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Bibliography: Conqueror
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Title: Conqueror
Author: Stephen Baxter
Year: 2007
Type: NOVEL
Series: Time's Tapestry
Series Number: 2
ISFDB Record Number: 348561
User Rating: This title has fewer than 5 votes. VOTE
Current Tags: science fiction (1) Add Tags
Variant Titles:
Awards:
Publications:
Reviews:
Copyright (c) 1995-2011 Al von Ruff.
ISFDB Engine - Version 4.00 (04/24/06)
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Sugary drinks linked to obesity epidemic
PanARMENIAN.Net - New research powerfully strengthens the case against soda and other sugary drinks as culprits in the obesity epidemic, The Associated Press reports.
A huge, decades-long study involving more than 33,000 Americans has yielded the first clear proof that drinking sugary beverages interacts with genes that affect weight, amplifying a person's risk of obesity beyond what it would be from heredity alone.
This means that such drinks are especially harmful to people with genes that predispose them to weight gain. And most of us have at least some of these genes.
In addition, two other major experiments have found that giving children and teens calorie-free alternatives to the sugary drinks they usually consume leads to less weight gain.
Collectively, the results strongly suggest that sugary drinks cause people to pack on the pounds, independent of other unhealthy behavior such as overeating and getting too little exercise, scientists say.
That adds weight to the push for taxes, portion limits like the one just adopted in New York City, and other policies to curb consumption of soda, juice drinks and sports beverages sweetened with sugar.
Soda lovers do get some good news: Sugar-free drinks did not raise the risk of obesity in these studies.
"You may be able to fool the taste" and satisfy a sweet tooth without paying a price in weight, said an obesity researcher with no role in the studies, Rudy Leibel of Columbia University.
The studies were being presented Friday, Sept 21, at an obesity conference in San Antonio and were published online by the New England Journal of Medicine.
Sugary drinks are the single biggest source of calories in the American diet, and they are increasingly blamed for the fact that a third of U.S. children and teens and more than two-thirds of adults are obese or overweight.
Consumption of sugary drinks and obesity rates have risen in tandem — both have more than doubled since the 1970s in the U.S.
But that doesn't prove that these drinks cause obesity. Genes, inactivity and eating fatty foods or just too much food also play a role. Also, diet research on children is especially tough because kids are growing and naturally gaining weight.
Partner news
Top stories
Earlier, ArmRosgasprom CJSC addressed Armenia’s Public Services Regulatory Commission with an offer to reconsider natural gas price.
Armenian defense ministry’s spokesman described the maneuvers as ordinary exercises conducted several times a year.
Participants will learn basic skills in protecting IT systems and data as well as how to investigate computer-facilitated crimes.
“I wish to further promote the beauty of Armenian art and its principles of tolerance and respect to diversity,” Mnatsakanyan said.
Partner news
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International Union of Pure and Applied Chemistry nomenclature
(Redirected from IUPAC name)
Jump to: navigation, search
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
IUPAC nomenclature is a system of naming chemical compounds and of describing the science of chemistry in general. It is developed and kept up to date under the auspices of the International Union of Pure and Applied Chemistry (IUPAC).
The rules for naming organic and inorganic compounds are contained in two publications, known as the Blue Book[1][2] and the Red Book[3] respectively. A third publication, known as the Green Book,[4] describes the recommendations for the use of symbols for physical quantities (in association with the IUPAP), while a fourth, the Gold Book,[5] contains the definitions of a large number of technical terms used in chemistry. Similar compendia exist for biochemistry[6] (in association with the IUBMB), analytical chemistry[7] and macromolecular chemistry [8]. These books are supplemented by shorter recommendations for specific circumstances which are published from time to time in the journal Pure and Applied Chemistry.
This article treats the system of nomenclature in general, notably its aims and historical development. Separate articles treat the naming of organic compounds and inorganic compounds in more detail.
Aims of chemical nomenclature
The primary function of chemical nomenclature is to ensure that the person who hears or reads a chemical name is under no ambiguity as to which chemical compound it refers: each name should refer to a single substance. It is considered less important to ensure that each substance should have a single name, although the number of acceptable names is limited.
It is also preferable that the name convey some information about the structure or chemistry of a compound. CAS numbers form an extreme example of names which do not perform this function: each refers to a single compound but none contain information about the structure.
The form of nomenclature which should be used depends on the public to which it is addressed: as such there is no single correct form, but rather different forms which are more or less appropriate in different circumstances.
A common name will often suffice to identify a chemical compound in a particular set of circumstances. To be more generally applicable, the name should indicate at least the chemical formula. To be more specific still, the three-dimensional arrangement of the atoms may need to be specified.
In a few specific circumstances (such as the construction of large indices), it becomes necessary to ensure that each compound has a unique name: this requires the addition of extra rules to the standard IUPAC system (the CAS system is the most commonly used in this context), at the expense of having names which are longer and less familiar to most readers. Another system gaining popularity is the International Chemical Identifier—while InChI symbols are not human readable, they contain complete information about substance structure. That makes them more general than CAS numbers.
The IUPAC system is often criticized for the above failures when they become relevant (for example in differing reactivity of sulfur allotropes which IUPAC doesn't distinguish). While IUPAC has a human-readable advantage over CAS numbering, it would be difficult to claim that the IUPAC names for some larger, relevant molecules (such as rapamycin) are human-readable, and so most researchers simply use the informal names.
History
First page of Lavoisier's Chymical Nomenclature in English.
The nomenclature of alchemy is rich in description, but does not effectively meet the aims outlined above. Opinions differ whether this was deliberate on the part of the early practitioners of alchemy or whether it was a consequence of the particular (and often esoteric) theoretical framework in which they worked.
While both explanations are probably valid to some extent, it is remarkable that the first "modern" system of chemical nomenclature appeared at the same time as the distinction (by Lavoisier) between elements and compounds, in the late eighteenth century.
The French chemist Louis-Bernard Guyton de Morveau published his recommendations[9] in 1782, hoping that his "constant method of denomination" would "help the intelligence and relieve the memory". The system was refined in collaboration with Berthollet, de Fourcroy and Lavoisier,[10] and promoted by the latter in a textbook which would survive long after his death at the guillotine in 1794.[11] The project was also espoused by Jöns Jakob Berzelius,[12][13] who adapted the ideas for the German-speaking world.
The recommendations of Guyton covered only what would be today known as inorganic compounds. With the massive expansion of organic chemistry in the mid-nineteenth century and the greater understanding of the structure of organic compounds, the need for a less ad hoc system of nomenclature was felt just as the theoretical tools became available to make this possible. An international conference was convened in Geneva in 1892 by the national chemical societies, from which the first widely accepted proposals for standardization arose.[14]
A commission was set up in 1913 by the Council of the International Association of Chemical Societies, but its work was interrupted by World War I. After the war, the task passed to the newly formed International Union of Pure and Applied Chemistry, which first appointed commissions for organic, inorganic and biochemical nomenclature in 1921 and continues to do so to this day.
Types of nomenclature
For inorganic compounds there are a number of different ways in which compounds can be named. These are compositional, substitutive and additive. The different methods of nomenclature are covered in the article IUPAC nomenclature of inorganic chemistry 2005, which summarises the latest IUPAC recommendations.
Compositional nomenclature
Examples of compositional names are:
• PCl5 phosphorus pentachloride
• Ca2P3 dicalcium triphosphide
An alternative method uses the oxidation state on the metal in place of suffices e.g.:
• SnCl2, tin (II) chloride as an alternative to tin dichloride.
Substitutive nomenclature
This naming method generally generally follows established IUPAC organic nomenclature. Hydrides of the main group elements (groups 13-17) are given -ane base names, e.g. borane, BH3, phosphane, PH3(N.B. not phosphine). The compound PCl3 would be named substitutively as trichlorophosphane.
Additive nomenclature
This naming method has been developed principally for coordination compounds although it can be more widely applied. An example of its application is:
• [CoCl(NH3)5]Cl2 pentaamminechloridocobalt(2+) chloride
Note that ligands such as chloride become chlorido- rather than chloro as in substitutive naming.
See also
References
1. [1958 (A: Hydrocarbons, and B: Fundamental Heterocyclic Systems), 1965 (C: Characteristic Groups)] (1971 (3rd edition combined)) Nomenclature of Organic Chemistry, 3 (in English), London: Butterworths. ISBN 0408701447.
2. Nomenclature of Organic Chemistry, Oxford:Pergamon Press, 1979; A Guide to IUPAC Nomenclature of Organic Compounds, Recommendations 1993, Oxford:Blackwell Scientific Publications, 1993. (ISBN 3-540-41138-0)
3. Connelly NG, McCleverty JA (2001). Nomenclature of inorganic chemistry II: recommendations 2000. Cambridge: Royal Society of Chemistry. ISBN 0-85404-487-6.
4. Quantities, Units and Symbols in Physical Chemistry (3rd Edn.), Oxford:Blackwell Scientific Publications. (2007)
5. Compendium of Chemical Terminology, IUPAC Recommendations (2nd Edn.), Oxford:Blackwell Scientific Publications. (1997)
6. Biochemical Nomenclature and Related Documents, London:Portland Press, 1992.
7. Compendium of Analytical Nomenclature, Definitive Rules 1997 (3rd Edn.), Oxford:Blackwell Scientific Publications, 1998.
8. Compendium of Macromolecular Nomenclature, Oxford:Blackwell Scientific Publications, 1991.
9. Guyton de Morveau, L. B. (1782). J. Phys. '19', 310.
10. Guyton de Morveau, L. B.; Lavoisier, A. L.; Berthollet, C. L.; de Fourcroy, A. F. (1787). Méthode de Nomenclature Chimique, Paris.
11. Lavoisier, A. L. (1801). Traité Elémentaire de Chimie (3e edn.), Paris:Deterville.
12. Berzelius, J. J. (1811). J. Phys. '73', 248.
13. Jaime Wisniak (2000). "Jöns Jacob Berzelius A Guide to the Perplexed Chemist". The Chemical Educator 5 (6): 343–350. doi:10.1007/s00897000430a.
14. Bull. Soc. Chim. (Paris) '3'(7), xiii. (1892)
External links
bg:Номенклатура на Международния съюз за чиста и приложна химия ca:Nomenclatura orgànica da:IUPAC nomenklatur de:Nomenklatur (Chemie) et:IUPACi nomenklatuur fa:نامگذاری اتحادیه بینالمللی شیمی محض و کاربردیko:IUPAC 명명법 id:Tatanama IUPAC is:Nafnakerfi IUPAC he:מונחון IUPAC lt:IUPAC nomenklatūra nl:IUPAC-nomenclatuurno:IUPAC nomenklatursr:IUPAC номенклатура fi:IUPAC-nimeämiskäytäntö sv:IUPAC-nomenklatur th:ระบบการเรียกชื่อสารเคมีของ IUPAC
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Australian Bureau of Statistics
Celebrating the International Year of Statistics 2013
ABS Home
Current Issue Not Yet Released
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Here is a link to the previous issue: http://abs.gov.au/ausstats/abs@.nsf/mf/8762.0?OpenDocument
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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.
So I’m finishing up on my project, a real-time dictionary that works while you type in anything. I’m now getting to where I’m thinking through the integrating a license key to the buying of the software. That my software will be at version 1 at release makes me think that I won’t have the features quite right so but want enough protection that it would be an inconvenience to steel it and that if you like the product you’ll buy it.
So I want the minimum shopping cart (not really a cart but a simple buy) and minimum license integration. Looking at google cart and considering reviewing paypal as well.
I’m thinking for this first version that what I am really looking to achieve is the realization that the product and pricing are valid. So I am looking for that solution that makes it really easy for a customer to buy.
Suggestions on to buy or to make?
share|improve this question
3 Answers
up vote 1 down vote accepted
If you use a payment processor like AvanGate or FastSpring they offer licensing and shopping cart together, so you don't have to build your own.
From my, very recent experience, Paypal is the easiest to integrate but has no licensing as far I know.
I'm using AvanGate on my site and they offer both licensing with product key delivery and other more advanced options. Shopping cart is pretty advanced and has many options in pricing and customization.
Is not that easy to setup as Paypal thought.
share|improve this answer
If you're coding, here's a simple PHP <-> paypal ipn integration tutorial.
If you're not coding, why not use a cms framework like joomla and get a payment plugin?
share|improve this answer
If you experience any type of growth in your shopping cart experience, you will be re-inventing the wheel, from scratch, no matter how simple it looks now.
If you're using an off-site shopping cart (paypal, shopify, etc) use them and simply integrate and brand.
Where you end up behind the ball over time is the same hardening/security everyone has to build into every single site. Building a cart from scratch is an exercise in building some pretty serious technical debt, unless your needs are so special that they can't be fitted or adapted to something already out there.
If your core business is the carts, do it. If your core business is something else, find something close to the purchasing process you want and automate it some more.
I had good luck doing that with a product called Cartweaver 10 years ago. It has stayed with me and I've customized and developed it over the years for different projects. I'm sure you can find your equivalent.
All the best! Share what you end up doing and why.
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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'm relatively new to blogging - only been doing it for a few months. The common advice is to make your posts keyword rich for high search engine ranking. But I don't normally worry too much about that. I do take it into consideration, and make an effort to include keywords if it makes sense, but I don't go crazy if I can't. My biggest concern is making my posts informative and easy to read.
Just curious as to what your thoughts are on this topic. How do you approach your writing? Do you try to make your posts as keyword rich as possible? Do you not worry about it at all? And how successful (i.e. increasing readership) have you been with your approach?
Also, do you have any recommendations on how to increase the use of keywords in blog posts?
share|improve this question
5 Answers
up vote 2 down vote accepted
I've been writing for a year and a half, about to hit 300 articles on my site. While I don't ignore keywords completely, I usually take them into account after the fact, or when writing titles. That is, I write what I want to write, but will then modify the title to be link bait, or toss in a keyword.
The end result, though, is that it doesn't seem to make much difference in most cases. I'm still being found by people asking the questions I answer on my site, regardless of whether or not I've optimized that article in particular. I'm not getting a lot of hits for random keywords, but more for the overall content.
In summary, I would suggest you basically ignore the issue of keywords, and focus on writing good copy in general, and writing about interesting topics to your target audience.
share|improve this answer
None at all.
I know some people say it's the whole thing, but in the past three years of blogging I still get almost zero traffic from Google and tons from human beings sharing links (in every way: Twitter, FB, Reddit, blog posts, email, whatever).
You win when people like it and tell their friends.
It's too hard (IMHO) to compete on Google with everything else, especially when you're new to it.
share|improve this answer
Don't worry too much about the keywords in your posts. I agree with Jason that the best way to increase traffic to your blog is to write interesting content, good content will keep people coming back to your site. However, I believe it is also important to make it easy for people to subscribe to your blog, either by email, rss feed, etc... try to motivate people to comment by asking them to do it at the end of your posts, etc... and if you are interested in getting some traffic from search engines then you could use "good" keywords in the title of your posts, that should be sufficient.
I have a new blog, just started it a month ago and just like Jason mentioned above, most of the traffic comes from hacker news, twitter, StumbleUpon, etc... I don't worry about keywords, however, there have been a couple of posts where because of the title of the post, I rank 1 or 2 in Google from thousands of results... I just think that is interesting, since this is a new blog.
These are the some of the search where my blog ranks just below Google's own news site, I did nothing to accomplish this, just used descriptive blog post titles:
• texas education channel on itunes u
• 499.00 jet blue deals
• profit earn by dell (my site ranks higher than businessweek for this one... :))
• wpengine and secure ftp
Write good interesting content and you'll be fine, more importantly, be honest and do not try to make everyone happy.
Good luck!
share|improve this answer
Sometimes I look at my analytics for keywords that are bringing traffic to my site, and if its a phrase I haven't blogged on before, I'll write a blog about that phrase.
share|improve this answer
We don't. Our blog is very topic specific and trying to game Google would just alienate our readers and make for a less enjoyable experience for us. That being said the topic specificness of the blog means we tend to rank fairly well for almost anything in our core area of interest.
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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.
After researching a lot my team came up with a number of educational organisations those do not have their own websites. We primarily design websites of all kinds.
So we have decided to send all of them a business proposal to design their websites. I am not sure what to write in the letter so that I can explain about our company and also impress the concerned person.
a.should we mention the pricing scheme
b.how to convince them about the necessity of websites
sorry i forgot to mention that we are going to send the proposals via letters....not via emails.
share|improve this question
3 Answers
up vote 2 down vote accepted
Talk to them of the benefits that they will enjoy after owning a website. As a business person myself, with no knowledge of technology. I don't care of a website itself, or facebook or etc.
I just care about how many hundreds or thousand of people I will reach with a website. How will that impact my business?
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I don't think they are ready for proposals yet. Start with a lower barrier to action, like inviting them to get a free consultation. Otherwise you are just wasting your time and money.
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You should tailor each message to the individual site you are emailing. Otherwise you are wasting your time crafting a spam message that will be deleted upon arrival from 100% of the people you send it to.
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Study of Tensile Strength Distribution Based on Composite Materials for Aeronautical Engineering
Du Baojiang, Ji Changqin, Chen Ping, Guo Jingmin, Sun Anbo, Wei Xiong
Abstract
The Tensile strength of an composite materials for aeronautical engineering was tested and its distribution was analyzed based on the two parameter weibull distribution?The maximum normed residual (MNR) test was applied to eliminate abnormal data. A graphical method was used to estimate parameters. Furthermore?the validity of the assumed distribution was examined by the kolmogorov test (KS). The results show that MNR test can be used to exclude abnormal data. It also suggests that the gained two parameter weibull distribution can be used to express the tensile strength and predict its values accurately.
Full Text: PDF DOI: 10.5539/mas.v6n5p21
This work is licensed under a Creative Commons Attribution 3.0 License.
Modern Applied Science ISSN 1913-1844 (Print) ISSN 1913-1852 (Online)
Copyright © Canadian Center of Science and Education
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"url": "familysearch.org/learn/wiki/en/Delaware_Slavery_and_Bondage",
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Delaware Slavery and BondageEdit This Page
From FamilySearch Wiki
United States Delaware Slavery and Bondage
Adopt-a-wiki page
This page adopted by:
DEGenWeb Project
who welcome you to contribute.
Adopt a page today
Slaves in Delaware are sometimes mentioned in deeds (see "Land and Property"), in wills (see "Probate Records"), in tax records (see "Taxation"), and in court order books (see the "Court Records" pages of these Delaware Wiki pages). A few parish registers ("Church Records") list slaves who attended church with their masters.
For lists of licenses to import and export slaves see Mary Fallon Richards "New Castle County Licenses to Import and Export Slaves, Issued by Superior Court, Delaware Genealogical Society Journal 1, no. 1 (October 1980): The master is listed, with the names of the slaves, their ages, transported from where to where, dates, and other information.
For more information about slaves see the Place Search of the Family History Library Catalog under:
DELAWARE - MINORITIES
DELAWARE - COLONIZATION
DELAWARE - EMIGRATION AND IMMIGRATION
Need additional research help? Contact our research help specialists.
Need wiki, indexing, or website help? Contact our product teams.
Did you find this article helpful?
You're invited to explain your rating on the discussion page (you must be signed in).
• This page was last modified on 5 December 2012, at 02:42.
• This page has been accessed 1,170 times.
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COIN
Unique ID: NMS-EC33
Chronology
Broad period: ROMAN
Period from: ROMAN [scope notes | view all attributed records]
Date from: Circa AD 81
Date to: Circa AD 96
Dimensions and weight
Quantity: 1
Discovery dates
Date(s) of discovery: Wednesday 1st June 2005
Personal details
Found by: This information is restricted for your login.
Recorded by: Ms Katharine Kelland - [ view all attributed records]
Identified by: Adrian Marsden - [view all attributed records]
Other reference numbers
Materials and construction
Coin data (numismatics)
Denomination: Dupondius or as [scope notes | view all attributed records]
Ruler/issuer: Domitian [scope notes | view all attributed records]
Reece period: Period 4 [69-96] [scope notes | view all attributed records]
Mint or issue place: Rome (Italy) [scope notes | view all attributed records]
Obverse description: Head right
Obverse inscription: [..]
Reverse description: Illegible
Reverse inscription: [..]
Status: Regular
There are currently no images available.
Do you own this object, send us a picture!
QR barcode
The barcode on the right is a unique identifier for this record. If your phone has scanning software installed, then this can be used for sharing or you can print it off and attach it to the object.
Spatial metadata
Region: East
County: Norfolk
District: Breckland
Parish: Beeston With Bittering
Spatial coordinates
4 Figure: TF8915
Four figure Latitude: 52.699677 Four figure longitude: 0.795662
1:25K map: TF8915
1:10K map: TF81NE
Unmasked grid reference accurate to a 1 metre square.
Discovery metadata
Method of discovery: Metal detector [scope notes]
Adjacent Domesday Book places
Domesday data within 2 km of discovery point is surfaced via the excellent Open Domesday website.
References cited
No references cited so far.
Similar objects
Find number: HAMP10
Object type: COIN
Broadperiod: ROMAN
Workflow: Published
Find number: HAMP1011
Object type: COIN
Broadperiod: ROMAN
Sestertius of Hadrian
Workflow: Published
Find number: HAMP1032
Object type: COIN
Broadperiod: ROMAN
Workflow: Published
Spotted a mistake? Tell us. Be the first to comment
Comment on this artefact's record
Data entered via this form is checked against the akismet service to recognise spam.
Audit data
Created: Monday 19th March 2007
Updated: Thursday 24th February 2011
This page is available in: qrcode json xml geojson representations.
Social Bookmarking:
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FORCES FROM FLUID FLOW AROUND OBJECTS
John H. Nath, Tokuo Yamamoto
Abstract
All hydrodynamic forces on submerged objects are shown to be due to the acceleration effects of the fluid flow. However, it is useful to consider separately the influence from the various ambient flow and local flow conditions. At times certain aspects of the flow can be ignored, which simplifies the analysis. Examples are developed for circular cylinders near a plane boundary with a flow direction parallel to the boundary and perpendicular to the cylinder. Potential flow theory predicts that large vertical forces exist away from the boundary when the cylinder is against the boundary and that large negative forces exist toward the boundary when the cylinder is positioned a small distance from the boundary, when the viscous effects are small. When the cylinder is near the boundary, the added mass coefficient is the same regardless of the direction of the flow, providing the flow is perpendicular to the cylinder. In addition, the added mass coefficient is much larger for cylinders near the boundary than when they are in a free stream. Good agreement between theory and laboratory experimentation was obtained for various coefficients with waves on horizontal cylinders near a plane boundary.
Keywords
fluid flow; flow force; flow around objects
Full Text: PDF
This work is licensed under a Creative Commons Attribution 3.0 License.
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LONGSHORE CURRENT AND TRANSPORT ACROSS NON-SINGULAR EQUILIBRIUM BEACH PROFILES
Kevin R. Bodge
Abstract
The longshore current and longshore sediment transport distributions are described across an equilibrium beach profile comprised of an intersecting planar foreshore and a concave-up profile. Such a profile shape avoids the singularity associated with the infinite-slope at the shoreline described by traditional equilibrium profile forms and allows prediction of beach processes at and above the shoreline. The mathematical expressions which describe the distributions are simplified and can be more readily applied relative to expressions previously presented in the literature. The findings are in general agreement with similar previous analytic studies and indicate that the current and transport maxima are generally located at about the intersection of the planar and concave-up portions of the profile.
Keywords
longshore current; longshore transport; nonsingular equilibrium profile; beach profile; equilibrium profile
Full Text: PDF
This work is licensed under a Creative Commons Attribution 3.0 License.
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[hafqa] [hafqa] [Bug 630] Increased Bugzilla transparency - get the developers involved!
From: bugzilla-daemon at maemo.org bugzilla-daemon at maemo.org
Date: Sat Sep 16 02:04:30 EEST 2006
https://maemo.org/bugzilla/show_bug.cgi?id=630
------- Additional Comments From ferenc at maemo.org 2006-09-16 02:04 -------
Guys, why the hell we just do not explain things instead of doing this silly
fights behind the curtains?
We needed "maemo qa", because the team -who was busy implementing the 770
software- could not handle all the bugs over here. There is an other team -I am
member of that; taking care of maemo SDKs, the web services, public repos etc-
who decided to introduce "maemo qa" until the real development team will free up
resources and can assign someone for each software component.
There are two guys behind "maemo qa". One of them is active and investigating
every single report people file here and tries to find the best person inside
Nokia, who will proceed with the bug. The other one is myself, who is really
lazy, just observing stuff from a distance, but will stand behind the current
process as long as it lasts. So I hope the "personalization" of "maemo qa" can
be considered done with this. I take all the blames, my colleague takes care of
the real job.
I know, we know that there is an issue with handling bugs over here. We -inside
Nokia- have more hands now to take care of these, so hope that the situation
will change for the better. See Luc's comment on HAF stuff.
Until you see an improvement in the error management process and want to blame
"maemo QA" just send mails to me (me != /dev/null, I promise).
--
Configure bugmail: https://maemo.org/bugzilla/userprefs.cgi?tab=email
------- You are receiving this mail because: -------
You are the QA contact for the bug, or are watching the QA contact.
More information about the hafqa mailing list
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Quotation added by adonybus
Why not add this quote to your bookmarks?
Those who think they think eventually become the herd... Blum, Donald
This quote is about adonybus · Search on Google Books to find all references and sources for this quotation.
A bit about Blum, Donald ...
The author is me, I've been writing for myself and for others over a period of twenty five years.. Succint phrases such as those found in the "Quotations Book" have been my morning resonance... Thank you, Don H Blum
These people bookmarked this quote:
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"url": "redsarmy.com/tag/european-vacation/",
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Every morning, we compile the links of the day and dump them here… highlighting the big storyline. Because there's nothing quite as satisfying as a good morning dump. In a trip that could resemble Team USA's takeover of the world stage at the 2008 Beijing Games, Kobe Bryant, LeBron James, Dwyane Wade, Derrick Rose, Carmelo [...]
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The Thresher (Houston, Tex.), Vol. 35, No. 23.5, Ed. 1 Saturday, April 10, 1948
Files in this item
Files Size Format View
thr19480410.pdf 3.089Mb application/pdf
Show simple item record
Item Metadata
dc.coverage.spatial United States - Texas - Harris County - Houston
dc.coverage.temporal Into Modern Times, 1939-Present
dc.date.accessioned 2012-11-07T02:51:03Z
dc.date.available 2012-11-07T02:51:03Z
dc.date.issued 1948-04-10
dc.identifier.uri http://hdl.handle.net/1911/65867
dc.description two pages : ill. ; page 21 x 15 in.
dc.description.abstract A weekly student newspaper from the Rice Institute in Houston, Texas that includes campus news and commentaries along with advertising.
dc.language eng
dc.publisher Rice University
dc.relation.ispartof This digitized newspaper is also presented online at the Portal to Texas History, at http://texashistory.unt.edu/ark:/67531/metapth230749/
dc.relation.ispartofseries This Issue appears in Vol. 35 of the Rice Thresher.
dc.rights Rights to this material belong to Rice University. This digital version is licensed under a Creative Commons Attribution 3.0 Unported license.
dc.rights.uri http://creativecommons.org/licenses/by/3.0/
dc.subject.lcsh Harris County (Tex.) -- Newspapers
Houston (Tex.) -- Newspapers
Houston (Tex.) -- Periodicals
Student publications -- Texas -- Houston
College student newspapers and periodicals -- Texas -- Houston
dc.title The Thresher (Houston, Tex.), Vol. 35, No. 23.5, Ed. 1 Saturday, April 10, 1948
dc.digitization.specifications Page images were scanned by the UNT Portal to Texas History from microfilm as 8-bit grayscale at 400 dpi and saved as TIF masters, with OCR'd PDF access copies.
dc.source.collection Rice Thresher, Fondren Library, Rice University, Houston, Tex.
dc.citation.volumeNumber 35
dc.citation.issueNumber 23.5
dc.identifier.digital thr19480410
dc.contributor.publisher Rice Institute
dc.type.genre Newspaper
dc.type.dcmi Text
dc.identifier.citation (1948). "The Thresher (Houston, Tex.), Vol. 35, No. 23.5, Ed. 1 Saturday, April 10, 1948." vol. 35. no. 23.5,
Rights and Usage
This item appears in the following Collection(s)
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KDE
From Gentoo Wiki
Jump to: navigation, search
External resources
KDE is a powerful graphical desktop environment for Unix workstations.
Contents
Available versions
KDE SC 4 is the current KDE version supported by upstream. In Portage there is a stable version, and there might be one (or more) non-stable versions. Under normal conditions new versions get in stabilized after a month. In addition, KDE upstream provides live git source repositories. The Gentoo KDE team provides trunk and latest branch live ebuilds through the kde overlay.
