of a significantly longer working distance, even without using the zoom feature. This meant that the camera could be positioned in a way that did not interfere with the student's ability to see the dissection field while the camera was in place. Interestingly, the students tended to place the camera too close to the cadaver in an attempt to fill the field of view with just the structure they wanted identified. They were routinely asked to move the camera farther from the cadaver to give a larger field of view.
Less than a third of the class used Dr. PiB for help at the prosected cadaver. Several things can explain this low participation rate. Since use of the anatomy dissection laboratory outside of scheduled class hours is not monitored, the number of students that actually use the prosected cadaver is not known. Since Dr. PiB's 'office hours' were on the only afternoon that the students didn't have scheduled classes, the number of students using the prosected cadaver might be a reflection of how many students choose to spend Friday afternoon studying anatomy in the dissection laboratory. 90–95% of the students who came to the prosected cadaver during 'office hours' used Dr. PiB and the students who took advantage of Dr PiB were enthusiastic about the usefulness of the system. Although this might have more to do with students appreciating any extra help provided by the faculty, it suggests that the PiB system represents a viable alternative for providing help in the dissection laboratory when faculty are not able to be physically present. This also supports the idea that a geographically dispersed faculty can provide instruction in the anatomy dissection laboratory using distance-learning technologies. For instance, the University of Medicine and Dentistry of New Jersey has 3 medical schools under its umbrella. If each school had 3 full-time faculty members on-site to teach in the dissection lab, 6 additional faculty members could be available to each school remotely via the PiB system. By judicious scheduling of the 3 gross anatomy courses, all of the lecture and dissection laboratory teaching could be provided by the 9 geographically dispersed faculty employed by one university. Similar collaborations between groups of 3–4 medical schools could provide gross anatomy laboratory experiences for the current numbers of students with 66–75% fewer faculty.
An additional issue that we struggle with in anatomy is getting more clinicians helping in the dissection lab. The presence of clinicians in the laboratory creates a greater sense of relevance for the material being learned. Using the PiB system, clinicians could be available for consultation in the dissection laboratory without leaving the clinics.
The current version of Dr. PiB was fixed in place at one cadaver in the dissection lab. The next version of the system, Dr. PiB version 1.1 will be a mobile unit consisting of the same hardware mounted on a cart equipped with an uninterruptible power supply (battery). Since the computer has an 802.11g wireless card and the entire dissection laboratory has 802.11g wireless coverage, the mobile Dr. PiB can be used anywhere in the lab. This mobile Dr. PiB is being created in response to one of the student's suggestions. The PiB system might have more limitations for helping students at their own cadaver where the quality of the dissection might not be on a par with that of the prosected cadaver. Having a mobile Dr. PiB will allow these limitations to be determined.
The goals of this project were to demonstrate that the cameras and Internet AV software have sufficient resolution and bandwidth to make 'remote' identification of anatomical structures possible and to demonstrate a willingness on the part of the students to receive instruction from faculty at a different geographic location. The results presented here suggest that these goals have been accomplished.
Conclusion
Many of the functions of a faculty member in the gross anatomy dissection laboratory can be performed 'at a distance' using the PiB system. This suggests that a geographically dispersed faculty could assist in providing instruction in the dissection labs at multiple medical schools without needing to be physically present.
Competing interests
The author declares that he has no competing interests.
Acknowledgements
This project was initiated as part of the Harvard Macy Institute Program for Educators in the Health Professions. I thank Samuel Kennedy, Mairead Boohan, Maria Cole, Francesca Ruggiero, and Todd Thomsen for helpful discussions during the development of this project and Denise Dehnbostel for editing the manuscript. This work was supported with funds from NASA, NIH, and the State of New Jersey.
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Anat Rec B New Anat 2004, 281(1):9-11. PubMed Abstract | Publisher Full Text
5. McLachlan JC: New path for teaching anatomy: living anatomy and medical imaging vs. dissection.
Anat Rec B New Anat 2004, 281(1):4-5. PubMed Abstract | Publisher Full Text
6. Granger NA: Dissection laboratory is vital to medical gross anatomy education.
Anat Rec B New Anat 2004, 281(1):6-8. PubMed Abstract | Publisher Full Text
Pre-publication history
The pre-publication history for this paper can be accessed here:
http://www.biomedcentral.com/1472-6920/6/55/prepub
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<D <M <Y
Y> M> D>
(1) The Manahmanah Of Man: Omega Point. Bop be ba de ba.
(2) : We searched for my mother's name just now to see if there was anything of hers on the web that we hadn't seen. There wasn't a lot but we did find a magazine article she wrote in 1983 (yes, that whole URL does appear to be necessary). I knew the underlying story but I'm not sure if it's because I'd read this article or because she'd told me the story. Anyway, it's something new if you miss my mother's writing.