Choose what KDE SC version is most appropriate for you:
KDE SC version Repository Status
KDE SC 4.10.2 Portage Stable for amd64, ppc, ppc64 and x86; testing for arm
KDE SC 4.10.3 Portage Testing
KDE SC 4.10 stable branch kde overlay Live version
KDE SC trunk kde overlay Live version
Note
Users with stable systems need to put this keywords file in /etc/portage/package.keywords to install testing versions.
Note
If you are running KDE PIM and upgrade from 4.4 to 4.10, please have a look at the KDE PIM 4.7 Upgrade Guide first (it still applies)! If you want to stick with KDE PIM 4.4 you can mask KDE PIM 4.10.
Prerequisites
Profile
The Desktop profile has been split to KDE and GNOME subprofiles. This means that KDE and GNOME specific USE flags have been stripped from the basic desktop profile and have been migrated to the subprofiles. Choosing a subprofile does not restrict you to use only the equivalent desktop environment. In order to choose the profile that suits you, run
root # eselect profile list
to get the profile list, and
root # eselect profile set X
where X is the appropriate number of the profile you want to select. See the page on profiles for more details. For a full KDE desktop environment we recommend to use the desktop/kde profile, which is specially tailored for KDE.
Services
Before you install KDE SC it is recommended that you set up several services. Part of that is done automatically if you use a desktop/kde or desktop profile. In detail you should use:
• ConsoleKit: Enables the ConsoleKit framework for defining and tracking users, login sessions and seats.
• D-Bus: Enables use of the D-Bus message bus system.
• polkit: Enables the polkit framework for controlling privileges for system-wide services.
• udev: Enables support for udev Linux dynamic and persistent device naming.
• udisks: Enables support for some storage related services.
Follow the links for information how to set up these services. Note that other USE flag combinations than set in this profile may technically be possible (especially if you do not run a full KDE desktop environment but only selected applications), but may be unsupported, untested, or lead to unexpected loss of functionality.
X server
Read and follow the instructions in the X server article to setup your X environment.
Installation
Note
If you're updating, check the upgrade subpage.
Note
For live versions see the kde overlay article.
Packages
In Gentoo there are various packages that will install a KDE environment:
It's usually a good idea to start with kdebase-meta and install whatever else you need as you go:
root # emerge --ask kdebase-meta
There are other meta packages that can be installed to pull in parts of the KDE suite:
Localization
For localization of KDE install kde-base/kde-l10n. If you want only selected languages, define beforehand the LINGUAS USE flag, e.g. for German:
File/etc/portage/make.conf
LINGUAS="de"
root # emerge --ask kde-l10n
For localization of packages included in kde-base/kdepim-meta you need to install kde-base/kdepim-l10n.
app-office/calligra has its own localization package too, app-office/calligra-l10n.
Configuration
Boot service
Set KDM as your default display manager:
File/etc/conf.d/xdm
DISPLAYMANAGER="kdm"
To start KDE on boot, add xdm to your default runlevel:
root # rc-update add xdm default
To start KDE now:
root # /etc/init.d/xdm start
Add-on Software
Widgets
Many useful widget are in the kde-base/kdeplasma-addons package:
root # emerge --ask kdeplasma-addons
More KDE software
The most important KDE applications are in the portage tree and many are located in the kde-base and kde-misc categories.
See also
External resources
Personal tools
Namespaces
Variants
Actions
Go to: Gentoo Home Documentation Forums Lists Bugs Planet Store Wiki Get Gentoo!
Navigation
Toolbox
Categories
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Help Wikitravel grow by contributing to an article! Learn how.
Talk:Kumamoto
From Wikitravel
Jump to: navigation, search
Contents
Great idea for a class project. I think you will get it formatted right eventually. Good luck.
[edit] Individual attractions
Folks, while I'm glad to see your English class is using Wikitravel as a teaching tool, I would appreciate it if you took a look at Wikitravel:What is an article?. In general, individuals attractions (like the temples and museums listed below) are not articles, they should be listed under the nearest town of interest. Jpatokal 05:16, 28 Oct 2005 (EDT)
[edit] editing issues
Hi. I'm the English teacher who is working with students to add information to the wikitravel article on Kumamoto. I have a mixed class of students (primarily Japanese with Chinese, Westerners) and we are working on not just filling out the wikitravel article, but also getting a handle on which information to present. This is a bit difficult because the students have very little web authoring experience, and no cooperative editing/writing experience, especially across cultures. I've asked the students (in pairs, a foreigner and a Japanese person) to physically go to these sites and try and get down as much information as possible, and then discuss if the information is appropriate. If I give the students a simple template to fill out, the exercise will become a fill in the blank one rather than an attempt to understand online communication.
With that in mind, I would appreciate a little more time before people delete pages. I understand that there are some guidelines to these articles, but the process of collecting information takes time and the students only have 1 90 minute class per week and we are about half way through the term. I will work to get the article up to standard, but I want the students to be able to make mistakes and discuss them rather than dictate what is correct and what is not. If this is a problem, I hope that we can discuss it.
PS I'd also ask that people avoid phrases like 'eikaiwa terror squad' when discussing edits and such, as it serves to demotivate the students. Thanks.
Thanks for getting in touch, although speaking as one of the guys who has had to spend time cleaning up after you, I would have appreciated if it you had contacted us before you embarked on this experiment.
So. Wikitravel is a travel guide, not an eikaiwa teaching tool, and I'm afraid we can't start changing our format just to suit your needs — for example, the Wikitravel:What is an article? concept is really quite fundamental to our operation. What I can suggest is that you use either the Wikitravel:Sandbox or, better yet, create a user account and then use the Talk page to create drafts of your articles. These are 'outside' the guide and thus yours to use freely. When the content is reasonably polished up, then you can move them into the main guide, and everybody will be happy. Does this sound OK to you? Jpatokal 21:16, 12 Nov 2005 (EST)
Thank you, that would be workable. A couple of points
• This is the first time I have used Wikitravel. A colleague recommended it, so I guess that you cleaned up after him.
• I do want to emphasize that I am not asking that the format be changed, just that a bit more time be given to second language speakers (operating under guidance) in working with the articles.
My apologies for not contacting you in advance, but the opening page says 'you can edit any page right now and it is a bit difficult to know who to contact.
If possible, I'd like to implement your suggestion and edit this page with a note at the top discussing what is being done so as to not confuse the students with this discussion. I leave this note for any other editors who might want to weigh in, and I will contact you offline. Thanks.
Sounds good. Let's get the show on the road, and a belated welcome to Wikitravel to you and your students! Jpatokal 20:43, 13 Nov 2005 (EST)
[edit] Visitor to Kumamoto
Hello there, I'm currently living in the Kumamoto area and I've already added some of my newfound knowledge of the city.
The bits I added: Shimotori Kamitori Ginza Additional info on Aso, Kumamoto Castle and arrival by plane
Hope I didn't screw it up too badly.
Great work, we want more! Note that Mount Aso already has its own article. Why not register an account? Jpatokal 07:45, 28 August 2007 (EDT)
[edit] Directions to Yokobachi added
I got lost so you don't have to! Hopefully more people will be able to find this wonderful restaurant now. I also deleted the info that it's close to Ni no Ni and on the same street, and added into the directions 'Across from Ni no Ni'. Since there are directions, maybe the info about Ni no Ni can be cut out altogether, but I'm not comfortable deleting other people's writing so I'll leave that for someone else to decide.
[edit] Romanization of names
While St. is an accurate translation of 通り, wouldn't it be more effective to just leave it in romaji (Tori/Toori) to make asking directions easier? That's unless of course there's actual english signs somewhere that read St... I was going by the Japanese and didn't notice
[edit] Tidying
May I please extend a big thankyou to all the locals who posted info on here. For an eikaiwa experiment, it may have ended up rough around the edges but the variety and depth of useful information is by far the best I have encountered for any location on Kyushu and as a traveller, has proven truly invaluable.
To do my bit, Ive gone through and tidyed this up a tiny bit (moved a few stray bits to their correct categories and cleaned one or two duplicated headers, I hope thats OK!) as well as adding some additional arrival and accomodation info I dug up by asking around. Thus, I feel, this article is a pretty complete guide without any glaring holes based on the wikitravel guidelines.
With regards to tori/dori/street, typically what Ive seen on other articles is Tori/Dori with the kanji bracketed. In some Japanese towns, katakanarised "street" is used in addition so Tori/Dori is probably least confusing. -Snave
Although this more subtle meaning was probably unintended, I must say I laughed out loud at the otherwise perfectly sly use of the term "tolerant towards" in the Toyoko Inn entry, given the company reputation.
Personal tools
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feeds
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In other languages
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Usuari:SabineCretella
De Wikitravel
Revisió de 08:21, 16 maig 2007; SabineCretella (Discussió | contribucions)
(dif) ←Versió més antiga | Versió actual (dif) | Versió més nova→ (dif)
Dreceres ràpides: navegació, cerca
Hi, my name is Sabine Cretella. I am German and speak Italian and English - I read Catalan quite well, but I am not able to write at all.
I am the initiator of http://omegawiki.org together with Gerard Meijssen and I started the Neapolitan Wikipedia where I am a Bureaucrat. Furtermore I started to work quite at the beginning on the Italian Wiktionary where I am a Bureaucrat as well. I am an admin on various other wikis of the Wikimedia Foundation and outside.
My job in this period is quite a mixed one ;-) I am a translator in a first place (even if I very much select what I translate nowadays). Besides that I am Community and Integration Manager for Open Progress and Community Development Director on Yellowikis.
As for Wikitravel I did some editing on the German version time ago - mainly on Maiori, the city where I live. Now what I try to do is combine and link the various projects among each other and therefore I will start to add the adresses of hotels here on the Spanish Wikitravel as well. My aim always was to make the Amalfi Coast better known. Not being able to write Spanish I will be able to only contribute with certain stuff like photos, adresses etc. and links to the other projects and from the other projects here. Eventually you can help me to build some basic sentences about the various cities so that linking here makes more sense. So I hope in a good co-operation among all these various projects. Step by step I will also subscribe to the other langauge versions.
Eines de l'usuari
Espais de noms
Variants
Accions
Navegació
Docents
Eines
En altres llengües
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Australian Bureau of Statistics
Celebrating the International Year of Statistics 2013
ABS Home > Statistics > By Catalogue Number
1292.0 - Australian and New Zealand Standard Industrial Classification (ANZSIC), 2006 (Revision 1.0)
Latest ISSUE Released at 11:30 AM (CANBERRA TIME) 19/09/2008
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Group 223 METAL CONTAINER MANUFACTURING
This section contains the following subsection :
Class 2231 Boiler, Tank and Other Heavy Gauge Metal Container Manufacturing
Class 2239 Other Metal Container Manufacturing
Previous PageNext Page
© 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
5609.0 - Housing Finance, Australia, Jan 2011 Quality Declaration
Previous ISSUE Released at 11:30 AM (CANBERRA TIME) 09/03/2011
Page tools: Print Page Print All RSS Search this Product
JANUARY KEY FIGURES
Trend estimates
Seasonally adjusted estimates
Jan 2011
Dec 2010 to Jan 2011
Jan 2011
Dec 2010 to Jan 2011
Value of dwelling commitments(a)(b)
$m
% change
$m
% change
Total dwellings
20 914
0.2
20 290
-5.3
Owner occupied housing
14 371
0.4
13 959
-4.6
Investment housing - fixed loans(c)
6 543
-0.4
6 331
-6.8
Number of dwelling commitments(a)(b)
no.
% change
no.
% change
Owner occupied housing
50 223
0.4
48 871
-4.5
Construction of dwellings
4 839
-0.5
4 561
-9.4
Purchase of new dwellings
2 243
-1.5
1 984
-13.5
Purchase of established dwellings
43 142
0.6
42 326
-3.5
(a) Includes refinancing (see Glossary).
(b) Excludes alterations and additions.
(c) Excludes revolving credit.
Value of dwelling commitments, Total dwellings
No. of dwelling commitments, Owner occupied housing
JANUARY KEY POINTS
VALUE OF DWELLING COMMITMENTS
January 2011 compared with December 2010:
• The trend estimate for the total value of dwelling finance commitments excluding alterations and additions rose 0.2%. Owner occupied housing commitments rose 0.4%, while investment housing commitments fell 0.4%.
• In seasonally adjusted terms, the total value of dwelling finance commitments excluding alterations and additions fell 5.3%.
NUMBER OF DWELLING COMMITMENTS
January 2011 compared with December 2010:
• In trend terms, the number of commitments for owner occupied housing finance rose 0.4%.
• In trend terms, the number of commitments for the purchase of established dwellings rose 0.6%, while the number of commitments for the purchase of new dwellings fell 1.5% and the number of commitments for the construction of dwellings fell 0.5%.
• In seasonally adjusted terms, the number of commitments for owner occupied housing finance fell 4.5%.
• In original terms, the number of first home buyer commitments as a percentage of total owner occupied housing finance commitments fell from 15.8% in December 2010 to 15.2% in January 2011.
NOTES
FORTHCOMING ISSUES
ISSUE Release Date
February 2011 6 April 2011
March 2011 16 May 2011
April 2011 8 June 2011
May 2011 11 July 2011
June 2011 9 August 2011
July 2011 7 September 2011
IMPACT OF THE FLOODS
Extensive flooding began in late December 2010 in Queensland, and was more extensive in both Queensland and other states in January 2011. The collection and processing of data included in this publication were not disrupted.
On a month to month basis, original and seasonally adjusted series can be impacted by a number of factors including interest rates, supply constraints, consumer confidence and unusual influences. In January 2011, in seasonally adjusted terms, the number of housing finance commitments fell in a number of states including Queensland, Victoria and New South Wales. However, the specific impact of floods on these estimates can not be quantified.
The trend series provide an estimate of the underlying behaviour of a series over time but, in the short term, may be distorted by unusual influences impacting on the original and seasonally adjusted estimates. Trend series will be subject to revision in future issues as additional monthly original estimates become available. Users are advised to exercise caution when using the most recent trend estimates.
For further information please refer to page 3 of the August 2009 issue of Australian Economic Indicators (cat. no. 1350.0).
REVISIONS
In this issue revisions have been made to the original series as a result of improved reporting of survey and administrative data. These revisions impact on:
• Owner occupied housing for the period September 2010 to December 2010;
• Housing loan outstandings to households quarterly series for the period June 2009 to September 2010; and
• Housing loan outstandings to households monthly series for the period July 2010 to December 2010.
Seasonally adjusted and trend series have been revised as a result of revisions to the original series, the incorporation of estimates for the latest month and the revision of seasonal factors due to the concurrent seasonal adjustment methodology.
INQUIRIES
For further information about these and related statistics, contact the National Information and Referral Service on 1300 135 070 or Wolfgang Hertel on Canberra (02) 6252 7883.
© 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
8301.0.55.001 - Manufacturing Production, Australia, Dec 2008
Previous ISSUE Released at 11:30 AM (CANBERRA TIME) 17/02/2009
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EXPLANATORY NOTES
INTRODUCTION
1 This publication presents estimates of production of selected manufacturing commodities for Australia.
SCOPE AND COVERAGE
2 Data presented in this publication are collected from ABS surveys of manufacturing production.
3 Production statistics sourced from ABS manufacturing production surveys are not collected from single establishment manufacturing businesses with fewer than four persons employed, nor from establishments predominantly engaged in non-manufacturing activities but which may carry out some manufacturing in a minor way. However, in general, the contribution of these small producers to statistical aggregates is only marginal, and data contained in this publication provide reliable information for the evaluation of movements in commodity production.
ACKNOWLEDGEMENT
4 ABS publications draw extensively on information provided freely by individuals, businesses, governments and other organisations. Their continued cooperation is very much appreciated: without it, the wide range of statistics published by the ABS would not be available. Information received by the ABS is treated in strict confidence as required by the Census and Statistics Act 1905.
RELATED PUBLICATIONS
5 Other ABS publications which may be of interest are:
Australian Industry (cat. no. 8155.0)
Electricity, Gas, Water and Waste Services, Australia (cat. no. 8226.0)
Manufacturing Industry, Australia (cat. no. 8221.0)
Manufacturing Production, Monthly (cat. no. 8301.0.55.003)
Pre-mixed Concrete Production, Preliminary (cat. no. 8301.0.55.002)
ABS DATA AVAILABLE ON REQUEST
6 More detailed breakdowns and other commodity items collected by the ABS are available on request for a charge.
7 Items for which additional production data are available are:
8 Monthly
Plasterboard
Pre-mixed concrete
Water heaters
9 Quarterly
Beer
Cars and station wagons
Clay bricks (for structural purposes)
Clay bricks (for other than structural purposes)
Concrete bricks, blocks and pavers
Electricity
Hosiery
Gas
Portland cement and cement clinkers
Roofing tiles
Textile floor coverings
Women's footwear
Women's and girls' undergarments
10 Half-yearly
Malt
11 Annual
Flour
Men's and children's footwear
Semi-trailers
12 Discontinued items for which historical production data are available are:
13 Half-yearly
Lawn mowers
14 Annual
Cotton broadwoven fabric
Man-made fibre broadwoven fabric
Selected clothing
Brassieres
Knitted cardigans and jumpers
Knitted sweatshirts and sloppy-joes
Knitted underwear
Long jeans
Men's and boys' shirts
Men's and boys' shorts
Men's and boys' trousers
Men's and boys' woven coats, blazers and jackets
Men's complete suits
Men's industrial overalls
Sleepwear
Swimwear
Tracksuits and sweatsuits
Women's and girls' overalls, slacks and other long trousers
Women's and girls' shirts and blouses
Women's and girls' woven coats, blazers and jackets
Synthetic fibre yarn
Wool broadwoven fabric
Wool yarn
15 For further information, please contact Damian Sparkes on Adelaide (08) 8237 7425.
16 The value of sales for commodities produced (classified in accordance with the Manufacturing Input-Output Commodity Classification) is collected in the annual manufacturing industry survey, and is available on request for a charge. For further information, please contact Phillip Lui on Sydney (02) 9268 4541.
© 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
5676.0 - Business Indicators, Australia, Sep 2004
Previous ISSUE Released at 11:30 AM (CANBERRA TIME) 29/11/2004
Page tools: Print Page Print All RSS Search this Product
ABOUT THIS RELEASE
Replaces:5651.0 and 5629.0
Contains quarterly estimates of profits, income from the sale of goods and services, wages and salaries, and the book value of inventories. These data are classified by broad industry, and original, seasonally adjusted and trend estimates are included for Australia, in current price terms. Volume measures are published for sales and inventories. State/territory data will also be included for sales, and wages and salaries, in current price terms.
© 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
8101.0 - Innovation and Technology Update (Newsletter), Apr 2001
Previous ISSUE Released at 11:30 AM (CANBERRA TIME) 30/04/2001
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Contents
Introduction
Information Technology (IT) Statistics
Research and Experimental Development (R&D) Statistics
Biotechnology Statistics
Knowledge-based Economy and Society Indicators
Innovation
For More Information...
© 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 Catalogue Number
6102.0.55.001 - Labour Statistics: Concepts, Sources and Methods, 2013
Latest ISSUE Released at 11:30 AM (CANBERRA TIME) 07/05/2013
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A comprehensive discussion and description of the concepts and definitions underpinning Australian labour statistics and the data sources and methods used in the collection and compilation of these statistics. It explains what the statistics measure, how the various measures relate to each other and how they are produced. It also discusses the factors influencing their accuracy and reliability. To ensure that the concepts used and the references are relevant and current, chapters of this publication will continually be updated.
© 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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Culturally Inclusive Practice: A Case Study of an International Student Support Initiative at an Australian University
Jianli Wang
Abstract
This article explores from the students’ as well as the coordinator’s perspectives the effectiveness of an integrated culturally inclusive initiative in terms of facilitating international students’ adaptation. This initiative is a program that celebrates international students’ diverse learning cultures through sharing and understanding different cultural ways of learning. This study builds upon the extensive research conducted focusing on international students’ adaptation processes with a case-study approach consisting of participant observation, document analysis, questionnaire and in-depth interviewing. My findings support this initiative as a successful program providing support for international students. It is an effective practice for students, educators and policy makers in wider fields where intercultural dialogues are cherished.
Full Text: PDF DOI: 10.5539/ass.v8n4p68
This work is licensed under a Creative Commons Attribution 3.0 License.
Asian Social Science ISSN 1911-2017 (Print) ISSN 1911-2025 (Online)
Copyright © Canadian Center of Science and Education
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Using Student Reflections to Explore Curriculum Alignment
Marina Harvey, Chris Baumann
Abstract
The concept of curriculum alignment is held as a guiding principle of good curriculum design in higher education. Curriculum alignment can be mapped using a variety of strategies and tools. This paper reports on a project that expands the horizons of curriculum review by applying a novel methodology, word clouds, to investigate the use of student reflections for exploring curriculum alignment.Students, from Australia and Denmark, engaged in written reflections about their learning in a Business Brand Marketing subject. These reflections provide the data that is analysed for its alignment with the subject’s learning outcomes. The word cloud analysis is found to be useful in providing evidence of curriculum alignment and indicators for directing deeper textual analysis.
Full Text: PDF DOI: 10.5539/ass.v8n14p9
This work is licensed under a Creative Commons Attribution 3.0 License.
Asian Social Science ISSN 1911-2017 (Print) ISSN 1911-2025 (Online)
Copyright © Canadian Center of Science and Education
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Vol 5, No 5 (2012)
Computer and Information Science, Vol. 5, No. 5, September 2012
Table of Contents
Articles
Incorporating Information Security in Analysis of Business Strategy: A Conceptual Framework PDF
Mingtao Shi p1
Automatic Measurement of Shoreline Change on Djerba Island of Tunisia PDF
Maged Bouchahma, Wanglin Yan p17
Hybrid-Based Compressed Domain Video Fingerprinting Technique PDF
Abbass S. Abbass, Aliaa A. A. Youssif, Atef Z. Ghalwash p25
Characterization of Ventricular Tachycardia and Fibrillation Using Semantic Mining PDF
Mohd Afzan Othman, Norlaili Mat Safri, Ismawati Abdul Ghani, Fauzan Khairi Che Harun p35
A Review of Users Adoption of Open Source Software in Africa PDF
John Kamau, Sylvester Namuye p45
Air Traffic Forecast Empirical Research Based on the MCMC Method PDF
Jian-bo Wang, Chong-jun Fan, Lei Bai p50
Growth of ICT Capital and Deceleration of Labour Productivity in the EU Countries: The Missing Links PDF
Pradip Kumar Biswas, Alberto Moreira Baptista p55
Evaluating Model for E-learning Modules According to Selected Criteria: An Object Oriented Approach PDF
Qabas Abdal Zahraa Jabbar p69
Sigma-Delta Modulator Simulation and Analysis Using MatLab PDF
Thuneibat S. A., Ababneh M. S. p76
A Kind of CTA Bone Removal Technology Based on the Improved Watershed Algorithm PDF
Tan Jianhao, Zhang Jing, Wang Ya p81
Finite Element Method for Internal Wave Equation for Stratified Fluid PDF
Dawletbay Utebaev p88
The Age or Excess of the M|G|inf Queue Busy Cycle Mean Value PDF
Manuel Alberto M. Ferreira, Marina Andrade, José António Filipe p93
This work is licensed under a Creative Commons Attribution 3.0 License.
Computer and Information Science ISSN 1913-8989 (Print) ISSN 1913-8997 (Online)
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LAMP Developer, Brooklyn, NY | 80-120k
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This is a full time, on-site, salaried LAMP Developer position located in Brooklyn, NY paying $80,000-$120,000 depending on experience + equity + benefits. No telecommuting allowed. US Citizens or Green Card holders only please. Local candidates only. Thank you.
The ideal candidate should have a genuine interest in new technologies and up-to-date on coding practices as well as an appreciation for simplicity in design and programming practices. Ideally, s/he will be an experienced and skilled programmer who can write lean PHP 5 code. Although exact years of experience won't be an issue for the right person, we are interested in developers with enough experience to jump on board and start contributing immediately In addition, this person will want to work with:
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About this Journal Submit a Manuscript Table of Contents
Gastroenterology Research and Practice
Volume 2013 (2013), Article ID 192794, 6 pages
http://dx.doi.org/10.1155/2013/192794
Clinical Study
Clinical Study of the Relation between Mucosal Healing and Long-Term Outcomes in Ulcerative Colitis
Department of Gastroenterology, Kitasato University School of Medicine, 2-1-1 Asamizodai, Minami, Sagamihara 252-0380, Japan
Received 11 February 2013; Accepted 27 February 2013
Academic Editor: Devendra Amre
Copyright © 2013 Kaoru Yokoyama et al. 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
Background and Objectives. Mucosal healing (MH) is considered an important therapeutic goal in ulcerative colitis (UC). We evaluate the severity of intestinal inflammation and clarify the relation between MH and long-term outcomes. Methods. The study group comprised 38 patients with UC in clinical remission on total colonoscopy who were followed up for at least 5 years. Clinical remission was defined as a Mayo score of 0 for both stool frequency and rectal bleeding. Colonoscopic findings were evaluated into 4 grades according to the Mayo endoscopic subscore (MES). Results. During clinical remission, the MES was 0 in only 24% of the patients, 1 in 40%, 2 in 26%, and 3 in 10%. Seventy-six percent of the patients thus had active disease on colonoscopy. After initial colonoscopy, the cumulative rate of remission maintenance was 100% in MES 0, 1 in 93%, 2 in 70%, and 3 in 50% at 6 months and 78%, 40%, 10%, and 0%, respectively, at 5 years (). Conclusion. Many patients with UC in clinical remission have active lesions. Patients with a higher MES have a higher rate of recurrence. To improve long-term outcomes, an MES of 0 should be the treatment goal.
1. Introduction
The treatment response and prognosis of inflammatory bowel disease (IBD) have been evaluated on the basis of clinical remission, dose reduction of steroids, avoidance of surgery, and other factors. However, since the advent of potent drugs such as antitumor necrosis factor-α monoclonal antibody preparations, treatment response has been assessed on the basis of “mucosal healing” as evaluated on colonoscopy [13]. However, standard criteria for the evaluation of disease severity and definitions of mucosal healing on colonoscopy are currently unavailable [4]. Moreover, long-term studies examining whether mucosal healing actually contributes to remission maintenance in IBD are scant.
We performed colonoscopy in patients with ulcerative colitis (UC) in clinical remission to evaluate the presence or absence of intestinal inflammation and to retrospectively analyze the relation between mucosal healing and long-term outcomes during 5 years of followup.
2. Methods
2.1. Patients
Among 46 patients with ulcerative colitis in clinical remission who underwent colonoscopy in our hospital from January 2005 through December 2006, we studied 38 patients in whom the severity of intestinal inflammation was evaluated on total endoscopy; all patients were followed up for at least 5 years. Eight patients who received corticosteroids at the time of colonoscopy were excluded from the study because steroids can mask clinical signs and symptoms.
As for the demographic characteristics of the patients, there were 18 males and 20 females. The mean age at the onset of UC was years (range, 16 to 73). The mean disease duration at colonoscopy was years (range, 1 to 37). The disease type was flare-ups and remission in 37 patients and initial attacks in 1 (Table 1). Disease extent at the onset of UC was pancolitis in 11 patients (29%), left-sided colitis in 11 (29%), proctitis in 11 (29%), and unknown in 5 patients (13%) who were initially treated at other hospitals. Overall, 13 patients (34%) had previously received treatment during hospitalization.
Table 1: Demographic characteristics of patients.
At the time of colonoscopy, 36 patients (95%) were receiving drug therapy, which included 5-aminosalicylic acid (5-ASA) in 34 patients (94%), immunomodulators in 1 (3%), and local therapy such as 5-ASA and steroid suppositories and enemas in 7 (19%) (some overlap).
2.2. Evaluation of UC Activity
The Mayo score [5] was used to evaluate UC activity. The Mayo score consists of 4 components: stool frequency, rectal bleeding, endoscopy findings, and physician’s global assessment. Each component is assigned a score of 0 to 3; the total score ranges from 0 to 12. The higher the score, the higher is the disease severity. In the present study, clinical remission was defined as a score of 0 for both stool frequency and rectal bleeding. Flare-ups were defined as the need for additional drugs or modification of the treatment regimen because of exacerbation of clinical symptoms.
2.3. Colonoscopic Examination and Evaluation of Intestinal Inflammation
Before colonoscopic examination, all patients were provided with a detailed explanation of the examination objectives and gave written informed consent. An oral polyethylene glycol lavage solution was used for bowel preparation. An anticholinergic agent (scopolamine butylbromide 10 mg) or glucagon (1 mg) was given intramuscularly as premedication. A small-bore, high-magnification colonoscope (PCF-Q240ZI, Olympus Co. Ltd., Tokyo, Japan) was used. All examinations were performed by 3 endoscopists specialized in the diagnosis and treatment of IBD who each had at least 15 years of experience in colonoscopy.
The Mayo endoscopic subscore (MES) was used to evaluate the severity of intestinal inflammation on colonoscopy [5] as follows: MES 0, normal or inactive disease; MES 1, mild disease (erythema, decreased vascular pattern, and mild friability); MES 2, moderate disease (marked erythema, absent vascular pattern, friability, and erosions); and MES 3, severe disease (spontaneous bleeding and ulcerations) (Figures 1(a) to 1(d)). The entire colon was observed by white-light colonoscopy, and sites with the most severe inflammation were evaluated.
Figure 1: (a) An endoscopic image of the colonic mucosa, a Mayo endoscopic subscore of 0. The mucosal has a visible vascular pattern, and scattered white ulcer scars are evident. (b) An endoscopic image of the colonic mucosa, a Mayo endoscopic subscore of 1. The vascular pattern of the mucosa is decreased, with mild erythema. (c) An endoscopic image of the colonic mucosa, a Mayo endoscopic subscore of 2. The vascular pattern of the mucosa is decreased, with marked erythema and multiple erosions. (d) An endoscopic image of the colonic mucosa, a Mayo endoscopic subscore of 3. The mucosa shows marked erythema and ulcers.
2.4. Study Variables
The severity of intestinal inflammation was evaluated on colonoscopy during clinical remission of disease. The relation between the severity of colonoscopic findings and the maintenance of clinical remission was then studied up to 5 years after initial colonoscopy. The study was approved by the ethics review committee of our hospital.
2.5. Statistical Analysis
Data are presented as means ± standard deviation. For statistical analysis, the chi-square test and Fisher’s exact test were used to compare incidence rates. One-way factorial analysis of variance and Scheffe’s test were used to compare parametric variables between multiple unpaired groups. The Kruskal-Wallis test was used to compare nonparametric variables among multiple groups. Cumulative rates of remission maintenance were calculated using the Kaplan-Meier method. Log-rank tests (Peto & Peto modification) were used to determine whether differences among multiple groups were statistically significant. values of less than 0.05 were considered to indicate statistical significance. Statistical analyses were carried out using StatMate IV software, version 4.01 for Windows (ATMS, Tokyo, Japan).
3. Results
3.1. Mucosal Healing Rates
The MES at initial colonoscopy during clinical remission was 0 in 9 patients (group A), 1 in 15 (group B), 2 in 10 (group C), and 3 in 4 (group D) (Table 2). Active intestinal lesions were found in 29 patients in clinical remission (76%), despite no diarrhea or bloody stools. Demographic characteristics such as disease duration and disease extent did not differ significantly among the 4 groups. Remission induction regimens at the time of flare-ups before the most recent colonoscopic examination and the duration of remission maintenance up to the time of colonoscopy also did not differ among the 4 groups. There was also no difference in drug therapy at the time of initial colonoscopy.
Table 2: Treatment regimens according to the Mayo endoscopic subscore.
3.2. Cumulative Rates of Remission Maintenance after Colonoscopy
The cumulative rate of remission maintenance 6 months after initial colonoscopy as evaluated by the Kaplan-Meier method was 100% in group A, 93% in group B, 70% in group C, and 50% in group D. At 2 years the cumulative rates of remission maintenance were 78%, 67%, 20%, and 0%, respectively, and at 5 years the rates were 78%, 40%, 10%, and 0%, respectively. The cumulative rate of remission maintenance differed significantly among the 4 groups (multiple log-rank test (Peto & Peto modification), ) (Figure 2). Regimens during followup after colonoscopy did not differ among the 4 groups (Table 2). Adherence to drug therapy was good. At the time of flare-ups, 1 patient in group B and 1 in group D were admitted to receive treatment.
Figure 2: Cumulative rates of remission maintenance according to Mayo endoscopic subscore.
4. Discussion
UC is a chronic IBD that develops in relatively young adults and requires long-term, continuous drug therapy to stabilize disease. However, a substantial number of patients are unable to strictly comply with drug therapy during followup, increasing the risk of relapse [6]. In fact, some patients request dose reduction or treatment withdrawal soon after the resolution of symptoms such as bloody stools and abdominal pain. A considerable number of patients thus do not take medication as directed. Not only patents, but also some physicians instruct patients to decrease the dose or discontinue drug therapy soon after the resolution of symptoms, often leading to relapse. In Japan, the number of patients with UC has been increasing annually. We speculate that increasing numbers of patients with UC are being treated by not only IBD specialists, but also general internists. Even if patients with active UC are initially treated by IBD specialists, maintenance therapy after remission induction is probably often entrusted to general internists.
Colonoscopy is essential for an in-depth assessment of intestinal inflammation in UC. Recent studies have reported that narrow band imaging (NBI) and magnifying endoscopy in addition to white-light endoscopy are useful for detailed assessment of the mucosa and facilitate evaluation of the severity of intestinal inflammation. These techniques are also useful for predicting outcomes, including the risk of recurrence [7, 8]. However, NBI and magnifying endoscopy can be routinely performed in only a limited number of hospitals. In general hospitals, the severity of intestinal inflammation is evaluated, and the treatment policy is decided on the basis of white-light colonoscopic findings. We therefore studied variables that can be evaluated on white-light colonoscopy. Moreover, the inclusion of many variables in the colonoscopic evaluation of the severity of intestinal inflammation in UC leads to complexity, as well as considerable variation in the results of evaluation among endoscopists [9]. In the present study, we therefore used the MES [5], a relatively straightforward evaluation system that has been widely used in clinical trials of new drugs and other clinical studies in patients with UC. To ensure that lesions were accurately diagnosed, the following precautions were taken. Because small lesions are difficult to diagnosis after inadequate intestinal lavage, all patients received pretreatment with oral intestinal lavage solution (polyethylene glycol). The same model of colonoscope was used in all patients to examine and evaluate the entire colorectum. Colonoscopy was performed by specialists of IBD who had at least 15 years experience in colonoscopy. In addition, colonoscopic findings were evaluated by endoscopists who were blinded to the patients’ outcomes.
Our results showed that about three-fourths of all patients continued to have active intestinal inflammation even during clinical remission of UC. All patients received drug therapy to induce remission at the time of flare-ups before the most recent colonoscopic examination. The treatment regimens did not differ among the 4 groups. The duration of clinical remission before colonoscopy also did not differ significantly among the 4 groups. In addition, therapy being received by patients at the time of colonoscopy was similar in the 4 groups. However, the 4 groups had different severities of intestinal inflammation on colonoscopy, ranging from an MES of 0 to 3. Intestinal lesions thus did not resolve in many patients, despite the clinical remission of disease. Our results support the importance of evaluating the degree of mucosal healing on colonoscopy. Frequent divergence between clinical remission and the remission of intestinal lesions in UC has also been confirmed in previous prospective studies [10, 11].
Many previous studies evaluating the effects of various types of treatment on remission maintenance in UC were relatively short (about 1 year) [10, 11]. In contrast, we analyzed long-term outcomes over the course of 5 years by assessing the severity of intestinal lesions on colonoscopy. Relapse occurred within 5 years in nearly all patients who were in clinical remission, but had erosions and ulcers with an MES of 2 or 3 on colonoscopy. Even among patients with an MES of 1 who had erythema and decreased vascular pattern on colonoscopy, the rate of remission maintenance at 5 years was only 40%. In contrast, the rate of long-term remission maintenance was 78% in patients whose condition improved to an MES of 0 with no evidence of inflammation on colonoscopy. The rate of remission maintenance in UC may be related to the remission maintenance regimens given during followup and adherence to drug therapy [6]. In our study, the regimens given after colonoscopy did not differ from those used at the time of colonoscopy, and adherence to treatment was good. Because patients with active lesions did not have symptoms at the time of colonoscopy, some patients did not perceive the need for, or agree to receive, more aggressive therapy, but adherence with the treatment regimen being used was good. From 2005 through 2006, when initial colonoscopy was performed in this study, treatment with antitumor necrosis factor-α monoclonal antibody preparations was not covered by the National Health Insurance in Japan. In the latter half of 2006, treatment with azathioprine, an immunomodulator, finally became eligible for reimbursement by the National Health Insurance. Owing to these factors, patients continued to receive generally the same regimens during followup as those received at the time of initial colonoscopy. The differences in the remission maintenance rates among the 4 groups are therefore most likely attributed to differences in the severity of intestinal inflammation at the time of colonoscopy and not to differences in or modifications of treatment regimens. Therefore, we believe that the treatment goal should be an MES of 0.
However, many previous clinical studies defined mucosal healing as an MES of 0 or 1 [10, 11]. One study evaluating the effectiveness of mesalazine for remission maintenance reported no difference in the rate of relapse at 1 year between patients with an MES of 0 and those with an MES of 1 [10]. In a prospective study assessing the effectiveness of infliximab for remission maintenance, the symptomatic remission rate after 54 weeks was 73% in patients with an MES of 0 on colonoscopy performed after remission induction and 47% in those with an MES of 1, indicating that more than half of the latter patients had relapse. However, among patients who had clinical remission 8 weeks after treatment with infliximab, there was no difference in clinical outcomes (including colectomy) at 54 weeks between patients with an MES of 0 and those with an MES of 1 at 8 weeks [11]. In the ACT 1 trial [1], the rate of steroid-free remission after 54 weeks was 63% in patients with an MES of 0 on colonoscopy after 8 weeks of treatment, as compared with only 46% in patients with an MES of 1. Whether a difference between an MES of 0 and an MES of 1 influences clinical outcomes thus remains controversial. In addition, these findings were obtained from studies with relatively short follow-up periods of about 1 year. In our study, the cumulative remission maintenance rate 6 months after colonoscopy was similar in group A (MES 0, 100%) and in group B (MES 1, 93%). However, the cumulative remission maintenance rate was 78% in group A and 67% in group B at 2 years and 78% in group A and 40% in group B at 5 years, indicating that the cumulative remission maintenance rate decreased with time in patients who had an MES of 1; moreover, the divergence between group A and group B increased. These findings also support the notion that an MES of 0 should be the goal of treatment. Indeed, it may be difficult to accurately assess colonoscopic findings and in particular to distinguish between an MES of 1, indicating mild disease, and an MES of 0, indicating normal or inactive disease [9]. Efforts should be made, including adequate pretreatment, to ensure that evaluations can be performed as accurately as possible. Because our study was conducted in a single hospital, differences in the conditions of endoscopic examination and in the assessment of endoscopic findings were most likely minimal. However, further multicenter, prospective studies of larger numbers of patients are needed to confirm our findings and to establish the clinical positioning of an MES of 0 and an MES of 1.
As mentioned above, even patients with UC in clinical remission who have active lesions on colonoscopy have a high rate of relapse during followup. To achieve remission maintenance, the goal of therapy should be to downgrade inflammation in patients who have intestinal inflammation. Physicians should recognize that intestinal inflammation accompanied by findings such as erythema and erosions persists after the resolution of symptoms in an appreciable number of patients. Education of patients is also important. Patients should be advised not to stop drug therapy on their own initiative, even if clinical symptoms resolve.
Substantial progress has been made in drug therapy for UC. Antitumor necrosis factor-α monoclonal antibody preparations, potent immunosuppressants such as tacrolimus and cyclosporine, and new treatments such as cytapheresis are now available to complement conventional preparations such as 5-ASA and steroids. Consequently, mucosal healing can now be achieved in increasing numbers of patients. Immunomodulators such as azathioprine and 6-mercaptopurine are widely known to be effective as remission maintenance therapy. Further prospective studies are needed to examine the relation between mucosal healing and long-term remission maintenance for each of these newer treatments.
We evaluated the effects of mucosal healing on long-term outcomes in patients with UC. However, our study had several limitations: it was conducted in a single center and had a small sample size. Further multicenter prospective studies in larger numbers of patients are needed to confirm our findings and to further delineate the clinical significance of mucosal healing in UC.
References
1. P. Rutgeerts, W. J. Sandborn, B. G. Feagan et al., “Infliximab for induction and maintenance therapy for ulcerative colitis,” The New England Journal of Medicine, vol. 353, no. 23, pp. 2462–2476, 2005. View at Publisher · View at Google Scholar · View at Scopus
2. J. F. Colombel, W. J. Sandborn, W. Reinisch et al., “Infliximab, azathioprine, or combination therapy for Crohn's disease,” The New England Journal of Medicine, vol. 362, no. 15, pp. 1383–1395, 2010. View at Publisher · View at Google Scholar · View at Scopus
3. P. Rutgeerts, G. Van Assche, W. J. Sandborn et al., “Adalimumab induces and maintains mucosal healing in patients with Crohn's disease: data from the EXTEND trial,” Gastroenterology, vol. 142, no. 5, pp. 1102–1111, 2012. View at Publisher · View at Google Scholar
4. M. F. Neurath and S. P. Travis, “Mucosal healing in inflammatory bowel diseases: a systematic review,” Gut, vol. 61, no. 10, pp. 1619–1635, 2012. View at Publisher · View at Google Scholar
5. K. W. Schroeder, W. J. Tremaine, and D. M. Ilstrup, “Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis: a randomized study,” The New England Journal of Medicine, vol. 317, no. 26, pp. 1625–1629, 1987. View at Scopus
6. S. Kane, D. Huo, J. Aikens, and S. Hanauer, “Medication nonadherence and the outcomes of patients with quiescent ulcerative colitis,” American Journal of Medicine, vol. 114, no. 1, pp. 39–43, 2003. View at Publisher · View at Google Scholar · View at Scopus
7. T. Kudo, T. Matsumoto, M. Esaki, T. Yao, and M. Iida, “Mucosal vascular pattern in ulcerative colitis: observations using narrow band imaging colonoscopy with special reference to histologic inflammation,” International Journal of Colorectal Disease, vol. 24, no. 5, pp. 495–501, 2009. View at Publisher · View at Google Scholar · View at Scopus
8. M. Fujiya, Y. Saitoh, M. Nomura et al., “Minute findings by magnifying colonoscopy are useful for the evaluation of ulcerative colitis.,” Gastrointestinal Endoscopy, vol. 56, no. 4, pp. 535–542, 2002. View at Scopus
9. K. T. Thia, E. V. Loftus Jr., D. S. Pardi et al., “Measurement of disease activity in ulcerative colitis: interobserver agreement and predictors of severity,” Inflammatory Bowel Diseases, vol. 17, no. 6, pp. 1257–1264, 2011. View at Publisher · View at Google Scholar · View at Scopus
10. G. Meucci, R. Fasoli, S. Saibeni et al., “Prognostic significance of endoscopic remission in patients with active ulcerative colitis treated with oral and topical mesalazine: a prospective, multicenter study,” Inflammatory Bowel Diseases, vol. 18, no. 6, pp. 1006–1010, 2012. View at Publisher · View at Google Scholar
11. J. F. Colombel, P. Rutgeerts, W. Reinisch et al., “Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis,” Gastroenterology, vol. 141, no. 4, pp. 1194–1201, 2011. View at Publisher · View at Google Scholar
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About this Journal Submit a Manuscript Table of Contents
Journal of Electrical and Computer Engineering
Volume 2012 (2012), Article ID 290390, 9 pages
doi:10.1155/2012/290390
Research Article
Minimum Symbol Error Probability MIMO Design under the Per-Antenna Power Constraint
Department of Electrical and Computer Engineering, Polytechnic Institute of NYU, 6 MetroTech Center, Brooklyn, NY 11201, USA
Received 21 October 2011; Revised 26 January 2012; Accepted 31 January 2012
Academic Editor: D. Laurenson
Copyright © 2012 Enoch Lu and I.-Tai Lu. 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.
Linked References
1. A. Scaglione, P. Stoica, S. Barbarossa, G. B. Giannakis, and H. Sampath, “Optimal designs for space-time linear precoders and decoders,” IEEE Transactions on Signal Processing, vol. 50, no. 5, pp. 1051–1064, 2002. View at Publisher · View at Google Scholar · View at Scopus
2. D. P. Palomar, J. M. Cioffi, and M. A. Lagunas, “Joint Tx-Rx beamforming design for multicarrier MIMO channels: a unified framework for convex optimization,” IEEE Transactions on Signal Processing, vol. 51, no. 9, pp. 2381–2401, 2003. View at Publisher · View at Google Scholar · View at Scopus
3. D. P. Palomar, “Unified framework for linear MIMO transceivers with shaping constraints,” IEEE Communications Letters, vol. 8, no. 12, pp. 697–699, 2004. View at Publisher · View at Google Scholar · View at Scopus
4. F. Rey, M. Lamarca, and G. Vazquez, “Robust power allocation algorithms for MIMO OFDM systems with imperfect CSI,” IEEE Transactions on Signal Processing, vol. 53, no. 3, pp. 1070–1085, 2005. View at Publisher · View at Google Scholar · View at Scopus
5. Y. K. Yazarel and D. Aktas, “Downlink beamforming under individual SINR and per antenna power constraints,” in Proceedings of the IEEE Pacific Rim Conference on Communications, Computers and Signal Processing (PACRIM '07), pp. 422–425, August 2007. View at Publisher · View at Google Scholar · View at Scopus
6. C. C. Weng and P. P. Vaidyanathan, “Per-antenna power constrained MIMO transceivers optimized for BER,” in Proceedings of the 42nd Asilomar Conference on Signals, Systems and Computers (ASILOMAR '08), pp. 1300–1304, October 2008. View at Publisher · View at Google Scholar · View at Scopus
7. M. C. H. Lim, M. Ghogho, and D. C. McLernon, “Reduced complexity design for weighted harmonic mean SINR maximization in the multiuser MIMO downlink,” in Proceedings of the IEEE 10th Workshop on Signal Processing Advances in Wireless Communications (SPAWC '09), pp. 206–210, June 2009. View at Publisher · View at Google Scholar · View at Scopus
8. M. T. Chu, “Constructing a Hermitian Matrix from Its Diagonal Entries and Eigenvalues,” SIAM Journal on Matrix Analysis and Applications, vol. 16, pp. 207–217, 1995.
9. H. Stark and Y. Yang, Vector Space Projections: A Numerical Approach to Signal and Image Processing, Neural Nets, and Optics, John Wiley & Sons, 1998.
10. S. Hu-yun, “Estimation of the eigenvalues of AB for A>0, B>0,” Linear Algebra and Its Applications, vol. 73, pp. 147–150, 1986. View at Scopus
11. R. A. Horn and C. R. Johnson, Matrix Analysis, Cambridge University Press, New York, NY, USA, 1985.
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Engineering » Biomedical Engineering » "Polymerase Chain Reaction", book edited by Patricia Hernandez-Rodriguez and Arlen Patricia Ramirez Gomez, ISBN 978-953-51-0612-8, Published: May 30, 2012 under CC BY 3.0 license
Chapter 7
BRAF V600E Mutation Detection Using High Resolution Probe Melting Analysis
By Jennifer E. Hardingham, Ann Chua, Joseph W. Wrin, Aravind Shivasami, Irene Kanter, Niall C. Tebbutt and Timothy J. Price
DOI: 10.5772/37111
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Publication Listing
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Locus1 Verified by Chris J on 2011-08-11 21:16:05
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Bibliography: Methuselah, Ltd.
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Title: Methuselah, Ltd.
Authors: Richard Barr and Wallace West
Year: 1953
Type: SHORTFICTION
Storylen: shortstory
ISFDB Record Number: 80738
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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Activity Not Available
Project Summary : Factoids
Analyzed 8 months ago based on code collected 8 months ago.
Mature, well-established codebase
The first lines of source code were added to Atheme IRC Services in 2005. Projects with recent activity, and a code base more than five years old are likely solving vital problems and delivering consistent value, and may be organized to reward sustained effort by an engaged team of contributors.
Such a lengthy source control history in conjunction with recent activity may indicate that this code base and community are important enough to attract long-term commitment, and may also indicate a mature and relatively bug-free code base.
Note: The source code for Atheme IRC Services might actually be older than the source control history can reveal. Many new projects begin by incorporating a large amount of source code from existing, older projects. You might be able to tell whether this is the case by looking for a rapid rise in the amount of code early in the project's history.
Large, active development team
Over the past twelve months, 10 developers contributed to Atheme IRC Services. This project has a relatively large team, in the top 10% of all project teams on Ohloh.
For this measurement, Ohloh considers only recent changes to the code. Over the entire history of the project, 44 developers have contributed.
Average number of code comments
Atheme IRC Services is written mostly in C.
Across all C projects on Ohloh, 19% of all source code lines are comments.
This holds true for Atheme IRC Services as well. It contains the same ratio of comment lines to code lines as the majority of C projects in Ohloh.
A high number of comments might indicate that the code is well-documented and organized, and could be a sign of a helpful and disciplined development team.
Decreasing Y-O-Y development activity
Over the last twelve months, Atheme IRC Services has seen a substantial decrease in development activity. This could mean many things. It may be a warning sign that interest in this project is waning, or it may indicate a maturing code base that requires fewer fixes and changes. It is also possible that development on this project has moved to a new source control repository somewhere else.
Ohloh makes this determination by comparing the total number of commits made by all developers during the most recent twelve months with the same figure for the prior twelve months. The number of developers and total lines of code are not considered.
See all possible factoids
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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[49] But this multitude that doesn't know the law is accursed."
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 Greek (Brooke Foss Westcott, Fenton John Anthony Hort, 1885)
load focus Latin (Saint Jerome, Bible Foundation and On-Line Book Initiative)
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Citation URN: urn:cts:greekLit:tlg0031.tlg004.perseus-eng1:7.49
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Complex Post Traumatic Stress Disorder
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Australian Bureau of Statistics
Celebrating the International Year of Statistics 2013
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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'm getting mixed answers. A fellow Canadian told me, "No revenue, No Incorporation".
Reading other answers here, I should incorporate early.
I am on verge of entering beta (fire off emails) but have not incorporated.
Currently what stops me from incorporating are:
1. Physical address (don't have office and don't want to use home address).
2. Bookkeeping gets complicated.
I guess I could get in hot water during beta testing. For example if a client abuses my software.
So the question is, should I incorporate now before launch? I've already paid for hosting, domain, libraries with my name. Does Cheddargetter require incorporation for merchant account?
share|improve this question
1 Answer
up vote 2 down vote accepted
I was always told that incorporating has no real taxation benefit until your revenue reaches 80 - 100k
share|improve this answer
Your Answer
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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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'm planning to start a startup with the help of a seed capital firm. The firm has presented its terms and I'm not sure if what they ask if acceptable/normal for the low-equity they are having (5%). Some of those terms include:
1) We cannot sell our stock and we cannot accept funding from other firms without their written approval.
2) The seed capital firm wants to be able to sell ALL the stock (founders stock + their part).
share|improve this question
3 Answers
Do you have your own lawyer and accountant? What do they think of the terms? If you don't have a lawyer, stop, do not pass go, do not collect $200 and go find one pronto.
share|improve this answer
Following Elie's lead, you should really think through what the term sheet is, what kind of money they are offering (hint: not the amount) and how it will impact your companies ability to move forward.
some good links:
share|improve this answer
I would be very leery of these terms.
From Venture Hacks: “[Our existing investors] had put in a right of first refusal. Since I was a young entrepreneur at the time, I didn’t understand that this basically meant that you couldn’t go to any other VC… We could not get a higher valuation because [our existing investors] wanted to put more money in the company themselves. So any time we would talk to another VC, they would talk him out of it: “This is not a good company, don’t worry about it.” So we were really stuck with [our existing investors] for the next round.”
Aside: TheFunded is a great forum for asking about deal terms. (answers.onstartups.com is great, but on questions like deal terms I haven't found that people like to drill into the implications.)
share|improve this answer
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Development Boxes
From NAS-Central Buffalo - The Linkstation Wiki
(Difference between revisions)
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(Old Locations)
(Old Locations)
Line 15: Line 15:
* Dusseldorf, Germany - bought from ebay <br>
* Dusseldorf, Germany - bought from ebay <br>
* Tampa, Florida, USA - tampakuro<br>
* Tampa, Florida, USA - tampakuro<br>
-
tampakuro revived it partly again. The microcontroller still is damaged but it can be used for further development.<br>
+
tampakuro completely revived it. <br>
'''LINKS:''' [[Hardware_Hacks_for_the_LS2]]<br>
'''LINKS:''' [[Hardware_Hacks_for_the_LS2]]<br>
Revision as of 01:51, 8 March 2007
Contents
What`s a Development Box?
We are currently buying some development boxes. These boxes are bought so some guys can work on them without having to look how to keep the services running why they initially bought the box. All boxes are owned by the community...this means that if georg/jonli447/linuxnotincluded think they absolutely have no time in the near future the boxes can be passed to another developer.
All this is based on confidence.
Needs for additional boxes?
• germany - andre - HG/HS for hosting of hvkls.dyndns.org
List of Development Boxes
Here we list all Development Boxes and the history of each one.
LS2 bought from ebay
This box was a hardware-brick. It did not boot anymore because the microcontroller was severely damaged.
Old Locations
• Dusseldorf, Germany - bought from ebay
• Tampa, Florida, USA - tampakuro
tampakuro completely revived it.
LINKS: Hardware_Hacks_for_the_LS2
Current status
• UK - linuxnotincluded
PLANED TASK: linuxnotincluded tries to port UBoot to the LS2
LSPro bought from doc007
doc007 got it from ebay. but it was a real brick in the end.
Old Locations
• unknown - doc007
Current status
• sent to Florida - tampakuro
PLANED TASK: use the components as spare parts for maybe fixing other LSPro boxes.
LSPro bought for georg
Current Status
• Germany - georg
LINKS: The Linkstation Community Forum / Software (arm9) / LS-GL Custom Updater Thread - ACP-Commander
PLANED TAKS: analyse the acp-commands, general testing
LS2 donated by Kaiten
Fully functional but dusty LS2 donated by Kaiten, our webinterface master ;)
Old Locations
Current status
• unknown - Kaiten
Next Locations
• Florida - tampakuro - installing headers
• Illinois - jonli447
PLANED TASK: soldering the JTAG + serial headers , trying to port 2.6 to the LS2-Board
LS2 bought from Pitty-t from nslu2-info.de
Hopefully only a flash-rom error and reviveable via JTAG.
Old Locations
• Germany - Pitty-t
Current status
• sent to Austria - mindbender
Next Locations
• Florida - tampakuro
PLANED TASK: soldering the JTAG + serial headers and reviving.
LS1 donated by 808
808 donated his LS1 to the community.
Old Locations
• UK - 808
Current status
• sent to Florida - tampakuro
PLANED TASK: for soldering the JTAG + serial headers and reviving.
Next Locations
• UK - timtimred
PLANED TASK: testing OpenLinkEmbedded on the LS1/Kurobox
Personal tools
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92648
Obsessed with having babies? Update on the Octuplets Story
With 6 children and adding 8 more, how will she be able to afford to raise all of them is the big question. One physician said anyone who knowingly transferred 8 embryos should be arrested for malpractice, so perhaps this story will continue to be updated as more information is gathered. This is not to take anything away from the physicians at Kaiser who delivered all 8 babies by any means, they did their job well.
Initially our fascination with multiple births was pretty positive, but in the current economic conditions we are in, will this perhaps change as the theme being talked about today is being responsible and making intelligent decisions. When you stop and think about it if these were the first set of babies born to a couple who had been trying to conceive and used artificial methodologies, the entire story might have a whole different perspective, and would a couple of sorts take on all 8 embryos too.
Certainly it is nice to have all the news coverage and be part of something that has only happened once before, but where’s the aftermath of all of this when real life returns and should the impact of the ability of science to create children be given some ethic standards for the future? ABC News has been talking to relatives and friends and adds a little bit more to the entire story here. BD
The California woman who gave birth to octuplets on Monday, although once married, apparently had all 14 of her kids out of wedlock by artificial means -- and various public records raise questions about the family's ability to support them.
ABC News has learned through San Bernardino Superior Court Records that the 33-year-old California woman, whose name is Nadya Doud (she filed to have her name changed to Nadya Suleman in 2001 -- though it was not clear if the request was granted), divorced her husband, Marcos Gutierrez, in January 2008.
The document indicates "no children of the marriage," suggesting that Gutierrez was not the father of Doud's previous six children.
ABC News: Octuplets' Mom: Can She Afford to Raise 14 Kids?
Reactions:
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Get free, personalized health advice and answers with HealthTap
Image credits: HealthTap
(3 votes)
Five months ago, HealthTap launched its public beta to help people share health information based not around symptoms or treatments, but around the individual. This week they've expanded the system by launching iPhone and Android apps.