[Main]
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You are here: Home / Data and maps / Indicators / Water temperature / Water temperature (CLIM 019) - Assessment published Nov 2012
Water temperature (CLIM 019) - Assessment published Nov 2012
Created : Nov 12, 2012 Published : Nov 20, 2012 Last modified : Nov 20, 2012 01:06 PM
Topics: ,
Generic metadata
Topics:
Climate change (Primary topic)
Tags:
climate | rivers | Water | CLIM | CLIM019 | water temperature
DPSIR: Impact
Typology: Descriptive indicator (Type A – What is happening to the environment and to humans?)
Indicator codes
• CLIM 019
Dynamic
Temporal coverage:
1901-2011
Geographical coverage:
[+] Show Map
Contents
Key policy question: What is the trend in the water temperature of rivers and lakes across Europe?
Key messages
• Water temperatures in major European rivers have increased by 1–3 °C over the last century. Several time series show increasing lake and river temperatures all over Europe over the last 60 to 90 years.
• Lake and river surface water temperatures are projected to increase with further projected increases in air temperature.
• Increased temperature can result in marked changes in species composition and functioning of aquatic ecosystems.
Key assessment
Past trends
The surface water temperatures of major rivers in Europe have increased by 1–3 °C over the last century. For example, the average temperature in the Rhine near Basel has risen by more than 2 °C in the last 50 years (Figure 1) [i]. The temperature of the downstream part of the Rhine increased by 3 °C between 1910 and 2010. Two thirds of the increase at the downstream Rhine is attributed to the increased use of cooling water and one third to the increase in air temperature as a result of climate change [ii]. A similar increase has been observed in the Meuse. The annual average temperature of the Danube increased by around by 1 °C during the last century. Increases in surface water temperature were also found in some large lakes. Lake Võrtsjärv in Estonia had a 0.7 °C increase between 1947 and 2011, and the summer (August) water temperature of Lake Saimaa, Finland increased more than 1 °C over the last century.
Several time series indicate a general trend of increasing water temperature in European rivers and lakes in the range of 0.05 to 0.8 °C per decade [iii]. The surface water temperature of some rivers and lakes in Switzerland has increased by more than 2 °C since 1950 [iv]. In the large lakes in the Alps the water temperature has generally increased by 0.1–0.3 °C per decade: Lake Maggiore and other large Italian lakes [v].
Projections
Lake surface water temperatures are projected to increase further, in parallel with the projected increases in air temperature. The exact amount of warming depends on the magnitude of global warming, on the region, on the season and on lake properties [vi]. Physical modelling studies predict that temperatures will increase more in the upper regions of the water column than in the lower regions, resulting in generally steeper vertical temperature gradients and enhanced thermal stability [vii]. Such increased lake thermal stability was observed both in Switzerland during the mild 2006/2007 winter [viii] and in Italy during the hot 2009 summer [ix].
[i] FOEN, „Indicator Water temperature of surface waters“ Federal Office for the Environment, 2011, http://www.bafu.admin.ch/umwelt/indikatoren/08605/08609/index.html?lang=en.
[ii] A.H.M. Bresser et al., The effects of climate change in the Netherlands (Bilthoven: Netherlands Environment Assessment Agency, 2006), http://www.rivm.nl/bibliotheek/rapporten/773001037.pdf.
[iii] M. Dabrowski, W. Marszelewski, and R. Skowron, „The trends and dependencies between air and water temperatures in lakes in northern Poland from 1961-2000“, Hydrology and Earth System Sciences 8 (2004): 79–87, doi:10.5194/hess-8-79-2004; D.G. George and M.A. Hurley, „The influence of sampling frequency on the detection of long-term change in three lakes in the English Lake District“, Aquatic Ecosystem Health & Management 7 (2004): 1–14, doi:10.1080/14634980490281164; B. Pernaravièiûtë, „The impact of climate change on thermal regime of Lithuanian lakes“, Ekologija 2 (2004): 58–63; Bresser et al., The effects of climate change in the Netherlands.
[iv] BUWAL, Auswirkungen des Hitzesommers 2003 auf die Gewässer (Bern-Ittigen: Bundesamt für Umwelt, Wald and Landschaft: Schriftenreihe Umwelt Nr. 369, 2004); R. E. Hari et al., „Consequences of climatic change for water temperature and brown trout populations in Alpine rivers and streams“, Global Change Biology 12 (2006): 10–26, doi:10.1111/j.1365-2486.2005.001051.x.
[v] W. Ambrosetti and L. Barbanti, „Deep water warming in lakes: an indicator of climate change“, Journal of Limnology 58 (1999): 1–9; D. M. Livingstone, „Impact of secular climate change on the thermal structure of a large temperate central European lake“, Climatic Change 57 (2003): 205–225, doi:10.1023/a:1022119503144; O. Anneville, S. Gammeter, and D. Straile, „Phosphorus decrease and climate variability: mediators of synchrony in phytoplankton changes among European peri-alpine lakes“, Freshwater Biology 50 (2005): 1731–1746, doi:10.1111/j.1365-2427.2005.01429.x; M. T. Dokulil et al., „Twenty years of spatially coherent deepwater warming in lakes across Europe related to the North Atlantic Oscillation“, Limnology and Oceanography 51 (2006): 2787–2793, doi:10.4319/lo.2006.51.6.2787.