HealthTap is an interactive health network that connects patients with physicians for quick, personal, localized answers 24/7 for free. Users choose their own profile names and images, so true identity disclosure is optional, offering privacy to those who may need help but don't want to visit a doctor. Personal information that is shared on the site is not shared outside of your personal account settings page. What you reveal is up to you.
Initially the service was targeted at pregnant women and mothers of children under one. The new mobile apps as well as the web platform are now open to a wider medical field and include advice from physicians in 82 specialties.
The app, HealthTap Express, has one version for patients and one for physicians. It puts “5,000 doctors at your fingertips” without visiting a doctor's office. Patients can get answers to just about any health question from 5,000 doctors across the US. Doctors benefit from having a "virtual practice," where they can help people by being able to talk to them in real time, which means they can better serve existing patients as well as potentially attract new office patients.
The HealthTap vision is of "a healthier, happier world — one person at a time. We envision people everywhere making confident, informed, fact and data based choices that maximize their health and improve their well-being. We see a future of true individualized medicine, where physicians are at the center of the health conversation, and where people’s increased control of their health reduces anxiety and increases optimism."
The company's values are open source values and include trust, openness, transparency, and collaboration, which they apply to try to improve health through sharing.
Learn more about how HealthTap works and watch its CEO, Ron Gutman, give a TED talk on "The Untapped Power of Smiling":
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Quotation added by staff
Why not add this quote to your bookmarks?
Where is Hollywood located? Chiefly between the ears. In that part of the American brain lately vacated by God. Jong, Erica
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11 Apr 2005 Varney » (Observer)
Well it is a long story but I am currently bed bound due to a back injury. The good news is that this has given my time to work on some designs for my next project. I plan on hacking my robosapien, I think a couple more brains will do him some good. I will post more details later.
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"url": "strategywiki.org/wiki/Paper_Mario:_The_Thousand-Year_Door/Chapter_8:_The_Thousand-Year_Door",
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Paper Mario: The Thousand-Year Door/Chapter 8: The Thousand-Year Door
From StrategyWiki, the video game walkthrough and strategy guide wiki
Jump to: navigation, search
Contents
[edit] Trial of Shadows
Palace of Shadow:
The Palace of Shadow will put all of your skills and partnerships to the test. It also seems to be a hot spot among Mario’s enemies-you’ll face no fewer than five boss battles by the end.
Use the quote as a warning. You will face 5 bosses here (and 1 mini-boss), one of which you face right after the other. If you feel you’re prepared, then by all means, go through the door.
Enemies:
• Bombshell Bill Blaster (doesn’t attack directly) - 10 HP, 4 DEF
• Bombshell Bill - 3 HP, 6 ATK, 2 DEF
• Chain Chomp - 7 HP, 6 ATK, 5 DEF
• Dark Bones - 20 HP, 5 ATK, 2 DEF
• Dark Wizzerd - 10 HP, 5 ATK, 2 DEF
• Dry Bones - 8 HP 5 ATK, 2 DEF
• Dull Bones - 1 HP, 2 ATK, 1 DEF
• Phantom Ember - 10 HP, 5 ATK, 0 DEF
• Red Bones - 5 HP, 3 ATK, 1 DEF
• Swoopula - 9 HP, 4 ATK, 0 DEF
This is it, the final dungeon. Please take in mind that this is the biggest in the game. So, if your not careful, you could find yourself low on items by the end (Don’t worry though, there’s still some healing items I here albeit not too many). So, only use them in an emergency. Now that that’s out of the way, go forward through the door at the end of the hall (listening to the kick-ass dungeon theme if you wish to). In the next room there’s a Stop Watch to the north. The three Swoopulas here can drain HP from you. In the next room, the item box has a shooting star. You’ll find some Dry Bones, Swoopulas, and B. Bill Blasters (along with Bombshell Bills of course). Use Supernova or Art Attack to take them out fast. Once in the next room DO NOT MOVE. Now, walk very slowly. Some spike will come out of the ground when you step near them, so avoid those. The All or nothing badge found here is very helpful later on. There are some Swoopulas here, but don’t let them distract you. Attack them when they are very close to you. In the next room, there are the classic fire bars waiting for you on the bridge. Save your game and avoid them as you cross. There’s a Boo’s Sheet in an invisible block directly above the small brown platform in the center if you want one. Switch to Vivian as you go down the stairs. Infinite rows of fire come towards you as you cross the bridge. Jump over the low ones and use her to hide from the higher ones. Go into the door on the other side. It’s quiet in here. TOO quiet... anyway, go to the end of the room and examine the dark bones guarding the door. Once you do, it’s déjà vu all over again. A bunch of Dry Bones suddenly comes raining down upon the room (just like in Hooktail castle). But this time, the Dark Bones runs away from you, so it’s more difficult to catch him this time. When you do get to him, you fight.
[edit] Mini-Boss
(1 Dark Bones and 4 Dry Bones)
Dark Bones:
Goombella’s Tattle: That’s a Dark Bones. It’s the baddest of the Bones gang. When its HP goes down to 0, it collapses into a pile, but it’ll eventually rise again. Fire and explosions will put a permanent end to it getting back up, though. Its HP is high so it’s hard to take it down. Like any other Bones, it sometimes builds friends if it feels outnumbered. It’s a tough enemy. You better take it and it’s buddies out all at once.
• Max HP: 20
• ATK: 5
• DEF: 2
• Difficulty:***
• Attack: Bone Throw
• Mulit-Bone Throw
• Regroup (builds more Dry Bones)
• Resurrect (comes back to life after several turns)
These guys hit hard so use items or special attacks that can take them all out at once (Bobbery’s Bob-ombast and Vivian’s Feiry Jinx can help permanently get rid of Dry Bones). Once their gone, take out the Dark Bones fast before it can regroup.
Once they run away, get the key and open the door. There’s an ultra shroom in the item box. A couple of B. Bill Blasters stands at the top of the some stairs in this hallway as well as some phantom embers. Defeat the enemies and go through the door at the end of the hall. There’s nothing special in this room. There are just some enemies and a few items. When you’re done go to the next room. The next few rooms have no enemies. That’s because they’re almost the same. It’s like a maze here. If you go through the wrong door, you’ll get warped to the previous one. Only go through the doors that have the torch (they will always be on the right side of the room. So, here’s the correct order: bottom, bottom, top, top, bottom, top, and bottom. You’ll soon find yourself in an open area (sort of).
[edit] Big Brother
Go through the palace garden and defeat the two chain chomps guarding the save point and health block. They have high defense so use Piercing Blow if you have that badge. When you beat them, use the health block and save point before moving on. Go through the door at the other end. Defeat the enemies while going through the series of long hallways (you’ll also come in contact with the dark wizzerd here. The wizzerds are probably the most frustrating enemy in the game.). Once you reach the end, save and enter (It’d be a good idea to equip the Feeling Fine badge). You’ll face the older sibling of an old boss.
[edit] Boss Fight
Gloomtail:
Goombella’s tattle: That’s Gloomtail. I think he’s Hooktail’s brother. I see the family resemblance... He’ll bite or stomp you, and he may also breathe poison on you. Great. When his HP gets low, he may throw in some other attacks as well. Wouldn’t surprise me. Especially watch out for his megabreath move, ‘cause the word is, it’s GNARLY! He also stores power for some attacks, so use Vivian to hide to avoid those."
• HP: 80
• ATK: 8
• DEF: 2
• Difficulty:****
• Attacks:
• Stomp
• Chomp
• Poison Breath (can poison you and your partner
• Charge (warning for Megabreath)
• Megabreath
• Earthquake
This guy is no pushover, unlike his younger sister. ALWAYS use Vivian’s Veil when he charges up. If you get caught in the megabreath that follows you WON’T be happy, I can guarantee that. Use items in an emergency. His earthquake attack does 10 HP of damage, so make sure you always have above 13 HP when you use veil. He’ll go down after a while.
Gloomtail spits out a treasure chest. Open it to get the Star key. Go to the right and look for a cracked space near the bottom of the right wall. Have Bobbery blow it up and go through the hallway. On the other end are two item blocks that contain an Ultra shroom and a Jammin’ Jelly. Go back to the palace garden. Save and heal at the corresponding blocks. Go to one of the Chomp statues and throw Bobbery into their mouth. When he explodes, the pipe will be unblocked. Go inside it and hit the nearby switch. Go back and do the same with the other statue. Now go south of the central bridge between save and health blocks and use the boat panel to sail to the other side of the moat. Dock at the opposite panel and go inside the building.
[edit] Triple Threat
You’ll have to collect the eight palace keys found in each room. Although you can obtain these in any order, I’ll be getting them in order (sort of). Start by going in the bottom left door. Hit the left red ! block three times and the right one twice. A chest will appear in a somewhat creepy manner. There’s nothing dangerous inside, so open it for your first palace key. Only seven more to go... Anyway, leave the room and go in the lower right corner. Go in the center and use flurrie to blow away the invisible barrier and reveal the next treasure chest. Next, go in the room in the upper right corner and just walk through the wall. Nothing special, just walk through and hit the switch for your third palace key. Ignore the final door down here for now and go upstairs to the second floor. Go inside the lower left door. Inside, you’ll find the entire bones family lying on the ground. You’re supposed to beat them in order from weakest to strongest. Just beat the weakling followed by their leaders: Dull Bones, then Red Bones, then Dry Bones, and finally Dark Bones. If you battle the wrong one, just run away (I mean, a few coins won’t make that much of a difference anyway, especially now). When they’re dead (again), hit the blue switch and get the key from the chest. Now we’re halfway there, so leave the room. Go to the lower right door and go in the center of the room. Use Vivian to hide into the shadows. The invisible block will appear as long as you are hidden. Memorize the place, reemerge, and hit the invisible block. Get your key and leave. Next, go to the room in the upper right corner. Inside, you have to blow up the wall, so throw Bobbery near the center of it and he’ll make a hole in it. Get the key from the chest and go back to the main room. The last two rooms are linked so go into the room in the upper left corner. If you destroy a block here, it will destroy the opposite colored block in the room below (If you smash a gray block, one of the red blocks in the lower room will disappear). Bash the gray block on the right pedestal and go to the room downstairs in the upper left corner. Destroy the two gray blocks here then return to the upper room. Hit the switch and grab the key from the chest. Smash the remaining gray block and return to the upper left corner room downstairs. Hit the switch here and get the key. Now that you have al eight keys, go to the very top of the stairs and watch the short scene. Put the star key in the pedestal and put the keys into the pillars that appear (in any order). Watch another scene and leave the building. Go back through the moat and save and heal (if need be). When you et near the door, you’ll find yourself in another boss fight.
[edit] Boss Fight
(The New Shadow Sirens: Beldam, Marilyn, and Doopliss)
Beldam:
Goombella’s Tattle: That’s Beldam. She’s the leader of the Shadow Sirens. Her special move is a blizzard blast. If it hits you, you’ll totally freeze. She has lots of other tricks up her sleeves, too. I wonder what that plan was that she mentioned? What do you think they’re up to?
• HP: 30
• ATK: 5
• DEF: 0
• Difficulty:***
• Attacks:
• Blizzard Blast (makes your party frozen)
• Short-Range Chill
• Status Change (does various status affects to anyone on the field)
Marilyn:
Goombella’s Tattle: That’s Marilyn. She’s Beldam’s sister, another one of the Shadow Sirens. She’ll attack you directly or use lightning. She also saves up energy for a big attack sometimes. So long as you avoid the brunt of her attacks, she shouldn’t be too tough...
• HP: 40
• ATK: 7
• DEF: 0
• Difficulty:***
• Attacks: Handclap
• Charge
• Lightning Blast (does 14-plus damage after charge)
Doopliss:
Goombella’s Tattle: That’s Doopliss. He’s a shapeshifter, and even turned into you once, Mario! He may turn into one of us and attack. When he does, he’ll have our abilities! Hey, how do you think he became one of the Shadow Sirens? Isn’t that...weird? How do you think he stands Beldam’s abuse? You think he’s all right in the head?
• HP: 40
• ATK: 6
• DEF: 0
• Difficulty:***
• Attacks:
• Ghastly Headbutt
• Copycat (changes into Mario or your current partner)
• (any of you or your partners basic attacks)
Bet you didn’t expect this, did you? As always, take care of Beldam first. She can freeze you, so that makes her dangerous. Next, Marilyn still has her Lightning Blast, so get rid of her next. Doopliss... is basically the same guy you fought in Chapter 4. The only thing is that his attack is raised and he uses copycat more often. But, since the attack uses his turn, it makes him more vulnerable, so take care of him last.
When you’re done, they’ll be on the ground unconscious. Save, heal, and move on. Go back to the series of long hallways that lead you to Gloomtail.
[edit] Tired Yet?
Tired yet? We’re just getting started. As you can see, the hallway has changed. So go down the new set of stairs. Defeat the dark wizzerds (use your spring jump to get the item block) and use Flurrie to blow away the fake part of the wall at the very right end of the hall. Go left behind where the wall was. At the top of the hidden stairs, use Yoshi to float to the other end. Go inside the door. Don’t hit the switch to the right yet. Instead, hold Koops’ shell to the left of it and go up the stairs to your left. Stand near the gap at the top and let go. Quickly jump across the platform that appears and to the other end. Go down the stairs and get the Repel Cape (if you wish to) found at the bottom. Go out the door. Go up the nearby stairs and through the door. Make your way up the sort-of narrow set of stairs and hit the small green block. Go back to the room to the right and stand on the yellow block. Use Yoshi to cross the gap to the other side. Go up the stairs and jump off the ledge. Hit the small purple block and quickly get on the larger one before it rises. At the top, use Yoshi again to get across the gap. Hit the small red block and hold Koops’ shell next to it. Get on the larger red block and let go. Jump into the right opening as the block lowers. Roll into a tube and jump over the gap in the openng (or you could use Yoshi again). Go into the door. In the next room, stand on the upper yellow lines on the carpet. Use your spring jump to get to the poles. Shimmy across and jump off at the end. This time, go to the lower yellow lines and use your spring jump again. Shimmy to the end and jump off. Go into the door and defeat the phantom ember and dark wizzerd to the left. You can get the shooting star in the chest if you have room left. Go to the top of the staris and throw Bobbery off the ledge. Watch out for the chain chomp as you quickly go across the ledge that appears. The stars on the wall here are important- memorize the order they are in. Go to the top of the stairs to the left and save your game. Go right and jump on the platform at the bottom of the wheel. Have Koops get the palace key and jump down. Go back to the door at the top of the stairs, unlock it, and go through. Use your spring jump to get the life shroom in the nearby block. Go up the stairs and roll into a tube. Use it to jump up the stairs. From right to left, hit the red blocks in the order of the stars on the previous room's wall (make sure to defeat the dark wizzerd first). Go back to the previous room and go back to the wheel. As you can see, it started moving. At the top of the wheel, there’s a life shroom if you need one. Go to the ledge to the right and go down the stairs. Go in the door and have Flurrie blow the cover off the big block. Smash it with your ultra hammer move and spin jump through the wooden panel. Jump on the coin block and jump again for a Point Swap (you’ll only get 1 coin if you hit the lower coin block). Go out the nearby door. Carefully cross the narrow walkway and enter the door to your right. Use the airplane panel to the door in the middle of the room (not at the door at the very end). Defeat the chain chomp at the bottom of the stairs and hit the red block it was guarding. Quickly switch to Yoshi and ride him up the stairs and get across the gap as fast as possible. Get the key out of the chest and go back to the previous room. Jump down the ledge and defeat the Phantom Embers and use the spring at the left side of the hall. Use the panel to fly all the way to the end of the hall (it might take practice if you’re not good at flying). Heal and save before moving on (also, have on your best badges). It’s about to get ugly.
[edit] Saving the World (again)
Climb to the top of the stairs!
[edit] Boss Fight
Sir Grodus:
Goombella’s Tattle: That’s Grodus! He’s the head of the X-Nauts who kidnapped Peach. But...when he has Grodus Xs surrounding him, his defense will go up by that number.He may also use electricity, fire, and time-stopping magic. That doesn’t sound good! Still, he’s a totally weird guy. Why’s he so intense and serious all the time? I guess we don’t have time to worry about that. Let’s beat him and find Peach!
• HP: 50
• ATK: 7
• DEF: 1
• Difficulty:****
• Attacks:
• Thunderstorm
• X-Create (makes 2 Grodus Xs at a time)
• Flame-thrower (attacks you and partner)
• Payback (makes himself able to counter direct attacks for 2 turns)
Grodus X (is created by Grodus during battle):
Goombella’s Tattle: That’s a Grodus X. It protects Grodus. This guy is no problem on his own, but Grodus’s Defense goes up for each of them. When he has four surrounding him, we won’t be able to damage him at all. So let’s dish out some hurt to them while we pound on Grodus. Got it?
• HP: 3
• ATK: 4
• DEF: 0
• Attacks:
• Ram
He may look easy because he only has 50 HP, but he's pretty hard. The Grodus Xs make him tough. It is very useful to go into this fight when you're about to level up, so you can heal before the next fight. You get about 30 star points when you defeat Grodus, so fight him when you have 70. Start off by getting rid of the Grodus Xs. Use attacks that attack all enemies at once. Once their gone, pound on Grodus. His attacks are powerful, but if you have high HP and guard well, it won’t matter that much. Art Attack is also very useful here as well as Supernova (although Art attack is better since you will face another boss after this). Continue to get rid of any Grodus Xs that appear as well as attacking Grodus. Soon, he will fall like the many video game villains before him.
It’s not over yet.
[edit] Boss Fight
(Bowser and Kammy Koopa)
Bowser:
Goombella’s Tattle: That’s Bowser, genius. You’ve only fought this guy like, a bazillion times. He’ll keep kidnapping Peach, and you’ll keep fighting him, until the end of time, I think. In addition to his fire breath, he jumps on you and bites. If you get jumped on, you’ll be unable to use a command for a while. Oh, and his bite sometimes poisons you as well. I don’t know what Bowser’s doing here, but we gotta defeat him quick!
• HP: 70
• ATK: 7
• DEF: 2
• Difficulty:****
• Attacks:
• Poison Bite
• Flame Breath
• Bowser’s Jump
Kammy Koopa:
Goombella’s Tattle: That’s Kammy Koopa. She’s an old evil witch who’s always helping Bowser out. She uses her magic to raise her Attack and Defense or get electrified or invisible. When her HP gets low, she may also use magic to restore HP. Her magic is totally annoying, so take her out before you focus on Bowser. Still, you gotta feel for her, having to hang out with Bowser all the time... Or do you think Bowser has a harder time enduring her?
• HP: 50
• ATK: 5
• DEF: 0
• Difficulty:***
• Attacks:
• Magi-projectile
• Heal
• Stat change (raises her ATK, DEF, and can make her invisible or electrified)
• Enlarge (makes Bowser bigger)
Take care of Kammy first, her magic can make this battle harder than it should be, but heal if you're low on HP. Trust me, a giant Bowser is something you DON’T want to fight, especially since you just beat Grodus. If you jump on her, she’ll fall from her broom and will stay on the ground temporarily. When you get rid of her, focus the rest of your attacks on Bowser. He’s not that tough without Kammy around. You just have to guard well. Continue the punishment and you’ll beat Bowser (yet again).
After the scene, follow Grodus into the tunnel. Get the ultra shroom from the chest and use the health block. Go all the way down the stairs and open the other treasure chest for a Jammin’ Jelly. Save your game and make sure you have the following badges equipped (if you have them and if you have enough badge points):
In no order...
• Piercing Blow
• Power Smash
• Power Jump
• Power Bounce
• Pretty Lucky
• Damage Dodge (the more the better)
• Defend Plus (the more the better)
• Close Call
• Feeling Fine
• All or Nothing (if you’re good at action commands)
• Charge and/or Charge P (useful if you don’t have anything else to do for your turn)
• Flower Saver (once again, the more the better)
• Last Stand
• (If you have any points left to spare, use them on the P versions of your badges, or any other useful ones)
When your ready, head inside. Watch the scene. If you answer yes to her question, you’ll get a Game Over (and will have to go through the cutscene again.) answer no and the battle begins.
[edit] Final Boss
Shadow Queen:
Goombella’s Tattle: Omigosh, what happened? I can’t believe Peach just got possessd! That’s AWFUL! Now she’s...the shadow Queen. The demon that destroyed this town 1,000 years ago. She’ll unleash big lightning attacks. She’ll also use magic to raise Attack and Defense, or to absorb HP... She might even try to drag us into darkness... I don’t feel good about attacking Peach, but we have to do SOMETHING! Don’t think of it as Peach! We just have to fight to the end! C’MON!!!
• HP: 150 (Hand’s HP: 5; Dead Hands’ HP: 8)
• ATK: 7
• DEF: 1
• Difficulty:*****
• Attacks:
• Dark Lightning
• Power Lift (raises ATK and DEF)
• Drag into darkness (attacks multiple times)
• Hand Slap
• Drain (drains HP and gives it to Shadow Queen)
• Multi-Hand Stampede
• Poisonbreath, Confuse breath, immune breath)
Remember, you should at least have 90HP, 35FP, and 30BP. Make sure you are level 30 or above. You should have lots of items with you, such as: ultra shroom, jammin jelly, jelly ultra, life shroom, etc.Once you enter the Shadow Queen's room, she will give you a chance to back out and be her servant. Don't become her servant! The game will automatically end and everyone was doomed. You will game over and start over from the last place you saved. Say "Refuse this witch" and let the battle begin! This fight is slightly similar to the last boss (Bowser) in the original Paper Mario. Start off with Power Lift and attack with everything you got (except don’t use items). After a while, she’ll transform and you won’t be able to damage her at all. Keep guarding and attack her for the next three turns and you’ll trigger a cutscene. After the cutscene, you’ll be completely healed (but so will the Shadow Queen. At least you can actually damage her. Once again, start off with Power Lift and attack her and her hands. When you destroy them she’ll switch to the Dead Hands after another turn. She’ll change back to the two hands when you destroy the Dead ones. Although, the two hands are more dangerous because they can drain your HP or FP and give it to the Shadow Queen and since their separate, they give her two extra turns to attack. The Feeling Fine badge will protect whoever has it equipped against her dangerous breath attack. Also, use Vivian to hide in the shadows when she charges up. This battle is hard, but if you use your items correctly, and use your best special attacks (it might also take some luck depending on your level) you’ll be able to beat her.
When you defeat her, watch the ending cut scene. Congratulations, you beat Paper Mario: The Thousand-Year Door.
[edit] Aftermath
Rogueport:
Save your game after the credits roll. Go back to the menu and start up your file again. You’ll see Mario return to Rogueport. You’ll have all of your items and stats as you had them before. Unfortunately, any lost HP and/or FP from your last battle will still be there. Heal at the inn and return to your favorite badge setup. You can talk to the people here. Most of them have changed their dialog and character.
Here’s the last message on the bulletin board:
When the light fades from Rogueport, a hero emerges, inscribing his name in legend.
Afterwards, go to the trouble center and take on the last three of them.
• Client: Doe T. (Boggly Woods)
• Title: Roust these cads!
• Reward: 20 coins
This is a simple task. Equip the First Attack badge if you have it (it will make things easier) and go to the first screen in Boggly Woods. Talk to the toad and defeat the enemies (jump on them or hammer them if you have the First Attack put on to kill them instantly). When they're all dead, the toad will give you your reward.
• Client: Bub (Poshley Heights)
• Title: Help me make up.
• Reward: 3 coins
You’ll need one of the three following items to solve this problem: A Shroom Cake (mix a Mushroom + a Cake Mix), Keel Mango, or a Fright Mask. Go to Poshley Heights (you can talk to Lady Bow (from Paper Mario 1) near the fountain) and talk to Bub to the left of the sanctum. Choose the item you bought and give it to him. Give the present to Sylvia (the lady Bob-omb next to Goldbob at Poshley train station) and go back and talk to Bub. No matter what item you gave him, he’ll give you the same reward, THREE STINKIN’ COINS!
• Client: Swob (Fahr Outpost)
• Title: Erase that graffiti!
• Reward: Snow Bunny
This is the last trouble. It’s also the longest and probably the hardest. Stock up and go to the Pit of 100 Trials. Go all the way to Level 50 (the enemies aren’t that hard) and use Bobbery to blow up the graffiti on the left wall. Get the Strange Sack in the chest (it doubles your item space) and get out of there (unless you feel lucky). Go back to Fahr Outpost and talk to the Bob-omb to the right of the cannon statue. He’ll give you your reward. Congratulations, you’re now the #1 Problem Solver in Rogueport (well, not technically, but still).
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Posts: 82 | Thanked: 58 times | Joined on Jan 2010 @ Australia
#1
Hi guys
Fist of all watch this
http://www.youtube.com/watch?v=iqObYqj1xpk
&
http://www.youtube.com/watch?v=Erd_oEdHc58
Source
https://github.com/mozilla-b2g
or
https://github.com/andreasgal/B2G
wiki
https://wiki.mozilla.org/B2G
Now, from what I understand, B2G uses Linux kernel + Mozilla gecko rendering engine.
There are heaps webapps now and it seems HTML5 is the way to go for cross-platform developing.
Plus there are webapps app stores coming up such Mozilla, Chrome and Facebook, not to mention the smaller once. I think developing something(OS) using B2G is better than wasting more time with Qt ;(
So, did anyone try? or is there anyone interesting in porting B2G to n9?
& yes I can't do it myself! I can donate
Thanks
Posts: 2 | Thanked: 1 time | Joined on Feb 2011
#2
I have it running on my Nexus S right now. Even in this early stage (it´s not even alpha I think) it is quite impressive. It lags like crazy and there are bunch of placeholders and non-working stuff all over the place but as I said, it´s not even alpha. Phone-calls, SMS and Wifi work though.
It uses the Android kernel with it´s drivers but instead of the Java-stuff on top it uses Gecko. The Web-content has direct control of the hardware through APIs that Mozilla and W3C develop and standardize. Pretty cool and it´s all open technologies!
I am as excited for B2G as I was for the N9 actually and would love to have it running on it. I am, however, not able to contribute, other than donate some $$ like you et3rnal. People already got Android running on Maemo devices so getting this running on them should´t be a problem. Anyone up for it?
The Following User Says Thank You to tomislavp4 For This Useful Post:
Posts: 82 | Thanked: 58 times | Joined on Jan 2010 @ Australia
#3
Thanks
I think people hear still doesn't like the idea of cloud OS! maybe after Tizen\B2G rocks they will change there mind! who knows
or maybe after Mozilla market place becomes alive?, and as you said it still in early stages, hopefully it'll become more interesting for developers to port it later on!
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Maidstone
From Wikitravel
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Maidstone [1] is a town in Mid-Kent, in the South East of England.
Understand
Straddling the river Medway, Maidstone [2] is the economic, administrative and agricultural centre of Kent. For many years the major employment in the town was provided by the agricultural markets, insurance brokers and the toffee factory to the south of the river. Nowadays, however, many residents use Maidstone as a base to commute into London, or are employed within the retail, administrative or service sectors within the town.
Get in
By air
The nearest major airport is London Gatwick Airport, which is 42mi/67km away.
By car
Maidstone sits just alongside the M20, which connects the M25 with Folkestone and the Kent coast. The A26 runs west to Tunbridge Wells, and the A229 heads north to Chatham, Gillingham and Rochester, and south (joining the A21) to Hastings.
Be warned - the centre of Maidstone is dominated by a complicated and sometimes frustrating one-way system.
Parking can be a problem if you do not know your way round, but it is recommended that you park in either The Chequers Center car park that is in the town center located in King Street, opposite the Bowling Alley. The entrance to this is up a ramp with a height barrier bar.
By train
Maidstone has rail links to London, Chatham, Ashford (for the Eurostar) and Tonbridge (via Paddock Wood).
Fare and timetable information is available from South East Trains, tel. 08457 484950.
Get around
By bus
Arriva is the bus company that operates in Maidstone. Timetables and fares are available on their website. Buy your ticket from the driver when you board the bus.
By taxi
If there is a large group of you, then it may be easier and cheaper to get a taxi from one of the local taxi companies, as Maidstone's bus service is not the cheapest!
• Payless Taxis: +44 (0)1622 661234 (24 Hour)
• Cavalier Taxis: +44 (0)1622 754000 (24 Hour)
See
• Maidstone Museum & Bentlif Art Gallery, St Faith's Street, ME14 1LH [3] Open Mon-Sat 10.00 - 17.15, Sun 11.00 - 16.00, Admission Free. A municipal museum with a wide ranging collection in 20 or so rooms. The local history collection on the ground floor gives an introduction to the recent history of the town. 3 rooms house a small art gallery.
• Maidstone Carriage Museum - The Tyrwhitt Drake Collection, Mill Street, ME15 6YE. Open summer only (was closed in Mid-May).
• All Saints Church, Mill Street, ME15 6YE, [4] Fine church rebuilt in the 14th century. Open Mon-Thur 10.00 - 16.00 Sat 10.30 - 12.30 May to September. The Archbishop's Palace next door is worth a look from the outside - it is now the registry office.
• Museum of Kent Life, Cobtree, Lock Lane, Sandling, ME14 3AU [5]
• The Hazlitt Theatre,Earl Street, ME14 1PL, 01622 758611 [6]
Do
Buy
Eat
• The Oak on the Green, +44 (0)1622 737976, A restaurant/pub situated next to a large cricket green in a small village just outside of Maidstone called Bearsted. The staff is friendly and helpful. At times, like most sucessful venues, it can be a tad busy and as such, service can be a little slow. The food is primarily mexican based. The fajita's are fantastic, and come in either steak, chicken or mixed. It is belived that Vegetarian options are available. Other recommendations are Stuffed Jelepeno Peppers and Fajitas (normally shared by two people). start at £12.00, beer about £3.00.
Drink
Sleep
Get out
Other places of interest in the Maidstone area
• Leeds Castle, near Maidstone, tel: 01622 765400, e-mail: enquiries@leeds-castle.co.uk, [7]. Described by Lord Cornway as "the loveliest castle in the world". Admission £12.50 for adults (£10.00 - gardens only), £9.00 for children (£6.50 - gardens only).
• The Hop Farm Country Park, Paddock Wood, tel: 01622 872068, e-mail: info@thehopfarm.co.uk, [8]. 10AM–5PM, Daily except Christmas Eve, Christmas Day and Boxing Day. Once a working hop farm, it now offers a wide variety of attractions and events. Admission £7.50 for adults, £6.50 for children.
This article is an outline and needs more content. It has a template, but there is not enough information present. Please plunge forward and help it grow!
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User:Fluglotse2000
From Wikitravel
Revision as of 19:26, 6 November 2012 by Fluglotse2000 (Talk | contribs)
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Dear Wikitravel user,
due to the recent developments at Wikitravel, I have decided to leave the community and to join the guys at WVoyage that created a fork of the German Wikitravel in December 2006 and have started versions in other languages as well now.
I am really sorry that I had to leave WT, because I invested a lot of time and effort into this project. But with current developments, I feel that I should devote myself to a project free of any non-community influence. I am grateful that I have met many wonderful people here, all passionate about traveling and willing tos share their experience and I hope to hear from one or the other some time.
Best wishes,
Felix Gottwald
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Research article
Consent for use of personal information for health research: Do people with potentially stigmatizing health conditions and the general public differ in their opinions?
Donald J Willison1,2*, Valerie Steeves3, Cathy Charles1,4, Lisa Schwartz1,5, Jennifer Ranford1, Gina Agarwal6, Ji Cheng7 and Lehana Thabane1,7
Author Affiliations
1 Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Ontario, Canada
2 Surveillance and Epidemiology Division, Ontario Agency for Health Protection and Promotion, Toronto, Ontario, Canada
3 Department of Criminology, University of Ottawa, Ottawa, Ontario, Canada
4 Centre for Health Economics and Policy Analysis, Hamilton, Ontario, Canada
5 Department of Philosophy, McMaster University, Hamilton, Ontario, Canada
6 Department of Family Medicine, McMaster University, Hamilton, Ontario, Canada
7 Biostatistics Unit, St Joseph's Healthcare, Hamilton, Ontario, Canada
For all author emails, please log on.
BMC Medical Ethics 2009, 10:10 doi:10.1186/1472-6939-10-10
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1472-6939/10/10
Received:12 January 2009
Accepted:24 July 2009
Published:24 July 2009
© 2009 Willison 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
Stigma refers to a distinguishing personal trait that is perceived as or actually is physically, socially, or psychologically disadvantageous. Little is known about the opinion of those who have more or less stigmatizing health conditions regarding the need for consent for use of their personal information for health research.
Methods
We surveyed the opinions of people 18 years and older with seven health conditions. Participants were drawn from: physicians' offices and clinics in southern Ontario; and from a cross-Canada marketing panel of individuals with the target health conditions. For each of five research scenarios presented, respondents chose one of five consent choices: (1) no need for me to know; (2) notice with opt-out; (3) broad opt-in; (4) project-specific permission; and (5) this information should not be used. Consent choices were regressed onto: demographics; health condition; and attitude measures of privacy, disclosure concern, and the benefits of health research. We conducted focus groups to discuss possible reasons for observed consent choices.
Results
We observed substantial variation in the control that people wish to have over use of their personal information for research. However, consent choice profiles were similar across health conditions, possibly due to sampling bias. Research involving profit or requiring linkage of health information with income, education, or occupation were associated with more restrictive consent choices. People were more willing to link their health information with biological samples than with information about their income, occupation, or education.
Conclusions
The heterogeneity in consent choices suggests individuals should be offered some choice in use of their information for different types of health research, even if limited to selectively opting-out. Some of the implementation challenges could be designed into the interoperable electronic health record. However, many questions remain, including how best to capture the opinions of those who are more privacy sensitive.
Background
The term "stigma" generally refers to a distinguishing personal trait that is perceived as or actually is physically, socially, or psychologically disadvantageous. [1] Because of the presence of that trait, an individual may be discriminated against – e.g. in employment or in social circles. Health conditions will vary in the extent to which they are perceived by those individuals having the condition and by others as being stigmatizing. Individuals with a potentially stigmatizing health condition may be more inclined than members of the public without such conditions to experience concerns over disclosure of their personal health information out of concern that this could result in discrimination against them. For example, a person with a prior history of cancer may be concerned over denial of certain employment opportunities, a mortgage, or life insurance. A person with HIV/AIDS may be concerned about social isolation because of others' concerns that their presence puts others at increased risk of contracting the condition.
There is now an emerging body of literature examining the opinion of the public regarding consent for use of one's health information for research. [2-9] However, the opinion of those who have health conditions that may be stigmatizing to a greater or lesser degree has been much less studied. [10] There are several reasons for considering – or even giving priority to – the values and expectations of these individuals. People who are unwell have the most at stake, both because they stand to benefit from research into their health condition and because a breach of privacy may potentially expose them to discrimination in obtaining loans, mortgages, insurance, or employment. Moreover, they are under-represented in surveys targeted to the general public and, to the extent that some health conditions are stigmatizing, the perspective of individuals with these conditions may be discounted by the general public. Further, if we listen only to the voice of the general public without attention to the concerns of this vulnerable minority we run the risk of committing a form of "tyranny of the majority". [11]
Objective
The purpose of this study was to examine the attitudes of people with a range of potentially stigmatizing health conditions concerning the need for consent for the use of their personal information for different types of observational health research, and to compare their attitudes with those of the general public. We hypothesized that:
- responses would differ across health conditions;
- some patient groups would be more permissive and others more restrictive than the general public; and
- people's view of the level of consent required for use of their information would vary directly with disclosure concern and inversely with perceptions of the benefits of health care and the potential for health research to improve the lifespan and quality of life of people with their health condition.
This paper reports on the testing of these hypotheses.
Methods
Choice of health conditions
In this study, we included seven health conditions with varying susceptibility to being labelled as stigmatizing. Four conditions – hypertension, diabetes, chronic depression and alcoholism – were used in a previous public opinion survey of members of the public, in which respondents were asked to imagine they had one of these health conditions. [4] In the previous study, hypertension and diabetes were found to be lower-stigma health conditions. Chronic depression and alcoholism were found to be higher-stigma conditions. In this study, we had the opportunity to obtain the views of people with these conditions. To these four conditions we added: HIV, to create an upper extreme category for potential stigma; breast cancer; and lung cancer. We anticipated that responses may differ between breast and lung cancer because of a greater general public support for breast cancer sufferers and a perception that lung cancer is self-inflicted through smoking.
Survey
The study proceeded in two phases. In Phase 1 (November 2006 to July 2007), we surveyed individuals with the target health conditions. In Phase 2 (July to September 2007), we held focus groups with a sub-sample of participants from Phase 1 – one group for each health condition. The chief purpose of Phase 2 was to help inform our analysis of the findings derived from Phase 1, by providing examples of the types of concerns some people took into account when making decisions around consent.
Setting and Participants
Survey participants were drawn from two sources: (1) a pre-existing cross-Canada panel of individuals with identified health conditions, maintained by Harris Interactive, a professional polling firm; and (2) patients recruited by the investigators through family physicians' offices and specialty clinics in the vicinity of Hamilton, Ontario, Canada. The reference group consisted of people recruited through Harris Interactive who had none of the target health conditions and no other serious health conditions. This group was used to approximate the response of the general public. All survey participants were 18 years or older.
Participants recruited directly by the investigators were either sent a letter from the physician's office in the mail explaining the study or handed an information brochure in the clinic by staff. In each case, information was provided for patients to contact the investigators if interested. In total, 892 brochures were mailed to patients' homes and 888 brochures provided to physicians and clinics for directly handing out to patients.
All participants recruited through Harris Interactive completed the survey over the internet. Participants recruited through local family physicians and clinics were given the choice to complete the survey via internet or by telephone. This was done to minimize refusal due to lack of access to or familiarity with the internet, particularly among older patients. Those opting to do the internet survey used the same system as the Harris participants. Those opting to complete the survey by telephone arranged a scheduled call with telephone surveyors from Harris Interactive. They were mailed a hard copy of the core questions of the survey beforehand, so as to minimize differences in response due to method of survey administration.
Sample size was calculated on the basis of the primary outcome variable – consent choice in the use of personal information for health research. This was expressed on a 5-point ordinal scale. (See Survey Data and Key Variables below.) This sample was determined with the primary goal of building a multivariable regression model to compare the overall attitudes among the seven groups and the general public controlling for several demographic and other confounding variables. Heuristics based on simulation studies indicate that at least five respondents per degree of freedom for each predictor variable are required for the stability of the model. [12] We have 7 predictor variables with a total of 21 degrees of freedom, which would require at least 105 participants. We aimed to recruit 1400 and obtained responses from 1137 (734 from Harris Interactive and 403 from physician offices and clinics) with the sampling stratified by health condition. We inflated our minimum sample size by a factor of over 10 to account for potential clustering of responses within a patient. Therefore, the sample size was adequate to ensure the stability of the model.
Survey Data and Key Variables
We collected information on participant demographics, attitudes about privacy, disclosure concern, and the benefits of health care and health research at improving longevity and quality of life, and the participant's health conditions. Where the participant had more than one target health condition, they were asked to answer the survey questions with only one health condition in mind. In earlier pilot work, we established an algorithm for determining which health condition would take priority, ranking the 7 health conditions according to level of disclosure concern. This algorithm placed HIV/AIDS first, followed by alcoholism, lung cancer, breast cancer, depression, diabetes and hypertension.
We presented five different scenarios involving use or linkage of personal information for health research: (1) use of health data for quality improvement; (2) use of the same data for marketing; (3) linkage of work/education/income information with health information; (4) linkage of biosamples with health information (a) assuming no profit and (b) assuming a profit element. (See additional file 1 for a more detailed description.) These scenarios were identical to those used two years earlier in a series of seven cross-Canada public dialogues. [13] Participants of the current study were advised that, in each scenario, names, addresses and any other information that could directly identify them were removed. Following each scenario, participants were asked which statement best described their view (words in italics not included in survey responses):
Additional file 1. Box 1 – Description of Research Scenarios. Provides information about the scenarios on which consent choices were made.
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(1) There is no need for me to know. Just use it.
(2) My permission is not needed, but I want to know this is being done and a chance to say "no." [i.e. notice with opt-out]
(3) My general permission is needed. This could be for several different research studies. I could withdraw my permission in future. [i.e. broad opt-in]
(4) My permission is needed each time. [i.e. project-specific consent]
(5) My information should not be used for this purpose.
The five response options above, hereinafter referred to as "consent choices", served as the outcome variable in a multivariable regression analysis using the following as predictor variables:
- demographics (age, sex, education, marital status, employment, and income)
- health condition (one of the 7 target conditions)
- self-reported health (6-point scale, varying from "very poor" to "excellent")
- scenario, and
- attitudinal variables (disclosure concern and medical benefits score. These are described below. Questions used to compile these scores and the scoring scheme are found in additional file 2.)
Additional file 2. Appendix 1. Survey questions that formed the elements for (a) the disclosure concern scale; (b) the medical benefits scale; and (c) the consent choices outcome variable. This document provides the core questions that were used in developing two key predictor variables (a measure of individuals' concern over disclosure of information about their health condition and a measure of individuals' perceptions of the benefits of health care and health research for their health condition) and the key outcome variable (consent choice).
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While there are many dimensions to stigma, for the purposes of this study, we chose to focus on individuals' disclosure concern – i.e. concern that others may find out about their health condition. For this, we asked: How concerned would you be if: (a) your employer found out about any health condition(s) you have; (b) your health insurer found out about any health condition(s) you have; or (c) a friend other than those you told found out about any health conditions you have. For each of these questions, respondents replied either: "not at all concerned"; "somewhat concerned"; or "very concerned".
For the medical benefits scale, people replied on a 5-point scale ("strongly agree, somewhat agree", "neither agree nor disagree", "somewhat disagree", or "strongly disagree") to the following statements: (a) Medical treatments can improve the quality of my life; (b) medical treatments can extend my life; (c) disease prevention programs have shown me how to live a healthier life; and (d) medical research can improve my life.
We re-scaled the disclosure concern and medical benefits scores to a 0–1 scale to facilitate interpretation of relative attitudes toward disclosure and medical benefit across health conditions.
Dealing with potential sampling bias
We checked for sampling bias chiefly through two methods. Harris Interactive sampled questions from our survey in an omnibus random-digit dialled telephone survey and compared the responses from the telephone survey with those from their internet sample. In addition, we compared the consent choices of the reference group from this study regarding the five scenarios with the consent choices of the people who participated in the public dialogues in our previous study. [13]
Statistical methods
Consent choices were analysed graphically across scenarios and across health conditions. We also plotted disclosure concern and medical benefit scores across health conditions using a radar graph.
To test our chief hypotheses, we used regression analysis controlling the correlation across scenarios using the method of generalized estimating equations (GEE) assuming an exchangeable correlation structure. [14] The results are reported as estimates of model coefficients (with corresponding 95% confidence interval) and associated p-value. Statistical computations used SAS, version 9.1.3 (Cary, NC.). In earlier work, we found the results of linear regression to yield equivalent results to multinomial logistic regression which is the more correct analysis but more difficult to interpret. [4]
Initially, individual predictor variables were regressed onto consent choice using univarite analysis. Variables that met the criterion of alpha = 0.20 were then included in the multivariable regression model. The chief variables of interest – health condition, disclosure concern, and medical benefit scores – were forced into the model. We tested for interaction effects of disclosure concern and medical benefits scores with research scenarios and health condition, No significant interactions were found.
Focus Groups
At the end of the survey, those participants recruited directly by the investigators in the Hamilton area were asked if they would be willing to participate in a focus group to discuss the reasoning that participants may have used to make their consent choices. Those who agreed were contacted by the study coordinator. One focus group was convened for each health condition except for alcoholism, as the survey sample size was too small for this group. We sampled from the pool of survey participants to provide a representative sample in each focus group with regard to age, gender, and self-reported health status. When making selections, investigators were blind as to volunteers' responses to survey questions.
Six focus groups, ranging in size from 6 to 10 individuals, were conducted between July and September 2007. Focus groups were 90 minutes in length. Participants received an honorarium of $75 following the session. These meetings were moderated by two of the researchers. Upon arrival, participants completed a mini-survey comprised of the key questions from the Phase 1 survey. During the focus group, a structured interview protocol was used to ask participants to reflect on the survey findings regarding consent choice for the five different research scenarios. Participants were then asked to consider how the survey responses compared with their own responses and to consider the reasons for their responses and any possible variance from the response pattern from the Phase 1 survey. Focus group participants were also asked to comment on the relative importance of individual control over use of their information and safeguards and the relation between them. This question was addressed both in the abstract and by giving them the opportunity to rate specific controls and safeguards. Immediately following the meeting, participants again completed the mini-survey, so a comparison of the responses of focus group participants with those of the larger sample could be made. Discussions were audio recorded and transcribed for analysis.
Verbatim transcripts from all focus groups were read independently by at least two members of the research team and quotations were selected to exemplify the types of reasoning that focus group participants used to make their consent choices. These quotations are used below to help illustrate the broader survey analysis, and to provide a window on the kinds of issues some people may address when making consent choices.
Ethics Review
The research was reviewed and approved by the research ethics boards of St. Joseph's Healthcare, Hamilton, Ontario, McMaster University Health Sciences REB, Hamilton, Ontario and the Social Sciences and Humanities REB, University of Ottawa, Ottawa, Ontario.
Results
Participants
Four hundred three survey participants were recruited directly by the investigators and 734 were recruited through Harris Interactive. Recruitment of survey participants through the investigators' sources is summarized in Figure 1.
Figure 1. Summary of recruitment process, using the investigators' sample.
Demographic data
Additional file 3 summarizes the demographic characteristics of study participants by sampling source. Those recruited directly by the investigators are presented by method of survey completion. Overall, the reference group was younger (mean age 46 years) than participants with target health conditions (mean 55 years), regardless of sampling source. Their self-reported health was better than those with the target health conditions. Those with the target health conditions completing the survey over the internet were comparable between the two sampling sources on most demographic variables. However, the Harris sample was less wealthy and reported poorer health than the sample assembled by the investigators. Survey participants recruited by the investigators who completed the survey by telephone were older (mean age 62) with a greater percentage of women (68% vs. 60% in general public and 53% and 57% in the Harris and investigator internet samples). Telephone survey participants had a greater percentage with high school education or less (56%) than those who completed the survey over the internet (28%). In addition, telephone respondents were more likely to be separated, widowed, or divorced (30% vs. 14–24%). Fewer were employed (21% vs. 49–72%) and a greater percent had an income less than $40,000 per year (42% vs. 20–35%).
Additional file 3. Table 1. Summary of Participant Demographics. This describes basic demographic features of survey participants broken down by survey method and sample source. We divided investigator sample source into those who responded by telephone and internet to determine whether demographic characteristics varied more by sample source or self-selected method of completion of the survey.
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Attitudes
A summary score of participants' perceptions about the benefits to be accrued from health care and health research (medical benefits score) and disclosure concern is provided in Figure 2. Each axis on this radar plot represents one health condition or the reference group. The scale on the axis for both attitudes was standardized to (0,1) to facilitate comparison. The medical benefits score was uniformly high across health conditions. On the other hand, there was substantial variation across the health conditions regarding the level of concern participants had about employers, insurers, or friends finding out about their health condition. Disclosure concern was lowest for those with hypertension, diabetes, and lung cancer. It was highest among those with chronic depression and HIV/AIDS. We note also that disclosure concern in the reference group was almost as high as the HIV/AIDS group yet, they had no serious or chronic health condition.
Figure 2. Attitudes of survey participants across health conditions.
Consent choice
Across scenarios, consent choice profiles were very similar for all health conditions. They were also very similar to the profile of the reference group. For ease of presentation, we have combined the responses across health conditions in Figure 3 and compared these with the reference group.
Figure 3. Consent choices across research scenarios – A comparison of the general population with a pooled sample of those with the target health conditions.
Effect of intended use and commercialization on consent choice
Scenario 1 involved the use of prescribing information from the medical record for quality improvement and, for this paper, serves as the comparator scenario. Figure 3 shows a relatively permissive consent profile for this scenario, with the most common response being "Just use it" (35–40%). By contrast Scenario 2, which used the same prescribing information for marketing purposes, elicited essentially the opposite profile, with over 40% of respondents indicating that this information should not be used (at all) for this purpose.
A similar, though less marked, shift in the pattern of consent choice was observed when comparing Scenarios 4a and 4b. In Scenario 4a, individuals' health information was linked with biological samples in the absence of any commercialization of any discovery. In this case, the consent profile was quite similar to that for Scenario 1. When a potential profit element was introduced through the development of a commercial lab test (Scenario 4b), the consent profile displayed a desire for greater control over use of that information, though not as strong as for the marketing scenario (Scenario 2), and with no particular consent choice being preferred.
In our focus groups, we probed for explanations behind the desire for greater control when commercialization was involved. The responses were wide ranging. A common sentiment was that people felt they were being taken advantage of:
"It was a matter of control. It's the whole idea of profit, that word 'profit'. Once I see that, I just have a sense of being taken advantage of. ... but on the other hand I wouldn't not do it because it is helpful. I would just want to know." (Participant 7, Diabetes group)
"First thing I thought of was 'Well, if they're selling it for a profit what do I get out this?' I just don't see your volunteering something, if somebody else is making a profit out of it. I don't see that." (Participant 3, Lung cancer group)
Different consent profiles for linkage with biological samples vs. income, education, and occupation, in the absence of profit
The consent profile for linkage of health information with biological samples in the absence of profit (Scenario 4a) was similar to that for the quality improvement scenario (Scenario 1). Thirty to 40% of respondents felt it was acceptable to link this information without notification. By contrast, linkage of health information with income, education, or occupation (Scenario 3) was associated with a consent profile that reflected a desire for greater control over use of the information. For this scenario, only 11–15% felt it was acceptable to link this information without notification and 30–43% of respondents felt their consent should be sought for each use before the information could be linked.
Because this finding surprised us, we probed this in our focus groups. Similar sentiments were expressed across groups, around 3 categories of explanations:
1. Participants felt that information about income, education or occupation says a lot about "who we are" whereas a biosample only provides information about "what we are".
"I think the simple answer is that physical tissue sample is just a piece of what you are, what you might be...where the rest of the information [education, income, and employment] is more of who you are. People are more afraid of the revelation of who you are than what you are." (Participant 8, HIV group)
2. Participants believed that access to information about education, income, and occupation can lead to the identification of the individual, but biosamples cannot.
"The work, education and your income. If somebody looks at a biological sample they can't look up and say 'That's you or you.' You can identify somebody by all that, those other things." (Participant 6, Depression group)
"The only thing you can get from tissue or bodily fluids is DNA and what the disease is. They can't get information about you per say. Right?" (Participant 3, Lung cancer group)
3. Participants trusted that their doctor and the medical system will ensure that the information will be used appropriately.
"I think with tissue you can see a real concrete connection. You can imagine a scientist in a lab studying that tissue, looking for an answer. With income and work you're not sure what types of people are analyzing that. It's not a white lab coat, microscope it's more of a psychological marketing." (Participant 7, Depression)
"I trust giving out the information to most of the medical profession but it's not something I would give willingly to people that I don't really know well." (Participant 3, Depression)
"I have found when I've been asked to [do] this that my family Doctor, where I go – and I have trust in him and in his staff – and he sent a letter saying 'This is what they are asking you to do and I believe in it.' And so I feel that gave me the confidence that this wasn't just some little thing that showed up at my door. My family doctor... I have trust in him." (Participant 8, Diabetes)
These (and other) references to high trust were directed more toward doctors and hospitals or, even more personally, to their doctor. While there was also a relatively high trust toward university researchers (Figure 4), that trust was more tentative than for doctors.
Figure 4. Trust in organizations.
Regression analyses
Additional file 4 compares three regression models. The full model examines the independent contributions of health condition and attitudes toward disclosure concern and medical benefits, controlling for scenario, survey method, and sex. Reduced model 1 removes disclosure concern and medical benefit from the model while reduced model 2 removes health condition from the model.
Additional file 4. Table 2. Regression analysis of consent choice predictors. This table presents the results of regression modelling of predictors of consent choice – scenario, survey method, health condition, sex, disclosure concern score, and medical benefits score. The latter two variables were a composite of several questions in the survey. (See Additional File 2.) The comparison of reduced models 1 and 2 allows one to compare the relative amount of explained variance in consent choices that would be attributable to (a) health condition and (b) the combination of perceptions of medical benefit and disclosure concern.
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In the full model, consent choices among survey participants did not differ significantly across health conditions, compared with the reference group. Increased disclosure concern was associated with a more restrictive consent choice while greater perception of the benefits of medical care and medical research was associated with more permissive consent choice. When the attitude variables (disclosure concern and medical benefits scores) were removed from the model (Reduced Model 1), the coefficients for several of the health conditions moved in the direction of being more permissive compared with the reference group. In two cases (breast cancer and hypertension) these became statistically significant. On the other hand, when health conditions were removed from the model (Reduced Model 2), estimates for the attitude variables were s . This suggests that the stronger predictor of consent choice was individual attitude toward medical benefit and disclosure concern than was the person's health condition.
Regression results also confirm our perceptions that research involving an element of profit (Scenarios 2 and 4b) or requiring linkage of health information with income, education, or occupation (Scenario 3) were associated with more restrictive consent choices. Female respondents were also generally more restrictive in their consent choices. Those completing the survey by telephone were more permissive in their consent choices than were those completing the survey over the internet.
Discussion
Chief findings
We had hypothesized that consent choice would differ across the selected health conditions and also with individual attitudes regarding disclosure concern and perceptions of the benefits of medical care and research. While we recognized beforehand that hypertension and diabetes were relatively low in stigma and that HIV and alcoholism were likely higher in stigma, we did not assume strict ordinality across health conditions. We found that, collectively, participants with target health conditions were slightly more permissive in their consent choices compared against the reference group (Figure 3). However, when we controlled for survey method, sex, and attitudes, we found no statistically significant difference in consent choice across health conditions, compared with our reference group – this despite having chosen health conditions that differed widely in potential for stigma. When examining the confidence intervals around the parameter estimates for the health conditions, they did not appear to be of a magnitude that would be policy relevant. These findings surprised us. It may be that, across health conditions, those who were more privacy sensitive were less inclined to participate in the study and those were more permissive about use of their information were more inclined to participate. This is discussed further under "Limitations" below.
Disclosure concern differed across health conditions and was associated with more restrictive consent choices. By contrast, there was a uniformly high rating of medical benefits across health conditions. However, at the individual level, a lower perception of medical benefits was associated with more restrictive consent choices. Thus, individual attitudes – and disclosure concern in particular – were more predictive of consent choice than was one's health condition. This suggests that privacy attitudes may be formulated relatively early on and may be robust to one's health condition, which may develop later in life.
We also observed significantly more restrictive consent choices in research scenarios involving profit or when linking health information with income, education, or occupation. This is consistent with findings from our earlier public dialogues. [13] We also note that people were relatively trusting with regard to linking their health records to their biological samples – even more trusting than with linking to income, education, and occupation. This is an interesting finding worthy of further study, given that there is a much higher likelihood of commercial application and intellectual property protection in research involving biological samples and the great potential for stigmatization and discrimination. Our focus groups suggest that, at least in part, their lesser concern was attributable to perceptions that specialized knowledge was required to interpret one's DNA and those with that specialized knowledge were trusted to keep the information confidential. However, once one's genetic risk profile is recorded in the health record, this information is equally subject to misadventure as one's income, should that information fall into the wrong hands. With regard to trust, we note that most of the focus group discussion of trust was in reference to their doctors. Perhaps trust in one's doctor then confers benefits of trust to the researchers in the process.
Limitations
Based on a comparison with a subset of questions in an omnibus survey conducted by Harris Interactive, we determined that people recruited into the study were somewhat less privacy concerned and more research-friendly than the general public. Within our study sample, those who completed the survey by telephone were particularly less privacy concerned. This observation is reinforced by comparison of our current findings with those of our earlier study involving a cross-Canada sample of the general public using random-digit dialling. In the earlier study, the profiling of consent choices was somewhat less permissive than observed here – particularly around the linkage with genetic information. [13] Intuitively, one would expect that individuals willing to participate in ongoing internet consumer panels may be less privacy concerned and more open to participating in research. Our conventional sampling through clinics, though, was also subject to a similar selection bias. Current ethics rules require that a researcher not approach potential research participants directly, based on prior knowledge about that individual's health condition. Individuals must first be asked by someone who may be reasonably expected to have access to this information if they would be willing to have their name released so they could be called by the researcher, or if they would be willing to take the initiative themselves to contact the researcher. This two-stage process probably resulted in lack of access to more privacy-sensitive research participants.
The reference group in this study is not quite representative of the "general public", to the extent that: (a) they, too, were drawn from the Harris internet polling sampling frame; and (b) they consisted of individuals who did not have any of the target health conditions and who had no other major health conditions. A true random sample of the public would have some proportion of respondents with the target health conditions.
Given all this, we believe our study may have under-represented those in our society who are the most privacy sensitive. Moreover, depending on the severity of the selection bias, it may be that our failure to observe a difference in consent choice across health conditions may be a result of the absence of more privacy-sensitive respondents. These non-participants may represent varying proportions across health conditions. We cannot assess what proportion of the selection bias is due to self-selection or selective approaching by their physicians.