[vi] J. M. Malmaeus et al., „Lake phosphorus dynamics and climate warming: A mechanistic model approach“, Ecological Modelling 190 (2006): 1–14, doi:10.1016/j.ecolmodel.2005.03.017; G. George, M. Hurley, and D. Hewitt, „The impact of climate change on the physical characteristics of the larger lakes in the English Lake District“, Freshwater Biology 52 (2007): 1647–1666, doi:10.1111/j.1365-2427.2007.01773.x.
[vii] F. Peeters et al., „Modeling 50 years of historical temperature profiles in a large central European lake“, Limnology and Oceanography 47 (2002): 186–197, doi:10.4319/lo.2002.47.1.0186.
[viii] J. Rempfer et al., „The effect of the exceptionally mild European winter of 2006-2007 on temperature and oxygen profiles in lakes in Switzerland: A foretaste of the future?“, Limnology and Oceanography 55 (2010): 2170–2180, doi:10.4319/lo.2010.55.5.2170.
Data sources
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Contacts and ownership
EEA Contact Info
Peter Kristensen
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2012 2.0.1 (note: EEA internal system)
Dates
First draft created: 2012/11/12 15:57:36.983714 GMT+1
Publish date: 2012-11-20T14:06:10+02:00
Last modified: 2012/11/20 13:06:19.614389 GMT+1
European Environment Agency (EEA)
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Phone: +45 3336 7100
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"url": "www.familysearch.org/learn/wiki/en/Tullyallen_Civil_Parish,_County_Louth",
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Tullyallen Civil Parish, County LouthEdit This Page
From FamilySearch Wiki
Ireland County Louth Tullyallen Civil Parish
The following information is a starting point for records about the civil parish of Tullyallen. The information is based on locations and records before 1922.
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Government registration of births and deaths began in 1864. Registration of Protestant marriages began in 1845, with all marriages being registered by 1864. Go to the Ireland Civil Registration article to read more about these records.
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Washington State County Probate Records (FamilySearch Historical Records)Edit This Page
From FamilySearch Wiki
This article describes a collection of historical records available at FamilySearch.org.
Contents
Record Description
This collection includes digital images of probate records created in the following county courts:
• Clark
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• Grays Harbor
• Lewis
• Mason
• Pacific
• Skamania
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• Wahkiakum
Each county began keeping probate records from the time the county was created.
The collection covers the years 1832 to 1950.
Probate records were used to legally dispose of a person’s estate after his or her death. If the deceased had made a will, the probate process transferred the following from the deceased to an executor or executrix: the legal responsibility for payment of taxes, care and custody of dependent family members, liquidation of debts, and transfer of property title to heirs. If there was no will, the transfer went to an administrator or administratrix. A guardian or conservator was appointed if the deceased had heirs younger than 21 or if the heirs were incompetent due to disability or disease.
The death date, residence, and other facts that were current at the time of the probate proceedings are reliable, but realize that there is still a chance of misinformation. The records may omit the names of deceased family members or those who had previously received an inheritance. In some cases, the spouse mentioned in the will was not the parent of the children mentioned. Also, some wills do not name family members.
For a list of records by localities and surnames currently published in this collection, select the Browse.
Citation for This Collection
The following citation refers to the original source of the data and images published on FamilySearch.org Historical Records. It may include the author, custodian, publisher, and archive for the original records.
"Washington, County Probate Case Files, 1832-1950 ." Index and Images. FamilySearch. http://FamilySearch.org : accessed 2013. Citing State Archives, Olympia.
Suggested citation format for a record in this collection.
Record Content
Most probate records include the following genealogical information:
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How to Use the Record
To begin your search it is helpful to know:
• The place of residence
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Compare the information you find in the probate records to what you already know about your ancestors to determine which record is about your ancestor. You may need to compare the information of more than one person to make this determination.
When you have located your ancestor’s record, carefully evaluate each piece of information given. These pieces of information may give you new biographical details that can lead you to other records about your ancestors. Add this new information to your records of each family.
For example:
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• You may be able to use the probate record to learn about adoptions or guardianships of any minor children and dependents.
• Use the document (such as the will) or the recording dates to approximate a death date.
• Use the information in the probate record to substitute for civil birth and death records since the probates exist for an earlier time period.
• You may be able to use the probate record to learn about land transactions.
• Use the birth date or age along with the residence or place of birth of the deceased to locate census, church, and land records.
• Use the occupations listed to find employment records or other types of records such as military records.
• Compile the entries for every person who has the same surname as the deceased; this is especially helpful in rural areas or if the surname is unusual.
• Continue to search the records to identify children, siblings, parents, and other relatives who may have died in the same county or nearby. This can help you identify other generations of your family or even the second marriage of a parent. Repeat this process for each new generation you identify.
• When looking for a person who had a common name, look at all the entries for the name before deciding which is correct.
Keep in mind:
• Wills are more likely to be found in rural communities than in larger cities and industrial areas.
• The information in the records is usually reliable, but depends upon the reliability of the deceased or the testator.
• Earlier records may not contain as much information as the records created after 1900.
• There is also some variation in the information given from one record to another record.
If you are unable to find the ancestors you are looking for, try the following:
• Check for variant spellings of the surnames.
• Check for an index. There are often indexes at the beginning of each volume.
• Search the indexes and records of nearby counties.
Related Websites
Washington (State) Probate
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A suggested format for keeping track of records that you have searched is found in the wiki article Help:How to Cite FamilySearch Collections.
Citation Example for a Record Found in This Collection
"Washington, County Probate Case Files, 1832-1950: index and images, FamilySearch (https://familysearch.org: accessed 3 Fabruary 2012). r Fred Clark, 1892; citing Probate Records, FHL digital folder 004,113,963; Pacific County Clerk's Office, South Bend, Washington, United States.
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• This page was last modified on 5 March 2013, at 16:51.
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Virtual Hard Disk (VHD)
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User:John Crout
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read wchar_t from text file
Go4Expert Member
16Aug2006,22:57 #1
hello
let's say i type some spanish in a text file, how would i read them in as wchar_t type from a text file?
Contributor
17Aug2006,00:57 #2
Can you read a char from text file?
Go4Expert Member
17Aug2006,07:47 #3
yeah, i have no problem reading a regular text file, the problem is when i start typin in different languages, i can't seem to store them
Contributor
19Aug2006,11:04 #4
You probably want to store the text in utf-16 or utf-8.
Normally you'd write a byte order mark which most editors check for to see what encoding the file is in, then you write the encoded characters (wikipedia has information about both).
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Bibliography: Knights of Takhisis
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Title: Knights of Takhisis
Authors: Margaret Weis and Tracy Hickman
Year: 1995
Type: ESSAY
Language: English
ISFDB Record Number: 1127487
User Rating: This title has fewer than 5 votes. VOTE
Current Tags: None Add Tags
Publications:
Copyright (c) 1995-2011 Al von Ruff.
ISFDB Engine - Version 4.00 (04/24/06)
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The free office suite
Download LibreOffice
LibreOffice Linux - deb (x86_64), version 3.6.5, Albanian. Not the version you wanted? Change System, Version or Language
You need to download and install these files in order:
• Source code
LibreOffice is an open source project and you can therefore download the source code to build your own installer.
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BISC110:OpenWetWare
From OpenWetWare
Revision as of 08:17, 17 December 2009 by Tucker Crum (Talk | contribs)
(diff) ←Older revision | Current revision (diff) | Newer revision→ (diff)
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Wellesley College BISC110 Introduction to Cell Biology
Spring 2010
Using OpenWetWare in BISC110
• Some general information about the class wiki
Getting started on OpenWetWare
• Instructions for getting an OWW account and general editing etiquette.
Guidelines for editing the BISC110 wiki
• Some BISC110 specific guidelines for editing OpenWetWare.
Personal tools
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[8] 5. This subject has been discussed by me frequently on other occasions, but with somewhat more than ordinary care when my brother Quintus and I were together recently at my Tusculan villa. For the sake of a stroll we had gone to the Lyceum,1 which is the name of my upper gymnasium, when Quintus remarked:
[p. 233] “I have just finished a careful reading of the third book of your treatise, On the Nature of the Gods, containing Cotta's discussion, which, though it has shaken my views of religion, has not overthrown them entirely.”
“Very good,” said I; “for Cotta's argument is intended rather to refute the arguments of the Stoics than to destroy man's faith in religion.”
Quintus then replied: “Cotta2 says the very same thing, and says it repeatedly, in order, as I think, not to appear to violate the commonly accepted canons of belief; yet it seems to me that, in his zeal to confute the Stoics, he utterly demolishes the gods. ”
1 Cicero had two gymnasia at Tusculum: the Lyceum, so called from the place in which Aristotle taught at Athens, the other, the Academia, named from the place where Plato lectured. Cf. Cic. Tusc. ii. 3.
2 Gaius Aurelius Cotta, consul 75 B.C., an eminent orator, and Q. Lucilius Balbus were two of the disputants in The Nature of the Gods, the former as an Academician and the latter as a Stoic.
This work is licensed under a Creative Commons Attribution-ShareAlike 3.0 United States License.
An XML version of this text is available for download, with the additional restriction that you offer Perseus any modifications you make. Perseus provides credit for all accepted changes, storing new additions in a versioning system.
load focus Introduction (William Armistead Falconer, 1923)
load focus Latin (William Armistead Falconer, 1923)
load focus Latin (C. F. W. Müller, 1915)
hide References (4 total)
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Tell me more ×
Answers OnStartups is a question and answer site for entrepreneurs looking to start or run a new business. It's 100% free, no registration required.
I have a customer who is demanding a refund for a purchase made in August 2009. Usually my approach is to give refunds without a quibble, even if they are outside of my 30 day no questions asked guarantee period. I'd like to give this guy a refund too but my payment processor doesn't allow refunding CC charges past 90 days so my hands are tied.