Finally, in the consumer literature, stated privacy preferences are often much more stringent than those revealed in actual behaviour. [15] Thus, it is possible that the stated consent choices for use of one's personal information reported here may be different than what they are prepared to accept in the health care "marketplace".
Policy implications
No one consent option was preferred by even a simple majority of survey participants in any of the scenarios (Figure 3). This wide variation in opinion is consistent with our earlier work with the general public and with a recent American survey. [3] This high heterogeneity in consent choices makes it difficult to put forward any one model for consent for research use of one's personal health information. One possible response would be to offer individuals a menu of choices with a mechanism to track their choices re: secondary uses of data. While this is now technically possible, there are multiple challenges from a systems perspective. For example, who would broker the consent process and under what conditions? Anecdotal evidence suggests that physicians do not have the time for this. On the other hand, special "clinics" could be set up through hospitals and centres where applications are made for renewal of health cards. Information could be available through brochures and DVDs, and knowledgeable individuals could be available either in person or over the telephone. All these approaches would require a substantial investment in funds and an ongoing infrastructure for managing these consent choices. This could also be designed into the planned pan-Canadian interoperable electronic health record system, through secure web-based patient portals into their health record. [16,17] These portals are web-based interactive systems that allow individuals to view their health record and communicate in a secure fashion with their health care provider's office. Another consideration is whether consent choices should be totally unconstrained. There is growing evidence that opt-in consent processes can result in selection biases that may affect conclusions as to various causal associations. [18] Are there certain types of research (e.g. public health, quality of care) for which the default assumption would be that the information may be used for research and people's only option would be to selectively opt out? These are but two examples of issues that need to be addressed through further research.
Our survey and focus group participants placed high trust in medical researchers – higher than that found recently by Westin in the United States. [3] However, as in Westin's study, much of this trust was qualified. Approximately two-thirds of those expressing trust in university researchers only "somewhat trusted" them. Therefore, much of this trust in researchers is vulnerable to erosion in the event of a high-profile breach of confidence. Survey participants also valued highly the ability to monitor how their information was being used and the ability to say "No" to particular uses. This "trust but verify" attitude could also be accommodated through the development of a patient portal into one's electronic health record.
We observed a shift toward more restrictive consent choices when research involved a commercial element. Given the increasing importance of personal information to health research, and the pervasiveness of the private sector and commercialization in the research enterprise, continued public engagement would be worthwhile. This would help researchers to better appreciate the underlying concerns of the public around research and profit and to determine whether these views change or are reinforced with a better understanding of the role of both personal information and the private sector in research.
Conclusions
The public is generally supportive of research use of personal health information, but do not wish to entirely relinquish control. Despite having a relatively research-friendly sample, we still observed substantial individual variation in opinion as to the degree of control that people wish to have over use of their personal information for research. Opportunities for individual choice over use of one's personal health information could be designed into the planned pan-Canadian inter-operable electronic health record system.
People's desire for control over use of their personal health information increases when there is a commercial element to the research. Additional public engagement is required to better understand this.
Finally, this study attempted to address the question of how much control patients would like over use of their personal health information for research. While we fully appreciate the rationale for restricting researchers from directly recruiting patients on the basis of prior knowledge about their health condition, it is ironic that, to meet ethical requirements respecting individuals' privacy, this study has likely under-represented the interests of those very people whose voices need to be heard. When addressing questions like the one we have posed here, there need to be ways to better reach those who have the most at stake.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
DW conceived and designed the study, led the focus groups and the analyses and was the primary author of the manuscript; VS, CC, LS, JR and LT all contributed to the development of the protocol. JR led in the analyses of the text. LT provided statistical guidance. JC conducted the statistical analyses. All co-authors reviewed and revised drafts of the manuscript. All authors read and approved the final manuscript.
Acknowledgements
This study was supported by a grant from the Canadian Institutes of Health Research (Grant Number MOP-79315).
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Pre-publication history
The pre-publication history for this paper can be accessed here:
http://www.biomedcentral.com/1472-6939/10/10/prepub
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Rip Off Press, 1972 Series
Published in English (United States)
Publication Date:
July 1972
Number of Issues Published:
1
Format:
Standard modern US format; Black and white interior; Color covers; Saddle-stitched; Newsprint
Series Details:
Publisher's Brands:
Indicia Publishers:
• without indicia publisher information (1 issue)
Tracking
Numbering continued from Jesus Meets the Armed Services [Jesus Comics] (Rip Off Press, 1970 series) #[2]
Notes
#1 titled The New Adventures of Jesus.
#2 titled Jesus Meets the Armed Services.
#3 titled Jesus Comics.
Editing
Index Status
Indexed Partially Indexed Pending Approval Reserved Skeleton Data Only
3
Cover Status
Scan available Needs Replacement No Scan available
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FamilySearch Wiki Swedish User Group MeetingEdit This Page
From FamilySearch Wiki
Revision as of 18:02, 14 October 2011 by MorrisGF (Talk | contribs)
Back to Sweden Portal Page
Contents
Purpose and Time
The Sweden User Group meeting provides an opportunity to:
1. Learn the skills to work on a WikiProject for Sweden
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3. Accomplish more as a team
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This is a conference call meeting (by phone or phone and computer) every other Thursday from 3:00-4:00 pm (mountain time). The dates for 2011 are:
October 13
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Anyone is welcome to suggest topics for the meeting by posting on the Swedish User Group Dialogue page.
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The program used for the conference call is called MeetingPlace. It's easy to use. By joining online, you can see the discussion items and training on your screen.
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About this Journal Submit a Manuscript Table of Contents
Advances in Civil Engineering
Volume 2010 (2010), Article ID 675927, 13 pages
doi:10.1155/2010/675927
Research Article
A Neural-Wavelet Technique for Damage Identification in the ASCE Benchmark Structure Using Phase II Experimental Data
Department of Civil Engineering, The University of New Mexico, Albuquerque, NM 87131, USA
Received 15 December 2009; Revised 18 March 2010; Accepted 25 May 2010
Academic Editor: Yiqing Qing Ni
Copyright © 2010 Mahmoud M. Reda Taha. 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
Damage pattern recognition research represents one of the most challenging tasks in structural health monitoring (SHM). The vagueness in defining damage and the significant overlap between damage states contribute to the challenges associated with proper damage classification. Uncertainties in the damage features and how they propagate during the damage detection process also contribute to uncertainties in SHM. This paper introduces an integrated method for damage feature extraction and damage recognition. We describe a robust damage detection method that is based on using artificial neural network (ANN) to compute the wavelet energy of acceleration signals acquired from the structure. We suggest using the wavelet energy as a damage feature to classify damage states in structures. A case study is presented that shows the ability of the proposed method to detect and pattern damage using the American Society of Civil Engineers (ASCEs) benchmark structure. It is suggested that an optimal ANN architecture can detect damage occurrence with good accuracy and can provide damage quantification with reasonable accuracy to varying levels of damage.
1. Introduction
With the aging of infrastructure worldwide and the increasing availability of cost efficient sensing equipment, the necessity to implement damage identification and classification systems on civil structures has become imperative. Structural health monitoring (SHM) is the nonintrusive collection and analysis of data from structures for damage detection and diagnosis. The intention of SHM is to characterize the structure’s performance and to help maintain the structural performance over its years of service. SHM also helps reduce operation costs through early damage detection. Successful SHM techniques have been applied to other engineering disciplines where the mass of the structure is small compared with civil structures. Vibration-based SHM assumes that the structural dynamic response will depart from its normal pattern when damage occurs in the structure. Thus, damage detection is contingent upon successfully extracting sensitive damage feature(s), patterning such feature(s) and realizing changes in these patterns as damage develops.
Over the past two decades numerous research methods with the objective of extracting sensitive damage feature(s) have been suggested and tested on several structures [15]. Tools for damage detection using structural dynamics analysis such as modal update, Fourier transform and wavelets have been examined [6]. Some of those pertaining to the ASCE benchmark structure, described in Section 2, are reviewed below in Table 1.
Table 1: Summary of damage detection methods for the ASCE benchmark structure.
More recently, a few researchers have focused on the use of artificial neural networks (ANN) for damage pattern recognition. ANN consists of a group of interconnected processing units called neurons. Each neuron performs a simple computational process and has a transfer function associated with the layer that operates at the node level. ANN has the capability to learn from example datasets by changing the numerical biases and weights of the network [40]. For feed forward ANN that is considered here, the neurons are organized into layers where the first layer contains one neuron per input and the last layer contains one neuron per output; intermediate layers may contain any number of layers. While Tsou and Shen [41] used differences between healthy and damaged eigenvalues as training data for a neural network for damage detection of a spring-mass system, Sexton et al. [42] proved that optimizing neural networks using optimization can lead to better prediction capabilities in operation research modeling.
The application of such stiffness-based techniques to large civil structures has been challenging because of the insignificant effect of the relatively small changes in stiffness due to damage compared with the large mass of these structures. Elkordy et al. [43] trained a neural network using a finite element model for a large civil structure and compared the results to a physical model. The ability to train a neural network with finite element data is critical for evaluation of structures where sets of data representing healthy performance may not exist.
Several signal processing methods have been promoted for feature extraction such as Fourier transform, Wavelet transform and Wavelet Multi-Resolution Analysis (WMRA) [6, 44, 45]. These methods were combined with means of artificial intelligence (AI) such as ANN [46]. It has been noted by Lam et al. [47] and Yuen and Lam [48] that the influence of ANN architecture has been overlooked by many researchers using ANN for damage pattern recognition. The ANN architecture is crucial to the training of the network as well as getting good performance from the ANN. Lam et al. [47] suggested the use of a Bayesian method (conditional probability) to determine the optimal ANN architecture while using a Ritz vector and modal parameters, respectively, as damage features. A dual function ANN was used for the process of feature extraction and then to establish the needed damage classifier. The use of ANN for establishing nonlinear classifiers has also been suggested by other researchers [49]. A review of a number of combination of AI tools and signal processing techniques, particularly wavelets, for damage feature extraction for SHM, has recently been reported [45]. The use of wavelets and combining ANN and Wavelets for damage detection has also been recommended by investigators Yam et al. [50], Kim and Melhem [51], Diao et al. [52], Jiang and Adeli [53] and Jiang and Mahadevan [54, 55].
Much of the above noted research was focused on damage feature extraction rather than on damage pattern recognition. Sohn et al. [56] suggested classifying damage in structures using statistical pattern recognition methods. Lam et al. [47] discussed the possible use of Bayesian analysis to identify damage classes. Other techniques using fuzzy (nonprobabilistic) damage pattern recognition were reported to enable realizing other types of uncertainty, rather than random uncertainty in damage detection [57].
In this paper, we suggest using available damage observations to identify the optimal ANN structure (i.e., number of hidden layers and number of neurons in each hidden layer). An optimization process is suggested to identify the optimal ANN structure for successful damage pattern classification. Here we used acceleration data collected experimentally from Phase II of the ASCE benchmark structure to develop and test the proposed damage pattern recognition method. Our motivation was to demonstrate the possible use of an optimized neural-wavelet module to detect and quantify damage with reasonable accuracy in the ASCE benchmark structure. The proposed framework is extendable for damage detection and quantification in other structures.
2. The ASCE Benchmark Structure: Background
The American Society of Civil Engineers (ASCE) benchmark study was conducted by the International Association for Structural Control (IASC) ASCE Structural Health Monitoring Task Group as a resource for validating damage detection techniques. The ASCE Benchmark Group generated structural response data from a 2 2 bay, four story, rectangular steel test structure [9]. A schematic of the structure is shown in Figure 1(a).
Figure 1: (a) 3D schematic of the ASCE benchmark structure. (b) Location of the accelerometers and shaker on the ASCE benchmark structure.
Phase I of the ASCE benchmark study was generated by means of a finite element model considering varying levels of damage [7, 8]. Phase II included two parts: Phase II-S where “S” denotes simulation data and Phase II-E where “E” denotes experimental data. The data in Phase II-S was generated using structural dynamics finite element software under MATLAB environment [7]. Phase II-S model included a 120 degrees of freedom (DOF) model and a twelve DOF data model [7, 8]. Phase II-E included experimental data collected from the structural response of the ASCE benchmark rectangular steel structure tested at the University of British Columbia in August 2002 [9]. Table 1 presents a review of all previous research that examined the ASCE benchmark structure to date. It is obvious that the vast amount of this previous research used simulated data, not experimental data. Table 1 also provides a brief description of the damage detection techniques used by each researcher and the type of structural response considered for the cases where experimental data of the benchmark structure was used.
As presented in Table 1, many researchers had success in detecting damage in Phase I and Phase II-S of the benchmark structure, but similar success when using the same techniques to Phase II-E data have not been reported. For example, Nair et al. [31] showed promising results for detecting damage using the Phase II-S data from the benchmark problem with a pattern classification algorithm based on autoregressive analysis of acceleration signals in the time domain. However, Nair et al. [31] reported limited success in using Phase II-E data. Therefore, the research conducted on the experimental benchmark study is not complete or fully inclusive. A major limitation in most of previous work examining the benchmark structure was the focus on damage detection rather than damage quantification. As most researchers tried to validate their metrics for damage detection of the different scenario, no attempts were made to produce an overall damage quantification metric based on the damage feature elected for damage detection. Here, we try to provide a method that provides both damage detection and damage quantification and demonstrate its application to the ASCE benchmark structure.
The ASCE benchmark structure was built at approximately one-third scale and is located at the University of British Columbia [9]. A series of acceleration data was collected from the test structure using nine different levels of damage and three different types of excitation including a shaker using a sine sweep, random excitation and impulse testing [58]. Only the response data from the randomly excited structure was analyzed. Phase II-E data includes acceleration response recorded for Phase I structural configurations. These configurations are described in Table 2. It is important to note that such description in Table 2 does not provide a quantitative value of the level of damage. Therefore, judging a damage detection method becomes quite challenging. This is because of the fact that it is difficult to quantify how removal of one or more braces will affect structural response. While we propose a simple system to represent the level of damage based on the number of braces removed or joints loosened, we argue that further discussion from the SHM research community is needed to benchmark the levels of damage in the ASCE benchmark structure. Such benchmarking is essential for the experimental data’s use by the research community when examining new damage detection methods.
Table 2: Damage cases and quantified damage metric () based on experimental description of damage in ASCE benchmark structure.
Our proposed damage severity metric, denoted describes damage in the ASCE benchmark structure, is defined and normalized to a scale between 0 and 100 for the benchmark configurations. The damage severity for the th damage configuration is computed as The symbol is used to denote the number of braces removed in the North-South (strong axis) direction, while corresponds to the number of braces removed in the East-West (weak axis) direction. denotes the number of loosened bolted connections in the North-South (strong axis) direction whileis the number of loosened bolts in the East-West (weak axis) direction. Weight factors of 1.0, 0.5, 0.25 and 0.1 are used to describe the significance of each action (e.g., removal of braces) on the level of damage in the structure. For instance, a weight factor of 1.0 is chosen for removal of braces in the strong axis (North-South) direction. The weight factor (0.5) is used to describe the effect of removed bracing braces in the out-of-plane direction (East-West) direction. The weight factor (0.25) is also used to represent the relatively low effect of loosened bolts compared to the effect of removed bracingbraces. The factor (0.1) is used to represent the effect of out-of-plane loosened bolts. The reduction of damage severity in the out-of-plane direction is attributed to the fact that most accelerometers were placed in the North-South direction and the accelerations of interest used in the analysis were in the North-South direction. Figures 1(a) and 1(b) shows a three-dimensional schematic of the ASCE benchmark structure and the location of the accelerometers and shaker on the structure. There are nine testing configurations tested in the experimental investigation of the ASCE benchmark structure [9]. There was an unspecified error in data reported for Configuration 5 according to ASCE Benchmark Group, therefore that dataset for Configuration 5 was not used in this study. The descriptive damage metric was calculated for the eight damage configurations by means of (1). The damage metric values for these configurations are presented in Table 2. It became obvious that Configuration 1 can be classified as “healthy” (), Configurations 2–6 can be classified as “partially damaged” with ranging between 8.5 and 31.2 and Configurations 7–9 can be classified as “fully damaged” with ranging between 85.1 and 100. It is important to emphasize that the proposed descriptive damage metric developed for validation of the proposed damage detection method is very specific to the ASCE benchmark structure and the testing configurations examined herein. The weight factors were specifically selected for quantifying the overall damage in the benchmark structure given the structural configurations and the sensor locations.
3. Methods
Here we suggest a computational method for feature extraction and damage recognition based on integrating ANN and WMRA. The proposed method is used for damage feature extraction by realizing the changes in the energy of structural acceleration signals computed in the wavelet domain as a result of damage. The proposed method has been previously validated using simulated and experimental data on bridge structures [59, 60]. Moreover, optimization methods are used to establish a classifier that can provide efficient damage pattern recognition. Design of the classifier is based on minimizing the error of classification by the damage detection method. The classification error is minimized through identifying the optimal architecture of the neural network, including the number of layers and number of neurons in each layer.
The development of the integrated damage pattern recognition method outlined in this paper includes the following steps: () data acquisition and signal processing, () damage feature extraction, () development of a damage classifier, () optimization of the neural network architecture using the classifier and () evaluation of the integrated damage recognition method (in Section 4).
3.1. Data Acquisition and Signal Processing
The acceleration signals, denoted with subscript representing the sensor location, were processed using WMRA. WMRA was implemented using the discrete wavelet transform (DWT), specifically the daubechies (db4) mother wavelet [61]. Extensive study has been performed by the authors that showed the daubechies (db4) mother wavelet to be the most suitable wavelet to decompose acceleration signals [61]. Other wavelet functions proposed by other researchers [62, 63] were also examined. The energy of the approximation signal of the damage structures (as will be discussed below) showed more sensitivity to damage when the daubechies (db4) wavelet signal was used to decompose the original signal. Similar observation was reported on analysis of experimental data observed in monitoring of steel bridges [64].
WMRA enables the decomposition of the acceleration signal in the time domain into component signals at different frequency levels named approximations and details. Scaling a wavelet simply means stretching or compressing it. The smaller the scale, the more the wavelet will be compressed while the larger the scale, the more the wavelet will be stretched. Therefore, low scales allow analyzing rapidly changing details (high frequency components) and high-scales allow analyzing slowly changing features (low-frequency components).
In civil structures, it has been shown that most of the main frequency components are low-frequency components (ranging 5–30 Hz) [6, 31, 64, 65]. Therefore, the low-frequency components of the signal (the approximations) are very important parts of the signal. The “approximations signal” corresponds to the high-scale, low-frequency components of the signal. On the other hand, the high frequency contents carry the details of the signal. The “details signal” corresponds to the low scale high frequency part. WMRA decomposes the signal into various resolution levels as schematically shown in Figure 2. We suggest here using the third approximation signal in lieu of the original signal. This means that all high frequency components of the signal will be neglected. It is important to emphasize that these high frequency components might include useful information about the structure, but the proposed approach is based on the assumption that this information is not necessary for damage detection. The use of high frequency components might provide further insight on damage but will be accompanied with high computational expenses. The threshold at which signal decomposition is limited and the frequency components considered for damage detection shall be based on balancing the computational expenses versus the level of enhancement in damage detection accuracy [66].
Figure 2: Schematic representation of wavelet multi-resolution analysis showing the decomposition of the original signal into levels of decomposition and details signals.
Consider the discrete acceleration signal . With the wavelet scaling index and shifting index () defined, the coefficients for the approximation signals () and detail signals () can be calculated as where is the scaling function [61]. The acceleration signals acquired from the ASCE benchmark structure were decomposed to three levels of decomposition. The third approximation signal was used to represent the structure’s response.
3.2. Damage Feature Extraction
The proposed framework aims at establishing the complex relationship relating the structural dynamics (here accelerations) between different zones of the healthy structure. This general framework is shown schematically in Figure 3(a). The neural-wavelet module tries to build this relationship at the wavelet decomposed acceleration signals using artificial neural network. When damage occurs in the structure, the relationship between its zones is disturbed. The higher the severity of damage, the further the structure departs from the healthy relationship between its zones. Damage can be thus detected and classified.
Figure 3: Schematic representation of the neural-wavelet damage detection method (a) general application of method to any structure divided to zones (b) specific method application for damage detection in the ASCE benchmark structure (damage feature ).
We suggest a damage feature denoted computed using WMRA and ANN. Acceleration signals recorded at accelerometers 5, 6, 9, 12 and 15 were decomposed using WMRA and the third approximation of the signals were then used as inputs for the ANN. The third approximation of the acceleration signal at accelerometer 13 was used as the desired output as shown in Figure 3(b). Figure 3(b) shows a schematic representation of the computation of the damage feature in the ASCE benchmark structure.
The damage feature was obtained by comparing the monitored acceleration signal at sensor 13 and the signal predicted by ANN. The damage feature denoted can thus be calculated as: where is the approximation, is the level of wavelet decomposition. describes the energy of the signal representing the difference between the ANN predicted signal and the third approximation of the monitored acceleration signals and is the total number of discrete elements used to represent the signal. As ANN is trained to predict healthy performance, the difference between monitored and predicted signal represents the level of departure of the structural response at any time. This different signal is directly related to the level of damage in the structure. The lower the value of , the closer ANN’s prediction is to the monitored signal, therefore representing a healthy structure. The higher the value of , the further ANN’s prediction is from the monitored signal. This neural wavelet method has successfully identified damage in other structures, including prestressed concrete [60] and a structural steel model bridge [64].
Here, we only considered the structure’s response data from accelerometers 5, 6, 9, 12, 13 and 15 shown on the benchmark structure plans described in Figure 3(b). These accelerometers were excited by an electro-dynamic shaker placed on the top floor of the structure. The choice of this group of accelerometers to form the damage detection module is based on their location in relation to the damaged areas (areas of bracing removal) of the ASCE benchmark structure configurations as described by the ASCE benchmark study report ASCE Benchmark Group [58] and Dyke et al. [9]. The accelerometers chosen as the inputs to the ANN were primarily positioned along the East face of the structure where damage was induced. The output accelerometer was positioned on the West face of the structure where no damage was induced.
ANNs use an iterative process to learn a pattern and generate a nonlinear mapping system between system inputs and output. Here, ANN is used to learn the complex healthy signal of the structure at sensor 13 by observing the signals at sensors 5, 6, 9, 12 and 15. The input layer of ANN in this study has five neurons corresponding to the five acceleration data inputs acquired by accelerometers (5, 6, 9, 12 and 15) and one neuron at the output layer acquired by accelerometer 13. Each neuron has a transfer function associated with the layer that operates at the node level. All layers use the log-sigmoid transfer function, with the exception of the output layer, which has a linear transfer function. The choice of these transfer functions was based on a parametric investigation conducted on the benchmark data [37]. The parametric investigation also showed the need for optimization of the ANN architecture to enable efficient damage classification.
3.3. Developing Damage Classifier
The neural network’s ability to accurately mimic the healthy signal is dependent upon the architecture of ANN. In this study we target identifying the optimal architecture of ANN and defining the number of hidden layers and the number of neurons per layer such that damage detection is maximized. Design of ANN usually targets achieving a minimum training error which is considered a modeling tool criterion for acceptance of a neural network. Successful damage detection necessitates that the damage feature () is able to classify the level of damage in the structure. This means high values correspond to the “highly damaged” benchmark Configurations 7, 8, and 9. Moreover, low values correspond to the “healthy” Configuration 1, and values in between these extremes represent the “partially damaged” Configurations 2, 3, 4, and 6.
Successful development shall enable ANN to function as a damage classifier in addition to its role in damage feature extraction. This can be achieved by finding the optimal ANN architecture such that the maximum success rate of the damage classification is achieved. The process of successful classification rate maximization is performed here in the context of system optimization where the objective function that is used for defining the classifier is minimized. The optimization process can be described by defining the objective function, the design variables, the design parameters and the optimization constraints.
The objective function to be minimized is − with defined as: is the damage classifier, is the mean value of the damage feature for a healthy case and is the mean value of the damage feature for the damaged case. Where is a numerical counter, . represents the number of structural damage configurations considered when establishing the damage classifier. Defining as the objective function ensures that the difference between the mean damage feature at the healthy performance and other damage states is maximized and thus the success rate of damage detection is maximized. A schematic representation of the function describing the damage classifier is shown in Figure 4.
Figure 4: represents the distance between mean value of for healthy performance and the mean value of for a damaged state.
The design variables describe the number of layers and the number of neurons in each layer of the ANN architecture. The design parameters include those parameters that affect the optimization process but are assumed constant during the optimization process. This includes the level of wavelet decomposition, (here ), the mother wavelet function (here db4) and the transfer function per ANN layer (here log-sigmoid). Two optimization constraints were considered; the number of neurons per hidden layer constrained between 1 and 15, and the number of hidden layers also constrained between 1 and 3. Both constraints were established to limit computation time. The optimization process was performed using derivative-based (Newton gradient-decent) and derivative-free (genetic algorithm (GA)) optimization techniques [67, 68].
Considering the ASCE benchmark Phase II-E data, represents the mean value of the damage feature for the healthy Configuration 1, while represents the mean value of the damage feature of the th damage configuration in the ASCE benchmark structure. Benchmark Configurations 1, 6, 7 and 8 were used for training of the damage classifier , while Configurations 2, 3, 4 and 9 were reserved for testing the classifier after establishing the optimal ANN architecture. The mean value of the damage feature for the th damage configuration, , was computed as the mean of fourteen values of . Each represents the energy of an eight second window of the signal representing the difference signal between the third approximation of the measured signal and the ANN predicted signal. The energy of the difference signal is computed as is the difference signal between the third approximation of the measured signal and the ANN predicted signal, is the counter for the signal measurements within the 8 second window, represents the eight second time window and ranges from 1 to , which is the total number of windows, equals 14. The division of the acceleration signal into windows is presented schematically in Figure 5. The original acceleration signal was 120 seconds long sampled at 500 Hz with 4000 data points in each window. The original signal was decomposed using WMRA. The original signal and the third approximation signal of a typical acceleration signal are shown in Figure 6. The third approximation signal was divided into fifteen windows each 8 seconds long. The first window was neglected for avoiding inaccurate observations at the start of data acquisition. The following 14 windows were used to compute the damage feature as represented by (5). The WMRA decomposition was performed on the whole 120 second signal and not at the windows’ level to avoid the well known edge effect of the wavelet analysis when short signals are analyzed.
Figure 5: Schematic representation of the acceleration signals and the 15 windows in the signals.
Figure 6: Raw acceleration signal (red) observed at sensor 9 in the benchmark structure versus the third approximation of the acceleration signal (black) used for damage detection.
3.4. Testing the Damage Classifier
The optimal ANN architecture and the damage classifier were tested using the testing data including Configurations 2, 3, 4 and 9. These data sets were not used in developing the damage classifier. To consider uncertainty in damage recognition, the probability of damage is used as the damage metric to represent the level of damage in the structure for each testing configuration. The damage metric denoted (denoting damage quantified using the neural-wavelet (NW) method) at the th configuration of the benchmark structure can be evaluated using (6), where is the confidence limit established by considering a 95% level of confidence from the healthy performance and is the mean damage feature describing the th configuration of the benchmark structure where represents the probability that the damage feature will exceed the damage threshold . The probability of damage is schematically represented in Figure 7. The probability distribution function represents the damage feature at any instance. The probability of damage is calculated as the area under the probability density function of the damage state with for values higher than the confidence limit, . Therefore, a probability density function for a damage case that does not overlap with the healthy probability density function would have a 100% probability of damage. The suggested method for calculating the probability of damage assumes the damage feature to be monotonically increasing as the level of damage in the structure advances. The damage feature is also assumed to follow the normal (Gaussian) probability distribution which was confirmed by analyzing the healthy datasets.
Figure 7: Schematic representation of probability of damage. Hatched area represents the cumulative probability of damage representing the neural-wavelet damage metric .
4. Results and Discussion
The optimization process determined that the optimal ANN architecture includes three hidden layers consisting of 2, 7 and 10 neurons on the first, second and third hidden layers respectively. A schematic representation of the optimal network is shown in Figure 8. Figure 9 shows the change in the classifier objective function versus the number of neurons for classifier when the number of hidden layers is one (Figure 9(a)) and for two hidden layers in Figure 9(b). It is interesting to observe the large number of local minima that exist in both domains. The GA optimization technique was more successful than the gradient descent method in realizing the optimal solution. The derivative-based technique was caught in local minima and the optimization process occasionally did not converge.
Figure 8: Optimal ANN for damage detection using the neural-wavelet method.
Figure 9: Number of neurons versus classifier objective function. (a) One hidden layer for classifier () showing the peak classifier to occur at = 7 neurons. (b) Two hidden layers for classifier () showing the peak classifier to occur at and .