What should I do?
Edited to add: I am in Australia, they are in the USA.
share|improve this question
4 Answers
up vote 5 down vote accepted
If you want to send a refund just write him a check. Or use paypal. Or anything else.
Be creative. You can also offer to pay for a gift card to amazon.com or other vendor.
share|improve this answer
How about just cut the customer a cheque?
share|improve this answer
Your hands are not tied, you just can't refund their credit card. This doesn't mean you can't refund in some other way.
You have added that you live in Australia, so sending a cheque is no good. You can refund the customer by Pay Pal, but I would speak to them and explain the situation and that you are willing to refund, but you need to know which payment method is convienient for the both of you.
Don't let rules like this determine your business practices. If there are restrictions then create a system to work around it. I personally find it infuriating when a company tells me they can't do something because of a policy they have. Standing out and going the extra mile is what makes you stand out from the crowd.
share|improve this answer
Try to give them the refund electronically instead of writing a cheque. An Australian cheque will take weeks to clear an American bank account and the bank could hold the funds until it clears.
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discard
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Not the answer you're looking for? Browse other questions tagged or ask your own question.
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1. Skip to navigation
2. Skip to content
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Source link: http://archive.mises.org/6939/the-cant-do-government/
The Can’t-Do Government
August 5, 2007 by
On The Washington Post, John McQuaid has determined that the United States is now the can’t-do nation. He starts by mentioning the recent bridge collapse in Minneapolis and wonders whether there has “ever been a period in our history when so many American plans and projects have, literally or figuratively, collapsed? In both grand and humble endeavors, the United States can no longer be relied upon to succeed or even muddle through.”
McQuaid then continues to list a number of examples that show that the “United States has become become the superpower that can’t tie its own shoelaces.”
• Remaking the Middle East
• Medical care for veterans
• General foreign policy matters
• Defense from terrorism
• Managing natural disasters (Katrina in particular)
• Health crisis (such as the avian flu)
• Rebuilding Iraq’s infrastructure
• Intelligence
Does he fail to realize that these are all giant government programs? The can’t-do attitude is symptomatic in politics and not in the market, where they have to do or die, quite literally. The state is not driven by the same incentives and since they can tax and confiscate, they lack the ability to economize and rationally allocate resources.
McQuaid, interesting enough, then claims that
In a sense, big government has failed. The bitter disputes over the Great Society-era programs fractured the nation’s rough political consensus, and the purpose of government itself became a battleground. The ongoing political knife fights cumulatively damaged the government agencies that depend on some insulation from the fray — which is to say, most of them. In the case of the New Orleans levee system, for instance, pressures from state and local agencies and limited money from Congress pushed engineers to relax safety standards and err on the side of cheapness.
And finally, he blames some of the problems on outsourcing: “Outsourcing eliminates incentives to perform well and shields contractors from accountability.”
And the incentive to perform well exists in government? Has it ever existed? And are politicians not shielded? Is McQuaid serious? The government financed the bridges in Minneapolis. Regardless of whether it was built by a “private company” (a questionable name since the funding is public) or directly by a state agency, it’s still another government program. Moreover, politicians, central planners and bureaucrats are generally very well shielded from liability. Even the police has no legal right to protect us and therefore cannot be held guilty of not saving our lives and property.
McQuaid ends his awkward call for accountability not by suggesting that we dismantle that which doesn’t work (oh, the horror that would be!), but instead proposes that we “assemble our national will, power, technical expertise and vision.” In other words, more of the same. More socialism.
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Ubuntu installation guide
From NAS-Central Buffalo - The Linkstation Wiki
Revision as of 18:05, 27 February 2011 by Wladston (Talk | contribs)
(diff) ← Older revision | Latest revision (diff) | Newer revision → (diff)
Jump to: navigation, search
WARNING!
Ubuntu dropped support for powerpc on their latest 10.10 deboostrap script. This guide is kept here for archiving purposes.
WARNING!
Backup ANY Data, because during the installation all partitions will be deleted and your DATA WILL BE LOST.
Use this guide at your own risk!
Contents
Plan of action
Installing Ubuntu from scratch is a complex and lengthy process. This is our plan of action :
1. Partition the drive
2. boot to a temporary debian system on /dev/hda3, so we can
3. debootstrap ubuntu, chroot to it, configure it and
4. compile a vanilla mainstream kernel
5. reboot and see if everything is all right
For this guide, you need to have the newer Uboot version, with the netconsole working, available in Kurobox support in stock 2.6 kernels. The guide also assumes you are using foonas-em.
(Re)Partitioning the drive
Get on EM mode
Get on EM mode. On foonas-em this is done by pressing the Power button one time after the device powered on, and while the power light is still slowly blinking. If you can't get on EM mode by this way, you can enter 'run fooflboot' on the netconsole.
Partition the disk
We will create 3 partitions : one with about 3GB for the Ubuntu system, another one with 256MB for swap, and another one that takes the rest of the disk.
# fdisk /dev/sda
-> o ( enter ) (clean the partition table on the disk)
-> n, p, 1, (enter), +3000M; (New Primary partition in position 1, from start to 2048M after it)
-> a, 1; (Set partition 1 as bootable)
-> n, p, 2, (enter), +256M; (New Primary partition in position 2, from the first free spot to 256M after it)
-> t, 2, 82; (set Type of partition 2 as 82 (Linux Swap)
-> n, p, 3, (enter), (enter); (New Primary partition 3, taking the rest of the disk)
-> w (write the changes to the disk - THIS WILL REFORMAT YOUR HD! BACKUP YOUR DATA! - )
# mkfs.ext3 -j /dev/sda1 (Create a new journaled ext3 filesystem on /dev/sda1)
# mkfs.ext3 -j /dev/sda3 (Create a new journaled ext3 filesystem on /dev/sda1)
# mkswap /dev/sda2 (Create a swap filesystem on /dev/sda2)
Install a temporary Debian system on /dev/hda3
TIP
If you already have a working installation of Gentoo, you can debootstrap Ubuntu from there without having to first install Debian. See Debootstrap Ubuntu from Gentoo
TIP
If you have the newer foonas-em mode installed, it should be possible to debootstrap and chroot from the EM mode, since it does have a 2.6 kernel.
Now we will prepare to boot a pre-made image on /dev/hda3, so we can use the debootstrap tool later on to create our final system on /dev/hda1. One could chroot to the image, using the EM Mode, and try to deboostrap from there, but to be able to chroot to the Ubuntu partition, you need to be running a newer kernel, so it's mandatory to boot on a newer kernel. (It said "FATAL : Kernel too old" for me when I tried it)
Get the Debian image and a kernel image from Debian_sylver. Be sure to grab a kernel image that supports U-boot.
Also, before proceeding, have your netconsole running, we'll need to enter special boot parameters. (Run "nc -u -p 6666 -v -v 192.168.0.100 6666", replacing 192.168.0.100 for your Kurobox Ip. Make sure your kurobox/desktop are ready to use the netconsole)
Have the Debian image ready for boot
$ mount /dev/hda3 /mnt
-> Use your favorite tool to FTP the debian image to /mnt/
-> Use your favorite tool to FTP the kernel image to /mnt/
$ cd /mnt
$ tar xvfz debian_image.tar.gz
$ tar xzf linux-kenel_image.tar.gz
$ cp boot/uImage boot/vmlinux.UBoot (U-Boot is configured to boot from vmlinux.UBoot)
$ vi etc/fstab (make sure everything is ok - /dev/hda3 should mount on /, hda1 should mount on /mnt)
Before rebooting, you should check the network settings for this temporary Debian installation. In particular, the contents of:
• /etc/network/interfaces
• /etc/resolv.conf
(The necessary contents of these files are described below in 'Configuring your Ubuntu system')
$ write_ok (the box won't boot normally if you don't issue that command)
$ reboot
At this point, have your netconsole running on your pc, be ready to stop the boot procedure hitting 's'.
Running debootstrap on the Debian Image
These steps are done on the netconsole :
-> Hit 's' before the timeout comes
=> ext2load ide 0:3 800000 boot/vmlinux.UBoot (load the kernel on the memory)
=> setenv bootargs root=/dev/hda3 (set that the root file system is on hda3)
=> bootm 800000 (finally, boot from that memory address)
Hopefully the Debian image will boot. Back on the normal shell, telnet to it :
$ telnet 192.168.0.100 (username and password : tmp-kun )
$ su (root password : root )
$ apt-get update
Note that we need to use a special version from debootstrap, one that has the ubuntu scripts :
$ apt-get install debootstrap
$ wget http://br.archive.ubuntu.com/ubuntu/pool/main/d/debootstrap/debootstrap_0.3.3.2ubuntu3_all.deb
$ dpkg -i debootstrap_0.3.3.2ubuntu3_all.deb
$ debootstrap --arch powerpc feisty /mnt http://archive.ubuntu.com/ubuntu/ (place to pickup mirrors)
This will setup a base system on /mnt, and it will take a while. Nice time for a coffee :)
Configuring your Ubuntu system
At this point, we will get your Ubuntu system ready to be booted on.
$ cp /etc/fstab /mnt/etc/fstab (just a template that will help us configuring fstab later)
$ chroot /mnt /bin/bash
$ mount -t proc proc /proc
Note that we will use the mainstream kernel on this system. This means that we have to use the PATA drivers, instead of IDE. So edit your fstab file, make sure sda1 goes to /, and sda3 goes to /mnt. Ensure we have no "hda1", "hda2" or "hda3", replace for "sda1", "sda2", "sda3".
$ vim /etc/fstab
We have to ensure the box will connect to the network. So edit the /etc/network/interfaces file.