A comparison between the three optimal neural network architectures with one hidden layer denoted NN1 ( neurons), two hidden layers denoted NN2 ( and ) and three hidden layers denoted NN3 ( and and ) showed that the neural network NN3 with three hidden layers to have the highest classifier (). This comparison is shown in Figure 10. The comparison confirms that the optimal ANN architecture have the best ability to classify damage in the benchmark structure. The optimal ANN architecture shown in Figure 8 was used to identify damage in eight testing configurations of the ASCE benchmark structure (excluding Configuration 5) by computing the probability of damage (see (6)) in each configuration. This includes identifying damage in Configurations 2, 3, 4 and 9 that were not used in training the classifier.
Figure 10: Comparison between three optimal neural networks using one hidden layer denoted NN1 ( = 7 neurons), two hidden layers denoted NN2 ( and ) and three hidden layers denoted NN3 ( and and ) showing the neural network with three hidden layers to have the best performance with the highest classifier ().
Figure 11 shows the neural-wavelet damage metric of eight configurations as identified using the optimal damage classifier. The mean value and the standard deviation for each of the eight configurations was calculated as the mean of 14 time windows, each of them is eight seconds long. Figure 11 also shows the severity of damage metric based on the damage quantification suggested in this paper (see (1)). Configurations 7, 8, and 9 that were classified as “fully damaged” (Table 2) show probabilities of damage ranging between 90 and 100 percent. The “partially damaged” Configurations 2, 3, 4, and 6 have a damage metric ranging between 40 and 60 percent and a descriptive damage metric between 9 and 31. The “healthy” Configuration 1 showed a damage metric that is lower than 5% and a descriptive damage metric value of zero. It is therefore obvious that a good agreement exists between the descriptive damage metric and the neural-wavelet damage metric .
Figure 11: Neural-wavelet damage metric () and descriptive damage metric () for all ASCE benchmark structure configurations reported in Phase II-E (Configuration 5 is excluded).
The above results provide a damage detection method that can detect damage in eight damage configurations of Phase II-E in the ASCE benchmark structure; the proposed damage metric can also be used to classify/quantify damage severity in the benchmark structure with reasonable accuracy. This is attributed to the fact that the damage feature was optimized for classification of damage. The optimization process correctly categorized the “partially damaged” benchmark configurations resulting in probabilities of damage that range from between 40 and 60 percent. The “fully damaged” configurations were also correctly classified for having probabilities of damage ranging between 90 and 100 percent. The optimal neural-wavelet method has proven capable of detecting damage occurrence and showed good sensitivity in quantifying damage severity for low and high damage configurations. However, the model showed less accuracy in quantifying partially damaged cases which might be enhanced if other configurations of partially damage data were used in establishing the classifier.
Finally, the proposed neural-wavelet framework can be applied to damage detection and classification of real world structures. This requires developing a finite element model to simulate the structure dynamic behavior and validate this model using historical data observed from the structure. Damage can then be introduced to the finite element model with different levels of damage severity and at different locations. This simulated data can be used to optimize the ANN and establish the neural-wavelet module. The developed neural-wavelet module can then be used to detect and classify damage in the real structure.
We need to emphasize, however, that the overall damage metric is not unique but provides an indicator to damage severity. It is important to realize that damage is a nonmeasurable quantity and damage metrics cannot be directly compared. This damage quantification inaccuracy is an intrinsic characteristic of damage related to the definition of damage as suggested by many researchers [65, 6971]. Therefore, the use of absolute numbers for quantifying damage severity and the use of accuracy measures to validate damage quantification can lead to erroneous conclusions. Validation shall be limited to testing the metric ability to indicate the category of damage such as “low, moderate and high”. The wide range of probabilities describing the damage level in each configuration is attributed to considering uncertainty in quantifying damage. It is obvious that damage quantification is a challenging problem that lends itself to probabilistic, fuzzy or imprecise quantification.
5. Conclusion
We demonstrated that it is possible to establish a damage pattern recognition method by designing a damage classifier that integrates ANN and WMRA. An optimization technique using derivative free optimization (genetic algorithm) was used to identify the optimal ANN architecture. A neural network, including three hidden layers with 2, 7, and 10 neurons in the first, second and third hidden layers respectively, was capable of successfully detecting and quantifying damage in the ASCE benchmark structure with a reasonable sensitivity.
The neural-wavelet method aimed at establishing the underlying relationships between the structural dynamic responses (acceleration signals) at the different locations of the structure during healthy performance then recognized changes in such relationships as damage advanced in the structure. While the use of ANN to learn the underlying relation of structural dynamics proved successful, some drawbacks of ANN are related to their intolerance to uncertainty in training data. It is therefore suggested that other learning methods with higher tolerance to classification uncertainty such as neural-fuzzy inference systems, adaptive fuzzy learning from examples [72] or support vector machines might be examined as an alternative to neural networks in realizing structural dynamic relationships.
Acknowledgments
The author greatly appreciates the financial support by Defense Threat Reduction Agency (DTRA). Special thanks to research assistants: Scott Horton, Molly McCuskey and Erdogan Altunok for their efforts in the SHM research projects with the author.
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About this Journal Submit a Manuscript Table of Contents
International Journal of Rheumatology
Volume 2012 (2012), Article ID 198314, 4 pages
doi:10.1155/2012/198314
Review Article
The Utility of Serum IgG4 Concentrations as a Biomarker
1Center for Health, Safety, and Environmental Management, Shinshu University, 3-1-1 Asahi, Matsumoto 390-8621, Japan
2Department of Gastroenterology, School of Medicine Shinshu University, 3-1-1 Asahi, Matsumoto 390-8621, Japan
3Department of Medical Information, School of Medicine Shinshu University, 3-1-1 Asahi, Matsumoto 390-8621, Japan
Received 23 November 2011; Accepted 17 January 2012
Academic Editor: Yoh Zen
Copyright © 2012 Shigeyuki Kawa et al. 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
IgG4-related disease is a new disease entity involving IgG4 in its clinical presentation and having 6 characteristic features: (1) systemic involvement; (2) solitary or multiple lesions showing diffuse or localized swelling, masses, nodules, and/or wall thickening on imaging; (3) high serum IgG4 concentration >135 mg/dL; (4) abundant infiltration of lymphoplasmacytes and IgG4-bearing plasma cells; (5) a positive response to corticosteroid therapy; and (6) complications of other IgG4-related diseases. To date, most IgG4-related diseases have been recognized as extrapancreatic lesions of autoimmune pancreatitis. This paper will discuss the utility of IgG4 as a biomarker of IgG4-related diseases, including in the diagnosis of autoimmune pancreatitis and its differentiation from pancreatic cancer, in the prediction of relapse, in the long-term follow-up of patients with autoimmune pancreatitis and normal or elevated IgG4 concentrations, and in patients with autoimmune pancreatitis and extrapancreatic lesions, as well as the role of IgG4 in the pathogenesis of IgG4-related disease.
1. Introduction
IgG4-related disease is a new disease entity involving IgG4 in its clinical presentation. To date, 6 characteristic features of IgG4-related disease have been identified: (1) systemic involvement; (2) solitary or multiple lesions showing diffuse or localized swelling, masses, nodules, and/or wall thickening on imaging; (3) high serum IgG4 concentrations >135 mg/dL; (4) abundant infiltration of lymphoplasmacytes and IgG4-bearing plasma cells; (5) a positive response to corticosteroid therapy; (6) complications of other IgG4-related diseases [14].
IgG4-related disease involves organs throughout the entire body. The major manifestations of IgG4-related disease include autoimmune pancreatitis, lacrimal and salivary gland lesions known as Mikulicz’s disease, sclerosing cholangitis, retroperitoneal fibrosis, lung disease, and tubulointerstitial nephritis. In addition, many minor lesions have been reported in patients with IgG4-related disease, including hypophysitis, thyroiditis, hepatopathy, and prostatitis. At present, it is not clear whether these lesions are caused by the same etiology or merely show clinical and pathological findings associated with IgG4. Imaging modalities have shown diffuse or localized swelling in the pancreas and the lacrimal and salivary glands, masses in patients with retroperitoneal fibrosis, nodules in patients with lung pseudotumors, and wall thickening in the bronchi and bile ducts.
Most patients with IgG4-related disease have high serum IgG4 concentrations, over 135 mg/dL, [5] a finding both sensitive and specific for this disease, as well as useful for its diagnosis. Characteristic pathological findings include the infiltration of large numbers of lymphoplasmacytes and IgG4 bearing plasma cells [6]. Although storiform or swirling fibrosis and obstructive phlebitis are also characteristics of IgG4-related disease, they are rarely observed in specific lesions, such as those of the salivary glands. Most lesions, except for those that are predominantly fibrotic, respond positively to corticosteroid therapy. For example, patients with autoimmune pancreatitis show reduced swelling, patients with lung pseudotumors show the disappearance of nodules, and patients with sclerosing cholangitis show the disappearance of bile duct strictures after corticosteroid treatment. At present, most IgG4-related diseases have been recognized as extrapancreatic lesions of autoimmune pancreatitis [2, 7, 8].
This paper will discuss the utility of serum IgG4 concentrations as a biomarker of the major IgG4-related disease, autoimmune pancreatitis. Topics will include IgG4 concentration and the diagnosis of autoimmune pancreatitis, as well as its differentiation from pancreatic cancer; IgG4 and the prediction of relapse; long-term followup of patients with autoimmune pancreatitis and either normal or elevated IgG4 concentration; IgG4 and extrapancreatic lesions in patients with autoimmune pancreatitis; and the role of IgG4 in the pathogenesis of IgG4-related disease.
2. IgG4 and the Diagnosis of Autoimmune Pancreatitis
The sera of patients with autoimmune pancreatitis have a polyclonal band in the rapidly migrating fraction of γ-globulins, resulting in βγ bridging. Immunoprecipitation assays have confirmed that this band is always due to elevation of IgG4 concentration [5]. IgG is composed of 4 subclasses, IgG1, IgG2, IgG3, and IgG4. In normal subjects, IgG4 constitutes only 3–7% of total serum IgG. However, serum IgG4 concentrations are over 10-fold higher in patients with autoimmune pancreatitis. Elevated serum IgG4 has also been observed in individuals with allergic disorders, parasite infestations, and pemphigus. High serum IgG4 concentrations have been observed in 90% of patients with autoimmune pancreatitis, but rarely in patients with pancreatic cancer, chronic pancreatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and Sjögren’s syndrome, suggesting that IgG4 is a sensitive and specific marker of autoimmune pancreatitis and may be diagnostic for this disease [5]. Corticosteroid therapy significantly reduces serum IgG4 concentration and the IgG4/IgG ratio [5]. The utility of IgG4 for the diagnosis of autoimmune pancreatitis has been evaluated worldwide, with a sensitivity ranging from 50% to 92% and a specificity over 90%. Serum IgG4 concentration is therefore considered a reliable marker for the diagnosis of autoimmune pancreatitis and has been included in various diagnostic criteria [912]. Differences in sensitivity and specificity may be partly due to the use of different assays to measure serum IgG4 and different cut-offs for the upper limit of normal around the world, as well as variations in diagnostic criteria used in individual countries, which may be associated with histological differences between lymphoplasmacytic sclerosing pancreatitis (LPSP) [13] and idiopathic duct-centric chronic pancreatitis (IDCP) [14].
Clinical features of autoimmune pancreatitis have been reported to differ based on the serum concentration of IgG4. Compared with patients having normal serum IgG4 levels, those with elevated IgG4 are regarded as being in a highly active state, with a higher incidence of jaundice at onset, more frequent diffuse pancreatic enlargement on imaging, significantly higher 18F-2-fluoro-2-deoxy-d-glucose uptake by pancreatic lesions, more frequent extrapancreatic lesions, and more frequent requirement for maintenance therapy [15].
In addition, infiltration of IgG4 bearing plasma cells is a histological hallmark of autoimmune pancreatitis and is used in pathologic diagnoses [6].
3. IgG4 and the Differentiation of Autoimmune Pancreatitis from Pancreatic Cancer
Lymphoplasmacytic sclerosing pancreatitis (LPSP), which is similar pathologically to autoimmune pancreatitis, has been observed in 2.5% of patients undergoing the Whipple resection [16]. Therefore, it is necessary to differentiate autoimmune pancreatitis from pancreatic cancer. We reported that IgG4 had a sensitivity of 90%, a specificity of 98%, and an accuracy of 95% in differentiating between these conditions, [5] indicating that IgG4 is useful both for the diagnosis of autoimmune pancreatitis and for differentiating it from pancreatic cancer. Other reports have also shown the usefulness of IgG4 in differential diagnosis [1719]. The sensitivity and specificity of IgG4 were superior to those of IgG, ANA, and RF, although the additional measurement of ANA and RF further increased the sensitivity and negative predictive value of IgG4 [8].
4. IgG4 and Prediction of Relapse
Some patients with autoimmune pancreatitis experience relapse during their clinical course. For effective management, it is necessary to determine the frequency of relapse and its prevention. During the period from 1992 to 2011, a total of 93 patients with autoimmune pancreatitis were examined and treated at Shinshu University Hospital. Of the 84 patients followed up for more than 1 year, 28 (33%) experienced relapse. In Japanese patients, the relapse rate has been estimated to vary from 30 to 50%, [2022] although corticosteroid therapy significantly reduced relapse rates [22]. Japanese consensus guidelines for the management of autoimmune pancreatitis have stated that the indications for corticosteroid therapy include symptoms such as obstructive jaundice, abdominal pain, and back pain, and the presence of symptomatic extrapancreatic lesions. The major lesions at relapse included autoimmune pancreatitis (), sclerosing cholangitis (), lachrymal and salivary gland lesions (), and retroperitoneal fibrosis (). In addition, the involvement of other organs and symptoms were seen at relapse. We failed to identify any serum markers at diagnosis that could predict relapse, although we observed elevated concentrations of IgG and immune complex in the relapse compared with the nonrelapse group, although these differences were not significant. Serial changes in IgG4 and immune complexes in a 69-year-old woman with autoimmune pancreatitis who experienced 3 relapses showed that these markers were elevated in serum several months before clinically evident relapse, suggesting that regular measurements of these markers in an out-patient clinic may predict relapse [23].
5. Long-Term Followup of Patients with Autoimmune Pancreatitis and Normal or Elevated IgG4
We followed 2 patients with autoimmune pancreatitis for 10 years each, a 55-year-old man with a serum IgG4 concentration of 1135 mg/dL and a 65-year-old woman with a serum IgG4 concentration of 42 mg/dL [24]. The first patient experienced several recurrences, developing a pancreatic stone and pancreatic duct stenosis, whereas the latter patient showed no duct changes over time. These findings suggest that autoimmune pancreatitis accompanied by normal IgG4 concentrations may represent lower activity and a nonprogressive state [24].
6. IgG4 and Extrapancreatic Lesions in Autoimmune Pancreatitis
Extrapancreatic lesions in patients with autoimmune pancreatitis may involve organs throughout the entire body [7, 8]. Serum IgG4 concentrations were well correlated with the number of extrapancreatic organs involved, indicating a correlation between increased serum IgG4 and extrapancreatic involvement. Among the 5 types of extrapancreatic involvement, lachrymal and salivary gland lesions and hilar lymph adenopathy have been significantly associated with high serum IgG4 concentrations, suggesting that patients with high serum IgG4 should be assessed for the occurrence of these lesions [7]. However, a recent study of large numbers of patients with autoimmune pancreatitis and extrapancreatic lesions showed different results, as shown in Table 1. Patients with IgG4-related retroperitoneal fibrosis and kidney lesions had higher IgG4 concentrations than other patients, probably because these lesions were complications of many other IgG4-related diseases (Table 1).
Table 1: IgG4 concentrations, age and complications of more than 3 extrapancreatic lesions in patients with autoimmune pancreatitis and major extrapancreatic lesions.
7. Role of IgG4
IgG4 in these patients may be (1) pathogenic, (2) anti-inflammatory, or (3) as a rheumatoid factor. For example, anti-desmoglein3 IgG4 autoantibody has been reported pathogenic for pemphigus vulgaris [25]. Transfer of an anti-desmoglein3 IgG4 autoantibody from a pemphigus vulgaris patient to BALB/C mice resulted in a pemphigus vulgaris like lesion, suggesting the involvement of an IgG4 autoantibody directed against an unknown target antigen. Similarly, IgG4 deposits have been detected in tissues of patients with autoimmune pancreatitis [26]. In contrast, IgG4 was found to have anti-inflammatory effects against allergic reactions. IgG4 antibodies can bind to soluble antigens, blocking the interaction between these antigens and IgE on mast cells and inhibiting allergic reactions. A dynamic Fab arm exchange of IgG4 can occur, resulting in bispecific activity, loss of monospecific cross-linking activity, and loss of the ability to form immune complexes, resulting in anti-inflammatory effects [27].
IgG4 may act as an autoantibody against IgG or have rheumatoid factor activity. Western blotting has shown that IgG4 from the sera of patients with autoimmune pancreatitis can bind to IgG1, IgG2, IgG3, and IgG Fc [28]. Furthermore, IgG4 Fc, but not IgG4 Fab, was found to bind to IgG Fc [28], indicating that IgG4 binding to IgG Fc is via an Fc-Fc interaction, not via rheumatoid activity. ELISA showed that IgG4 from the serum of each patient with autoimmune pancreatitis could bind to IgG1 coated onto microplates, a binding well correlated with serum IgG4, but not rheumatoid factor, concentration [28]. The role of IgG4 Fc-IgG Fc is unclear, but it may have physiological and/or pathological effects, suggesting the need for further studies.
8. Conclusion
The utility of serum IgG4 concentration as a biomarker of the major IgG4-related disease, autoimmune pancreatitis, includes its ability to diagnose autoimmune pancreatitis as well as to differentiate this disease from pancreatic cancer. Moreover, serum IgG4 concentration may be a marker for predicting relapse and for the evaluation of extrapancreatic lesions. It remains unclear, however, whether IgG4 and its rheumatoid factor-like activity may be beneficial or pathogenic in these patients.
Acknowledgments
This work was supported in part by the Research Program of Intractable Disease provided by the Ministry of Health, Labor, and Welfare of Japan, and in part by Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan (23591012).
References
1. S. Kawa and S. Sugai, “History of autoimmune pancreatitis and Mikulicz's disease,” Current Immunology Reviews, vol. 7, no. 2, pp. 137–143, 2011.
2. S. Kawa, Y. Fujinaga, M. Ota, H. Hamano, and S. Bahram, “Autoimmune pancreatitis and diagnostic criteria,” Current Immunology Reviews, vol. 7, no. 2, pp. 144–161, 2011.
3. H. Umehara, K. Okazaki, Y. Masaki et al., “A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details,” Modern Rheumatology, vol. 22, no. 1, pp. 21–30, 2012. View at Publisher · View at Google Scholar · View at PubMed
4. S. Kawa, H. Hamano, and K. Kiyosawa, “Pancreatitis,” in The Autoimmune Diseases, N. Rose and I. MacKay, Eds., pp. 779–786, Academic Press, St Louis, Mo, USA, 4th edition, 2006.
5. H. Hamano, S. Kawa, A. Horiuchi et al., “High serum IgG4 concentrations in patients with sclerosing pancreatitis,” The New England Journal of Medicine, vol. 344, no. 10, pp. 732–738, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
6. H. Hamano, S. Kawa, Y. Ochi et al., “Hydronephrosis associated with retroperitoneal fibrosis and sclerosing pancreatitis,” The Lancet, vol. 359, no. 9315, pp. 1403–1404, 2002. View at Publisher · View at Google Scholar · View at Scopus
7. H. Hamano, N. Arakura, T. Muraki, Y. Ozaki, K. Kiyosawa, and S. Kawa, “Prevalence and distribution of extrapancreatic lesions complicating autoimmune pancreatitis,” Journal of Gastroenterology, vol. 41, no. 12, pp. 1197–1205, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
8. S. Kawa, K. Okazaki, T. Kamisawa, T. Shimosegawa, and M. Tanaka, “Japanese consensus guidelines for management of autoimmune pancreatitis: II. Extrapancreatic lesions, differential diagnosis,” Journal of Gastroenterology, vol. 45, no. 4, pp. 355–369, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
9. K. Okazaki, S. Kawa, T. Kamisawa et al., “Clinical diagnostic criteria of autoimmune pancreatitis: revised proposal,” Journal of Gastroenterology, vol. 41, no. 7, pp. 626–631, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
10. K. P. Kim, M. H. Kim, J. C. Kim, S. S. Lee, D. W. Seo, and S. K. Lee, “Diagnostic criteria for autoimmune chronic pancreatitis revisited,” World Journal of Gastroenterology, vol. 12, no. 16, pp. 2487–2496, 2006. View at Scopus
11. S. T. Chari, T. C. Smyrk, M. J. Levy et al., “Diagnosis of autoimmune pancreatitis: the mayo clinic experience,” Clinical Gastroenterology and Hepatology, vol. 4, no. 8, pp. 1010–1016, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
12. M. Otsuki, J. B. Chung, K. Okazaki et al., “Asian diagnostic criteria for autoimmune pancreatitis: consensus of the Japan-Korea symposium on autoimmune pancreatitis,” Journal of Gastroenterology, vol. 43, no. 6, pp. 403–408, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
13. K. Kawaguchi, M. Koike, K. Tsuruta, A. Okamoto, I. Tabata, and N. Fujita, “Lymphoplasmacytic sclerosing pancreatitis with cholangitis: a variant of primary sclerosing cholangitis extensively involving pancreas,” Human Pathology, vol. 22, no. 4, pp. 387–395, 1991. View at Publisher · View at Google Scholar · View at Scopus
14. K. Notohara, L. J. Burgart, D. Yadav, S. Chari, and T. C. Smyrk, “Idiopathic chronic pancreatitis with periductal lymphoplasmacytic infiltration: clinicopathologic features of 35 cases,” American Journal of Surgical Pathology, vol. 27, no. 8, pp. 1119–1127, 2003. View at Publisher · View at Google Scholar · View at Scopus
15. H. Matsubayashi, H. Sawai, H. Kimura et al., “Characteristics of autoimmune pancreatitis based on serum IgG4 level,” Digestive and Liver Disease, vol. 43, no. 9, pp. 731–735, 2011. View at Publisher · View at Google Scholar · View at PubMed
16. S. C. Abraham, R. E. Wilentz, C. J. Yeo et al., “Pancreaticoduodenectomy (Whipple resections) in patients without malignancy: are they all “chronic pancreatitis”?” American Journal of Surgical Pathology, vol. 27, no. 1, pp. 110–120, 2003. View at Publisher · View at Google Scholar · View at Scopus
17. A. M. Morselli-Labate and R. Pezzilli, “Usefulness of serum IgG4 in the diagnosis and follow up of autoimmune pancreatitis: a systematic literature review and meta-analysis,” Journal of Gastroenterology and Hepatology, vol. 24, no. 1, pp. 15–36, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
18. E. K. Choi, M. H. Kim, T. Y. Lee et al., “The sensitivity and specificity of serum immunoglobulin G and immunoglobulin G4 levels in the diagnosis of autoimmune chronic pancreatitis: Korean experience,” Pancreas, vol. 35, no. 2, pp. 156–161, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
19. A. Ghazale, S. T. Chari, T. C. Smyrk et al., “Value of serum IgG4 in the diagnosis of autoimmune pancreatitis and in distinguishing it from pancreatic cancer,” American Journal of Gastroenterology, vol. 102, no. 8, pp. 1646–1653, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
20. M. Takayama, H. Hamano, Y. Ochi et al., “Recurrent attacks of autoimmune pancreatitis result in pancreatic stone formation,” American Journal of Gastroenterology, vol. 99, no. 5, pp. 932–937, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
21. K. Hirano, Y. Asaoka, M. Tada et al., “No significant relation between relapse of autoimmune pancreatitis and substitution of aspartic acid at position 57 of DQβ1,” Journal of Gastroenterology, vol. 44, no. 7, pp. 799–800, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
22. K. Kubota, S. Watanabe, T. Uchiyama et al., “Factors predictive of relapse and spontaneous remission of autoimmune pancreatitis patients treated/not treated with corticosteroids,” Journal of Gastroenterology, vol. 46, no. 6, pp. 834–842, 2011. View at Publisher · View at Google Scholar · View at PubMed
23. S. Kawa and H. Hamano, “Clinical features of autoimmune pancreatitis,” Journal of Gastroenterology, vol. 42, no. 18, pp. 9–14, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
24. S. Kawa, H. Hamano, Y. Ozaki et al., “Long-term follow-up of autoimmune pancreatitis: characteristics of chronic disease and recurrence,” Clinical Gastroenterology and Hepatology, vol. 7, no. 11, supplement, pp. S18–S22, 2009. View at Publisher · View at Google Scholar · View at PubMed
25. B. Rock, C. R. Martins, A. N. Theofilopoulos et al., “The pathogenic effect of IgG4 autoantibodies in endemic pemphigus foliaceus (fogo selvagem),” The New England Journal of Medicine, vol. 320, no. 22, pp. 1463–1469, 1989. View at Scopus
26. S. Aoki, T. Nakazawa, H. Ohara et al., “Immunohistochemical study of autoimmune pancreatitis using anti-IgG4 antibody and patients' sera,” Histopathology, vol. 47, no. 2, pp. 147–158, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
27. M. van der Neut Kolfschoten, J. Schuurman, M. Losen et al., “Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange,” Science, vol. 317, no. 5844, pp. 1554–1557, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
28. S. Kawa, K. Kitahara, H. Hamano et al., “A novel immunoglobulin-immunoglobulin interaction in autoimmunity,” Plos ONE, vol. 3, no. 2, Article ID e1637, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
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Bibliography: The Necessity of His Condition
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Title: The Necessity of His Condition
Author: Avram Davidson
Year: 1957
Type: SHORTFICTION
Storylen: shortstory
ISFDB Record Number: 56772
User Rating: This title has fewer than 5 votes. VOTE
Current Tags: None Add Tags
Publications:
Copyright (c) 1995-2011 Al von Ruff.
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Very Low Activity
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Some SEOs Use Search Operators For Link Building & Some Don't
Mar 22, 2010 • 8:35 am | (0) by | Filed Under Link Building Tips & SEO
A few weeks ago we ran a poll asking SEOs if you use search operators to find link opportunities? Well, the results are in, and with a bit over 80 responses (not that many, which is out of the norm) we have the results. Honestly, the results are all over the place.
Here they are:
As you can see, 61% said they use it 50% of the time or more. 39% said they use it rarely or never. 22% said they use it all the time and 16% said they never use it.
This is a very interesting break down showing really that link builders are very diverse on how they handle discovering and acquiring links.
Forum discussion continued at WebmasterWorld.
Previous story: A Publisher Testing YouTube Rentals
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CMD sent two reporters to track ALEC in Oklahoma
Click here to help support our future investigations.
Atlas Economic Research Foundation
From SourceWatch
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Learn more from the Center for Media and Democracy's research on climate change.
This article is part of the Tobacco portal on Sourcewatch funded from 2006 - 2009 by the American Legacy Foundation. Help expose the truth about the tobacco industry.
The Atlas Economic Research Foundation was founded in 1981 by Antony Fisher. A "Johnny Appleseed" of antiregulation groups, it is closely affiliated with the U.K.-based Institute of Economic Affairs, the University of Buckingham (which has ties to the Global Warming Policy Foundation) and an international analogue, the International Policy Network (formerly known as Atlas Economic Research Foundation (UK)).
Contents
Mission - "Johnny Appleseed" of antiregulation groups
For over two decades, a Virginia-based organization has been quietly working as the Johnny Appleseed of antiregulation groups. With a modest $4 million dollar budget in 2003 and a staff of eight, Atlas Economic Research Foundation is on a mission to populate the world with new "free market" voices. In its 2003 review of activities, quaintly titled its "Investor Report," Atlas announced it worked with "70 new think-tank entrepreneurs from 37 foreign countries and several states of the U.S.," including Lithuania, Greece, Mongolia, Ghana, the Philippines, Brazil and Argentina.
The mission of Atlas, according to John Blundell (president from 1987 to 1990), "is to litter the world with free-market think-tanks."
Named after the Greek god condemned to bear the heavens on his shoulders, Atlas identifies, screens and offers initial support to individuals and groups who want to create local think tanks. "Our ideal 'intellectual entrepreneur,'" says Atlas, is "someone who communicates effectively with businessmen, academicians and the general public." By facilitating the establishment of local think tanks, Atlas increases both the reach and local credibility of their "free market" message, thereby having "the most cost-effective impact."
Since its formation in 1981, Atlas has funneled over $20 million in grants to think tanks that have passed its screening process. Atlas aims, it says, to "increase that amount tenfold in the next decade." In 2003, a little over $2 million of Atlas's 2003 budget was passed on to other think tanks. While the large conservative foundations take the approach of making large sustained and often untied grants, Atlas believes less is more, providing new think tanks with only small grants of $5,000 or less. Atlas weans their fledgling projects off this modest annual funding within five years, making exception only for specific innovative projects.