$ vim /etc/network/interfaces (configure to use with dhcp or static config)
If you use DHPC :
auto eth0 lo
iface eth0 inet dhcp
iface lo inet loopback
If you use a static setting (replace the ips to fit you) :
auto eth0 lo
iface eth0 inet static
address 192.168.0.100
network 192.168.0.0
netmask 255.255.255.0
broadcast 192.168.0.255
gateway 192.168.0.1
iface lo inet loopback
Ok, let's move on :
$ vim /etc/resolv.conf (make sure that is has your nameserver/router)
$ echo NameOfYourBox > /etc/hostname (this is the coolest part - name your host! )
$ vim /etc/hosts (Update your hosts file with your new IP & hostname (if using static IP)
127.0.0.1 localhost
192.168.0.100 NameOfYourBox
$ vim /etc/apt/sources.list ( you can generate one for you on http://www.ubuntu-nl.org/source-o-matic/ )
$ apt-get update
$ apt-get install console-data (reconfigure keyboard, if needed)
$ dpkg-reconfigure console-data
$ vim etc/hosts.allow (you should add your network there)
ALL : 192.168.0.0/255.255.0.0
ALL : 127.0.0.1
$ dpkg-reconfigure tzdata (adjust your timezone)
$ adduser YourUserName
$ passwd (change the root password)
$ visudo (add the following to the file, and save, so your user can use sudo)
YourUserName ALL=(ALL) NOPASSWD: ALL
$ apt-get install ubuntu-standard (This set of packages provides a comfortable text-only Unix-like environment)
$ apt-get install ssh (you'll need this to login to your Kurobox later)
Building the kernel
# apt-get install git git-core make patch unzip bison flex libncurses5-dev gcc (install the additional packages for compiling kernel)
# update-alternatives --config git (choose #2: git-scm - we need git to get the sources for dtc)
# chown -R YourUserName:users /usr/src (you need permission to write on that folder)
# su YourUserName (this part is meant to be run as a normal use)
$ cd /usr/src
$ wget http://www.kernel.org/pub/linux/kernel/v2.6/linux-2.6.21.tar.bz2 (get the most recent from http://www.kernel.org/pub/linux/kernel)
$ tar xjf linux-2.6.21.tar.bz2
$ ln -sf linux-2.6.21 linux
$ git clone git://www.jdl.com/software/dtc.git dtc (the dtc tool is used to compile a required special hardware database file)
$ cd /usr/src/dtc
$ make
$ sudo ln -sf /usr/src/dtc/dtc /usr/local/bin/
$ sudo apt-get install uboot-mkimage (that is needed to produce kernel images that the u-boot can boot into)
$ cd /usr/src/linux
$ cp arch/powerpc/configs/linkstation_defconfig .config
$ make menuconfig
$ make uImage modules
$ exit
# cd /usr/src/linux
# make modules_install
# cp arch/powerpc/boot/uImage /boot/vmlinux.UBoot
# cp arch/powerpc/boot/dts/kuroboxHG.dts /boot/
# cd /boot
# dtc -f -I dts -O dtb -o kuroboxHG.dtb -V 16 kuroboxHG.dts
# reboot
(User:Mflint suspects that 'jigit' package is not needed -- indeed, maybe it's really not, removed from the guide)
Boot your Ubuntu OS
Make the Power/Back button work
$ sudo apt-get install avr-evtd
$ sudo vim /etc/default/avr_evtd (tweak the configuration to suit your needs)
Make Hwclock work
Hwclock only reads from /dev/rtc, but the system makes /dev/rtc0. Add this command to have udev to link rtc->rtc0 every time the system boots, so you can use the hwclock command. Just add the line to the file:
$ sudo vim /etc/udev/rules.d/50-udev.rules
KERNEL=="rtc0", SYMLINK+="rtc"
Fix Perl locale-related problems
If you see the following error when running perl:
perl: warning: Setting locale failed.
perl: warning: Please check that your locale settings:
LANGUAGE = (unset),
LC_ALL = (unset),
LANG = "en_GB.UTF-8"
are supported and installed on your system.
perl: warning: Falling back to the standard locale ("C").
Then run:
# locale-gen en_GB.UTF-8 en_US.UTF-8
(be sure to choose an appropriate locale)
Install popularity-contest
Inform the repository that you are using the packages related to the Kurobox, so they don't get forgotten, run :
# sudo apt-get install popularity-contest
How could this guide be improved
• Provide a very slim base system, already using the newer u-boot kernel, and already having debootstrap installed;
Personal tools
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rcqp (0.3)
Interface to the Corpus Query Protocol.
http://www.r-project.org
http://cran.r-project.org/web/packages/rcqp
implements Corpus Query Protocol functions based on the CWB software. Rely on CWB (GPL v2), PCRE (BSD licence), glib2 (LGPL).
Maintainer: Sylvain Loiseau, University of Paris 13
Author(s): Bernard Desgraupes <bernard.desgraupes@u-paris10.fr>, Sylvain Loiseau <sylvain.loiseau@univ-paris13.fr>
License: GPL-2
Uses: plyr, reshape
Released 7 months ago.
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Page creatorFlorixc (Talk | contribs)
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Brazil HeraldryEdit This Page
From FamilySearch Wiki
In Brazil, members of the noble class were entitled to bear coats of arms. The Portuguese kings rewarded persons who performed a heroic deed, attained notable achievement, or held a prominent position in government by granting them a noble title and the right to use a coat of arms. These grants were documented.
Various authors in Brazil have prepared heraldry books. Heraldry books give descriptions of coats of arms and some information on the first person to bear it. It may briefly describe the person’s entitlement to that coat of arms. It may also note early bearers of that coat of arms, sometimes with relationships, birth dates, and other genealogical information. Each armorial (a book on heraldry) will differ from others and will include different names. The following sources are of particular interest in Brazil:
• Boletim (Bulletin). Rio de Janeiro: Colégio de Armas e Consulta Heráldica, 1955. (FHL book 981 B2c)
• Moya, Salvador de. Simbologia Heráldica (Heraldic Simbolism). São Paulo: Instituto Genealógico Latino, 1961. (FHL book 981 D6m) This publication gives many coats of arms.
The Family History Library has some armorials. These are listed in the Family History Library Catalog under:
BRAZIL- HERALDRY
Sources with information about noble ancestors may also be listed in the Family History Library Catalog under:
BRAZIL- NOBILITY
In addition, such families are often subjects of published genealogical books or articles. See Brazil Genealogy and Brazil Nobility.
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• This page was last modified on 29 April 2011, at 01:24.
• This page has been accessed 732 times.
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Putnam County, West VirginiaEdit This Page
From FamilySearch Wiki
Revision as of 17:50, 15 March 2012 by Murphynw (Talk | contribs)
United States West Virginia Putnam County
Putnam County, West Virginia
Map
Location in the state of West Virginia
Location of West Virginia in the U.S.
Facts
Founded March 11, 1848
County Seat Winfield
Courthouse
Contents
County Courthouse
Putnam County
3389 Winfield Road
Winfield WV 25213
Phone 304-586-0202
• County Clerk has birth records from 1848, death records from 1853
• Marriage and probate records from 1853
• Land records from 1841
• Circuit Court Clerk has divorce and court records[1]
History
The county is named after Revolutionary War Major General Israel Putnam (1718-1790).[2]
Parent County
1848--Putnam County was created 11 March 1848 from Kanawha, Mason and Cabell Counties. County seat: Winfield [1]
Boundary Changes
See an interactive map of Putnam County boundary changes.
Record Loss
Places / Localities
Populated Places
Neighboring Counties
Resources
Cemeteries
Census
For tips on accessing Putnam County, West Virginia census records online, see: West Virginia Census.
Join us in indexing the 1940 Census
Church
Court
Land
Local Histories
Maps
Map of 1850 Virginia and West Virginia
Military
West Virginia, Civil War Service Records of Union Soldiers, 1861-1865
Naturalization
West Virginia,Naturalization Records, 1814-1991
Newspapers
Probate
West Virginia Will Books
Vital Records
West Virginia Vital Records - Birth - Death - Marriages
Societies and Libraries
Putnam County Family History Hall of Fame
"May we preserve their memories & Contributions!"
Please write about deceased historians & Genealogist!
Family History Centers
Introduction to LDS Family History Centers. The closest family history centers are in the Huntingon Family History Center and in the Charleston Family History Center
•
Web Sites
Learning How to Edit our Wiki Sites
Genealogy courses: Learn how to research from an expert in Fun Five Minute Genealogy Videos.
References
1. 1.0 1.1 The Handybook for Genealogists: United States of America,10th ed. (Draper, UT:Everton Publishers, 2002).
2. "Putnam County, West Virginia," Wikipedia.
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Quotation added by staff
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Justice consists of doing no one injury, decency in giving no one offense. Cicero, Marcus T.
This quote is about justice · Search on Google Books to find all references and sources for this quotation.
A bit about Cicero, Marcus T. ...
Marcus Tullius Cicero (January 3, 106 BC - December 7, 43 BC) was an orator, statesman, political theorist, lawyer and philosopher of Ancient Rome. He is considered by many to be amongst the greatest of the Latin orators and prose writers.
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Conceit in weakest bodies works the strongest. Shakespeare, William
This quote is about conceit · Search on Google Books to find all references and sources for this quotation.
A bit about Shakespeare, William ...
Born ca. 1564 and died ca. 1616 during the Renaissance period (1450-1599). One of the greatest writers of all time, Shakespeare, the peerless poet of the Sonnets and the creator of such dramatic masterpieces as Romeo and Juliet, Hamlet, and King Lear, is a playwright of paradigmatic originality. In his discussion of the Western literary canon, critic Harold Bloom declared: "Shakespeare and Dante are the center of the Canon because they excel all other Western writer in cognitive acuity, linguistic energy, and power of invention." However, one could go a step further and suggest that Shakespeare defines the Western canon because he transcends it. If Shakespeare, as Ben Jonson declared, "was not of an age, but for all time," the great dramatist, one could argue, spoke to the ultimate concerns of humankind, regardless of period or cultural tradition.
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