Atlas' think tanks, Chaufen continued, have "remarkable successes" even though they were often faced with "unsympathetic local traditions and ideas. Still, these think tanks have become one of the first places opinion leaders and policy makers go when they are looking for market-based solutions to difficult social, economic or environmental problems".
Global warming
Atlas has cosponsored Heartland Institute events dedicated to the proposition that climate change is not a crisis and has supported organizations such as the John Locke Foundation which has attacked efforts by state elected officials working on climate solutions with the Center for Climate Strategies.[1]
Green Imperialism?
In 2003, Paul Driessen, a senior fellow at the free market Atlas Economic Research Foundation, published his book Eco-Imperialism: Green Power, Black Death.
Affiliations
Some of the other organisations that Atlas has supported include:
Closely affiliated organisations include:
They have a database called Freedom Directory with basic information about 600+ think tanks and similar organizations.
Personnel
Staff
These all appear to be former staff:
• Colleen Dyble, Associate Director of Institute Relations
• Jo Kwong, Director of Institute Relations
• Chris Martin, Associate Director of Programs
• Elena Ziebarth, Associate Director of Public Affairs
• Joyce Schroeder, Office Manager
• Priscilla Tacujan, Assistant to the Executive Vice President
Board of directors
From December 2011:[7]
Former members include:
Who funds Atlas
The foundation's funding comes from corporate and institutional sources. During 2002, $193,500 of the organisation's funding came from the Earhart Foundation, $100,000 from the Sarah Scaife Foundation, and $50,000 from the Carthage Foundation. The Earhart Foundation has given more than $1m since 1995. [8]
Known corporate donors include ExxonMobil, which according to the Greenpeace website ExxonSecrets.org., has contributed over $500,000 since 1998. Exxon itself discloses contributions of $65,000 in 1998 (then Exxon) [9] and $50,000 during 2002. [10]
Ironically, Atlas requires its protégé think tanks to be "independent." "That is, independent of corporations, independent of governments, independent of political parties and even independent of universities," Atlas President Alejandro A. Chaufen said in an April 1999 interview.
In a May 1998 fundraising pitch to tobacco giant Phillip Morris, Chaufen explained that keeping its think tanks off the dole of political parties, universities, government agencies and lobbies "helps keep their ideas and recommendations untainted by real or perceived political or organizational ties" and "helps protect them and us against potential scandal. Think tanks tied to politicians and parties can easily become instruments of corruption. Indeed, in several instances, public officials have enriched themselves and their allies through the 'think tanks' they control," Chaufen wrote.[11]
In 1995 alone Philip Morris contributed $475,000 to Atlas according to an internal budget document released as part of the settlement of the legal action brought by several U.S. states' attorneys general. In 1997, despite a tight budget, PM staff recommended Atlas receive $150,000 because of the organization's ability, through its events and public advocacy work, to "positively impact the regulatory environment, particularly in Latin America." The think tanks fostered by Atlas, PM staff wrote approvingly, results in "an improved operating environment for all PM businesses."
More recently, Atlas has gained financial support the British mutual fund businessman, John Templeton. The Templeton foundation - in conjunction with Atlas - has established the Templeton Freedom Prizes for Excellence in Promoting Liberty. The prizes, $10,000 for the winner and $5,000 for the runner up are for "market-oriented poverty programs; for ethics and values; for social entrepreneurship and for student outreach". Under the awards it is planned that $1.25 million will be distributed between now and 2007.
The Charles G. Koch Foundation and the Claude R. Lambe Foundation both support the Atlas Economic Research Foundation.[3]$113,800 received from Koch foundations 2005–2008 Total Koch foundation grants 1997–2008: $122,300 [4]
2005-2009 contribution amounts
2005-2009 donations to Atlas ranged from almost $4m in 2005 to almost 6.5m in 2008.[5] In 2006, one individual gave Atlas $743,000, according to the group's 2007 Form 990; the next highest donation was $500,000.
Atlas funding of think tanks
The 2007 Form 990 reports about $2.5m ($1.5m? see Part IIIa) going to think tanks, but didn't say which ones or where they are.
2009: mostly outside the U.S.; no transparency re recipients
The 2009 Atlas Form 990 shows under $650k in grants (to organizations, governments and individuals) in the U.S., and over $2m outside the U.S.
Outside the U.S., it listed "economic education" expenditures of:[5]
• $125k to Sub-Saharan Africa
• $392k to East Asia and the Pacific
• $39k to North America
• $1 million to Europe
• $427k to South America
• $54k to the Middle East
But because the IRS instructs filers not to identify their international grantees, the identity of the recipients is hidden.
Inside the U.S., Atlas listed mostly grants of roughly $10,000, including one to the Sam Adams Alliance ($10,200); though some grants were larger, e.g. the George Mason University Foundation got $50,000.
IRS status and Form 990 curiosities
Atlas's EIN# is 94-2763845, ruling date 12/1981. Its IRS Form 990s are available on its website.[6] (and are more complete than the filings on Guidestar or ERI, which were missing the 2008 990). The group's 2009 Form 990 Schedule I might be incomplete; while it does list the U.S. organizations it funded, in alphabetical order, it starts at "Fou". [7]
PR tips
While Atlas calculates that its "family" comprises approximately one-third of the world's 470 "market oriented" think tanks, it worries that "many young think tanks lack know-how regarding reaching the media and communicating a message effectively." To help build skills, Atlas recruited Vince Breglio, co-founder and senior executive with the market research and public relations company Wirthlin Worldwide.
At its mid-August conference in Salt Lake City, Breglio gave PR tips in a two-hour workshop titled "communicating the message of liberty." A veteran of the 1980 and 1984 Reagan Presidential campaigns, Breglio is no stranger to helping sell unpopular ideas. Internal tobacco industry documents reveal he advised both R.J. Reynolds and Philip Morris on public opposition to smoking.
According to an Atlas report on the conference, Breglio told participants in the two-hour workshop that building a larger supporter base depends on "persuading by reason, motivating by emotion".[12]
"Breglio showed the workshop a methodical approach to identifying the "emotional drivers" that motivate individuals on a given issue, and then developing a communications strategy that links a product or idea to the needs of an audience," the conference report stated. Download pdf copy of presentation - 450k file
Other SourceWatch resources
Contact information
2009:
Atlas Economic Research Foundation
1201 L St NW, 2nd floor
Washington DC 20005
Phone: 202-449-8449
(this is same address and phone as the American Friends of the Institute for Economic Affairs)
Website: atlasnetwork.org
Earlier addresses
(on 2007 990)
2000 North 14th St., Suite 550
Arlington, VA 22201
Phone: (703) 934-6969
(this was same address and phone as the American Friends of the Institute for Economic Affairs)
4084 University Drive, Suite 103
Fairfax, VA 22030
Phone: (703) 934-6969
Email: atlas AT atlasusa.org
Web: http://www.atlasusa.org
External links
References
1. "[1]"
2. [2]
3. "Page 13 [3]"
4. "[4]"
5. 5.0 5.1 [5]
6. [6]
7. Given the number of recipients, it seems unlikely that no recipient names were positioned earlier in the alphabet.
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Australian Bureau of Statistics
Celebrating the International Year of Statistics 2013
ABS Home > Statistics > By Release Date
5302.0 - Balance of Payments, Quarterly Summary, Jun 1968
Previous ISSUE Released at 11:30 AM (CANBERRA TIME) 31/07/1968
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Australian Bureau of Statistics
Celebrating the International Year of Statistics 2013
ABS Home > Statistics > By Release Date
8635.0.55.002 - Tourist Accommodation, Small Area Data, Australia, Jun 2012
Previous ISSUE Released at 11:30 AM (CANBERRA TIME) 05/10/2012
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TOURIST ACCOMMODATION, SMALL AREA DATA
This product presents results from the June quarter 2012 Survey of Tourist Accommodation (STA) for the following categories of establishments:
• hotels and resorts with 15 or more rooms
• motels, private hotels and guest houses with 15 or more rooms
• serviced apartments with 15 or more units
Data provide information on the supply of, and demand for, tourist accommodation facilities. Data include number of establishments, capacity and employment for the quarter and occupancy and takings from accommodation for each month; by type of establishment and by star grading.
Geography changes
The June quarter 2012 release of STA data is the second to incorporate the Australian Statistical Geography Standard (ASGS) as the geographical framework for the collection. Detailed information on the transition of the STA to the ASGS and how the data has been impacted by this change is contained in Information Paper: Future Changes to Tourist Accommodation, Australia (cat. no. 8635.0.55.003).
A summary of the main changes resulting from the move to ASGS are:
• Small area data is now produced at Statistical Area Level 2 (SA2), replacing Statistical Local Areas (SLA).
• Tourism Regions (TRs) are constructed from allocations of SA2s and as a result have changed. For some TRs, these changes are minimal.
• Data for Local Government Areas (LGAs) and Special area - Brisbane City Core are no longer produced.
To assist users transition to the new geography, this product contains data on both the ASGS and the ASGC geographic frameworks.
Further information
For further information on Tourism Accommodation statistics, including implementation of the ASGS in the Tourist Accommodation collection or changes to outputs, please contact the National Information and Referral Service on 1300 135 070.
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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.
My guess is as in most cases existing relationships and/or validated relevant past experiences are a great start, but wondering on a ad-hoc basis what the best way to evaluate startup co-founders based on testing their leanness and agility skills; think of it as speed dating format, or a standardized employee candidate test.
Just to be clear, by leanness I mean "lean startup", and by agile, to keep it simple, I mean a SCRUM based product/service development life-cycle. That said, there's nothing new about how important it is to be able to learn and adapt, and it's my understanding that these skills and related experiences have always been valued within the greater start-up community.
Also, while a qualitative methods would be nice, quantitative methods might just be as good, if not better -- in part because this would make it easier to evaluate a wider pool of possible co-founders. I would also guess that this question applies to investors in startups too, since knowing how fast a team is able to learn and adapt is very important in most cases.
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3 Answers
up vote 5 down vote accepted
Forget speed dating and forget standardised employee candidate tests.
When you find someone you think you might want to work with, the only way to know if they're a good fit, is to work with them. And eat with them. And drink with them. Hopefully you'll disagree with them, maybe even have a fight too. Once you've done that lot, and you're still having fun - you found your co-founder/employee.
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There is one fundamental problem that you will run into quantitatively and otherwise.
The interview is basically you describing yourself and unless you can see how person actually does what you want them to you will know nothing of whether or not the person just actually talks good game.
What you should be doing in an interview is telling the person that the company adheres to these principles and they should follow them as well. In which case people who don't want to or don't know will fall off your radar on their own.
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You need to make some clear distinctions.
Your startup can definitely be built around some shared values. It sounds to me as though you're taking the attitudes of Lean Startup in that kind of way. Without taking yourself too seriously, maybe you should sketch out your project's manifesto - how you want to be and do what you intend to become. And, by and large, you should be building a team that shares those core values, because that will make it easier to pull together in the tough days.
And your startup is going to need a whole set of skills and methodologies. Skills can be evidenced, and they can be learned. Methodologies, too, can be evidenced, learned and adapted. Having skills you know are going to be important represented in a team is clearly smart, but it's no guarantee of success. So surround yourself with smart, motivated, adaptable people. And wherever possible, find opportunities to work together with intensity.
Finding out if you're compatible enough to work together, different enough that the whole is greater than the sum of its parts, and broad enough that you can make it, is the fun and frustration at the heart of startup life. And you de-risk that by building commitment slowly, and by biting the bullet fast when it isn't working out.
Good luck. I hope you find yourself part of a dream team!
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Download references
This article is part of the supplement: 32nd International Symposium on Intensive Care and Emergency Medicine
The Oxygenation Index compared with the P/F ratio in ALI/ARDS
M Van Haperen*, PH Van der Voort and RJ Bosman
• * Corresponding author: M Van Haperen
Critical Care 2012, 16(Suppl 1):P91 doi:10.1186/cc10698
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From DDO wiki
Jump to: navigation, search
Name: Prismatic Ray
School: Evocation (Acid spells) (Death spells) (Electricity spells) (Fear spells) (Fire spells) (Mind-affecting spells)
Level: Sor/Wiz 5
Spell Point Cost: 25
Components: VerbalVerbal: A verbal component is a spoken incantation. You cannot cast spells that require this component if you cannot act or speak. This has no gameplay applications in DDO, as all characters can always speak and there are no effects which prevent you from doing so., SomaticSomatic: A somatic component is a measured and precise movement of the hand. You cannot cast spells that require this component if you cannot move causing arcane spell failure resulting in a ruined spell. Spells without a somatic component may be used with disregard to Arcane Spell Failure chance. Note - that characters make the same arm gestures for most spells in DDO, so you can't tell which spells require this component by watching your character's animations.
Metamagic: Empower, Heighten, Maximize, Quicken
Range: Double
Target: Foe, Directional, Breakable
Duration: Instantaneous
Saving Throw: Various: Reflex save takes half damage; Fortitude save negates Death and Stone effects; Will save negates Fear and Death
Spell Resistance: No
Cooldown: 4 seconds (Wiz), 2.5 seconds (Sor)
Description:
A shining ray of multicolored light blinds creatures with 8 Hit Die or less for 12 to 48 seconds, and does 1 of 7 harmful effects at random to one target, with a 12.5% of inflicting a second different effect from that 7. These 7 effects are detailed as follows:
Note that Spell Resistance does not protect against any of these effects, including the non-damaging ones.
The highest item based damage, critical hit rate and critical multiplier bonuses apply to this spell, regardless of the type of damage enhanced as long as it matches one of this spells 3 types (Fire, Acid or Electricity).
Enhancement bonuses and item bonuses stack.
For example, if you have an item that grants +30% fire damage, increases fire critical rates by 9%, and increases the critical damage multiplier by 0.25, and another item that grants +40% acid damage, increases acid critical rates by 6%, and increases the critical damage multiplier by 0.5, Prismatic Ray will deal 40% more damage, while its critical hit rate increases by 9%, and its critical damage multiplier increases by 0.5, the spell benefiting from the highest property from each category.
Expanding on this example, if you had enhancement bonuses that granted +10% damage to electricity spells, +3% to their critical hit rates, and +0.5 to their critical damage modifiers, and another set that granted +30% damage to fire spells, +6% to their critical hit rates, and +0.75 to their critical damage modifiers, Prismatic Ray would receive, in addition to all item bonuses, +30% damage, +6% to its critical hit rate, and +0.75 to its critical damage multiplier.
Combining the two examples, the final adjustment from items and enhancements would be: +70% damage (30% + 40%), +15% (9% + 6%) critical hit rate, and +2.25 (1 + 0.75 + 0.5) critical damage multiplier.
This spell is random, but interesting. The violet beam can be extremely powerful, especially when used against enemies who are otherwise immune to most other insta-kill effects.
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Wikia
SRD:Improved Sunder
Talk0
9,503pages on
this wiki
This material is published under the OGL
Improved Sunder [General]Edit
PrerequisitesEdit
Str 13, Power Attack.
BenefitEdit
When you strike at an object held or carried by an opponent (such as a weapon or shield), you do not provoke an attack of opportunity.
You also gain a +4 bonus on any attack roll made to attack an object held or carried by another character.
NormalEdit
Without this feat, you provoke an attack of opportunity when you strike at an object held or carried by another character.
SpecialEdit
A fighter may select Improved Sunder as one of his fighter bonus feats.
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GlobalVoices in Learn more »
Hungary: The Hungarian Guard Banned
This post also available in:
Español · Hungría: Inhabilitan a la Guardia Húngara
বাংলা · হাঙ্গেরি: হাঙ্গেরিয়ান গার্ডকে নিষিদ্ধ ঘোষণা করা হয়েছে
A long and complex story seemed to have reached its end some weeks ago. A paramilitary association called the Hungarian Guard (Magyar Gárda) of the Hungarian extreme-right party Jobbik was banned at the beginning of July after more than a year of investigation by Budapest Court.
In December 2008, Eva S. Balogh of Hungarian Spectrum reported on the first decision made by the court:
[...] It's hard to believe, but the first round of court proceedings against the Hungarian Guard (Magyar Gárda in Hungarian) is finally over. The judge agreed with the chief prosecutor's office of Budapest that the Hungarian Guard is illegal. Illegal in the sense that it is not a cultural association. [...] The prosecutors sent the indictment over to the Budapest Court on December 17, 2007. Exactly one year ago. The court was in no hurry. The case initially appeared on the docket in March 2008. [...]
There were some problems with the creation of the Hungarian Guard in 2007:
[...] The case was a little tricky because the organizers of the Magyar Gárda tried to insulate the troops from any litigation against the alleged cultural organization. They created a separate legal entity comprised of the uniformed fellows with their black boots and insignia suspiciously resembling that of the Hungarian Nazis of Ferenc Szálasi. It was legally distinct from the original organization with its self-described cultural mission. Thus we had a Magyar Gárda Mozgalom (Movement of the Hungarian Guard, the troops) and a Magyar Gárda Egyesület (Association of the Hungarian Guard, the so-called cultural association). It was with this legal separation that the lawyers working on behalf of Jobbik, the extreme right party responsible for the creation of the Hungarian Guard, tried to save at least the uniformed units that belong to the Movement. [...]
As Eva S. Balogh writes, the verdict of 2008 clearly declared that the separation is not enough to defend the existence of the Guard:
[...] This court case addressed the Association, not the Movement. However, this is still a blow to the whole Hungarian Guard because the judge very rightly pointed out that the Movement and the Association are in a symbiotic relationship amply demonstrated by the changes made in the original documents, by the signed documents of cooperation between the two organizations, and by the financial interconnections that exist between them. The judge decided that the Hungarian Guard's main aim is to spread fear among Gypsies. Judge Pataki noted that the Guard is also antisemitic because in a speech a spokesman of the Guard talked about “Zionist rats, locusts, and grave diggers of the nation.” The judge pointed out that all these activities are unconstitutional and not in conformity with Hungary's international obligations. [...]
The judgment was appealed and after the first round verdict Gábor Vona, Chairman of the Hungarian Guard Association, stated in an interview:
[...] Either way we will continue, even under a different association or civil group, we will serve our nation. [...] The Hungarian Guard Movement is not affected by the verdict, even the Judge confirmed this. The verdict is about the Association. Indirectly the court confirmed that the Guard will carry on and I can also confirm this. [...]
In early July, the final verdict was pronounced. Eva S. Balogh of Hungarian Spectrum wrote:
[...] It was last December that the presiding judge in a lower court found the Hungarian Guard guilty of violating the rights of an ethnic group. The lawyer representing the Guard appealed. Today the Hungarian Guard both as a “cultural association” and as a “movement” was found guilty as charged. [...]
Gábor Vona announced an official demonstration for the Hungarian Guard three days later, right after the day of a spontaneous rally that was held in the center of Budapest and disbanded by the authorities. Kuruc.info, an extreme right website related to Jobbik, stated:
Hungarian Law categorically permits demonstrations within a 72 hour window of contemporary events, without any form of prior permission from the authorities. [...] The subsequent protest, held by a few hundred members of the Hungarian Guard, their supporters and members of Jobbik, was in response to such a contemporary event. Namely, the ruling by the unelected judges of the Budapest Appeals Court on July 2, which called for the disbanding of the Hungarian Guard. [...]
The website reported that the protesters surrounded by the police sat down to keep on holding the peaceful rally:
The police responded with a series of callous attacks against the seated demonstrators, in an all too common display of the facial spraying of tear gas at close range and the brutal beating of protestors regardless of age or infirmity. [...] The police were compelled to forcefully remove and arrest the demonstrators by snatching them individually and dragging them away. [...]
Also Gábor Vona was arrested as responsible for the spontaneous rally. The second demonstration that was officially announced on July 11 was finally held peacefully. The organizers stated that they would relaunch the Hungarian Guard. At the rally, recently elected Members of the European Parliament (MEP) were present in black-and-white uniforms of the Guard.
Politics.hu reported that three days later one of the delegated Jobbik MEPs, Csanád Szegedi, was wearing the Guard's uniform at the inaugural session of the European Parliament, which was condemned by the Progressive Alliance of Socialists and Democrats.
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For the half-year to 30 June 2013, the IPKat's regular team is supplemented by contributions from guest bloggers Stefano Barazza, Matthias Lamping and Jeff John Roberts.
Two of our regular Kats are currently on blogging sabbaticals. They are Birgit Clark and Catherine Lee.
Friday, 26 June 2009
You want to complain?
The current issue of IPInsight ("the free e-newsletter brought to you by the Business Outreach and Education team" of the UK's Intellectual Property Office), leads with a feature entitled IP complaints. Its text reads as follows:
"Unhappy with your IP adviser? Your chances of holding them to account are about to improve.
A bill for £2,000 lands on your desk. It is from your IP attorney. Sure, they have been working on your case. But where has this bill come from? Did anyone ask whether you wanted the work doing? Actually, you might have liked it done differently. Or not at all.
At the moment, you can complain, of course. First, you raise it with your attorney. Then, go to one of the two professional institutes: The Chartered Institute of Patent Attorneys (CIPA) for patents, or the Institute of Trade Mark Attorneys (ITMA) for trade marks. But it feels as if they are all in the same boat. Nobody sees it your way round.
Next year, any such cosiness is being blown away. The professional institutes are losing their regulatory role. In future, they are being freed to concentrate on representing their members. From early next year, a new regulator, The Intellectual Property Regulation Board (IPREG), also known as IP Reg, will be responsible for ensuring high professional standards. The chief executive is Mike Knight, a former examiner at the Intellectual Property Office, who is used to casting a sceptical eye over IP attorneys.
In drawing up new policies for conduct, discipline and qualifications, he is under the direction of a board that includes IP users as well as attorneys. It will mean a big change in how the profession works. "We are turning it the other way round. We will be setting down standards in light of what the public expects. It will be no longer a question of what professionals think they ought to have achieved."
Knight will have little tolerance for anyone saying that IP varies too much from case to case. "Everyone is providing a legal service. We want to make sure attorneys tell their clients where they are going, what they are doing for them, what they can expect and how much it will cost. The best attorneys do it already. We want to spread these practices throughout the profession, so on each the client knows what to expect."
As a user, you can go to the IPREG website to take a look at the code of conduct and the qualifications expected of attorneys. Because the needs of a lone inventor and a global brand are so different, Knight is wary of producing a template for IP agreements, but in the code of conduct, you will find examples of what IPREG expects to see in a contract.
These standards, written under the influence of IP users, will be how the profession is judged in future. If you are unhappy, you will have a clear framework on which to base any complaint. If your attorney gives an inadequate response, you then go to another new independent body: the Office of Legal Complaints.
After taking an initial look at whether you have a genuine grievance, they will ask your attorney to put up a hefty sum to cover the cost of the investigation and any redress. If they are cleared, it will be returned to them.
But the principle is there that 'the polluter should pay', says Knight. "We want to win respect for a profession with high standards. If you are a bad attorney, you will pay for it."
The IPKat is happy to see all professions regulated, and he sees no reason why the IP professions should be treated differently. He is also pleased to see that IP users are being brought in to the review process. However, he wonders whether he is alone in considering the tone of this article to be unnecessarily offensive. It demeans the work that has gone into regulating the patent and trade mark professions in the past and the comment about cosiness strikes a gratuitiously unpleasant tone. Has the IPO fallen out with the professions, or is it merely sticking pins into them for the fun of it, to remind them that, while a dissatisfied client can change his professional representative, you can't change IPOs if you fall out with people working in the one you've already got?
IPReg website here
Rules of Conduct for Patent Attorneys, Trade Mark Attorneys and Other Regulated Persons here
"You want to complain!" -- the Monty Python sketch
Subscribe to the IPKat's posts by email here
Just pop your email address into the box and click 'Subscribe':
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Griffin:Western Blot Optimization
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Tubulin loading control Western blot is an important control experiment to know your reagents and protocol are in line and that equal protein amounts are loaded in each lane
No signal on a prolonged exposure could be an issue with either the primary antibody OR protein expression level
Your time and labor at the bench is extremely valuable. Below is a guide that will enable you to interpret your western blotting experience in a purposeful way so that each experiment will make a difference. Watch out for futile cycling in your work and focus your energy in a meaningful way.
There is an increasing number of available commercial antibodies from several vendors. Depending on who you buy from, the level of quality control the vendor performs is highly variable and this leaves you with the responsibility to optimize your own protocol in an efficient manner. Because every antibody is different, each one requires a different blocking/incbuation buffer in order to optimize the signal:noise ratio.
There are common themes in the types of incubation buffers that tend to work well for blocking and incubation.
Commercial antibodies have a wide range of specificity and sensitivity for the protein of interest. Effecient blocking of the primary and secondary antibodies can take place in a variety of different blocking agents that contain soluble proteins and nonionic detergent. When developing a new antibody by western blot, it is important to test several different blocking/incubation buffers for the best possible signal:noise ratio in the assay. No single blocking agent is ideal for every primary antiobody, since each antibody-antigen pair has unique binding characteristics.
Contents
The importance of the blocking/antibody incubation buffer
PVDF or nitrocellulose membrane has the ability to bind protein of all sorts. Since both the antibodies and the transferred lysate/extract are proteins, steps must be taken to optimze interactions between the membrane and the antibody used for detection of the target protein.
Blocking of non-specific binding is achieved by placing the membrane in a dilute solution of protein containing a low percentage of detergent such as Tween-20. The protein in the dilute solution attaches to the membrane in all places where the target proteins have not attached from the gel transfer to the membrane.
When the primary antibody is added, there is no room on the membrane for it to attach other than on the binding sites of the specific target protein. This reduces "noise" in the final product of the Western blot, leading to clearer results.
Band appearance/aesthetics
Dumbbell shaped bands are an indication of a hot run
Smile effect of the bands/Dumbbell shaped bands
1. Migration was too fast.
2. Migration was too hot (changing the pH and altering the migration). Slow down the migration or run the gel in the cold room or on ice.
Uneven band size in lanes probed for the same protein
Gel has set too quickly while casting and the acrylamide percentage is not even along the lanes. Review the recipe of the gel and the addition of TEMED to the gels, add a little 0.1% SDS in water to the top of the migrating gel while it sets to stop it from drying.
Molecular weight disparity
Laddering effects in a western blot may suggest that primary specificity is low and/or the antibody is overly sensitive
Always review protein molecular weight details in the primary literature through PubMed for the most informed perspective on your result. Below are possibilities to explain the infinite nuances of protein behavior in SDS-PAGE.
Post-translation modification
• phosphorylation: Tyrosine, Serine, Threonine phosphoryl additions are common.
• glycosylation: Carbohydrate additions due to ER/Golgi processing can increase the weight of the protein.
• cleavage: pro-proteins undergo cleavage to render the active form.
mRNA splice variation
• Alternative splicing of exons can create different sized proteins from the same gene. Depending on cell type, differentiation state, & tissue type, the transcript splicing can and will influence structure and function for certain genes.
Intrinsic structure
• Relative charge: The composition of amino acids (charged vs non-charged).
• Multimers: Modular proteins or proteins than can form multimeric complex can influence the observable weight. This is usually prevented in reducing conditions through the use of DTT, 2-Mercaptoethanol, or TCEP. However, strong interactions can result in the appearance of higher bands.
Black spots on film
Spotted film below the 140kDa Collagen Type I (COL1A1) precursor band
• Primary and/or secondary antibody aggregation in solution will cause the film exposure to appear speckled; either primary or secondary antibody. Antibodies may be sticking to the blocking agent.
Microfuge precipitate
• Microfuge the primary and secondary at 14,000xG for 15 minutes at 4C.
• 0.2 micron filter sterilize the antibodies into a fresh sterile tube and relabel the tube.
• 0.45 uM filter the blocking agent.
• Poor Transfer due to air bubbles during transfer to membrane, dirty film when adding to the developer, developer rolls are dirty
Remove air bubbles
• use a pasteur pipette as a roller. roll the membrane and gel in the submersed transfer buffer before transfer to remove bubbles. keep membrane and materials wet.
• keep film clean before adding to the developer
Concentration of antigen
Over abundance of antigen and/or too much primary antibody
The resolution of SDS-PAGE is limited to 50-100 bands. If the relative concentration of the antigen of interest is too low (less than 0.2% of total protein), it may be difficult to detect (for instance, synaptobrevin/VAMP comigrates with histones in cell homogenates which interfere with its detection). Signal enhancement may then lead to the appearance of artificial bands. Enrichment of the antigen by fractionation or by immunoprecipitation should be considered.
On the other hand, too much abundance of antigen or too much primary antibody may yield an overly robust signal.
Excess signal; multiple bands/too much banding
Extraneous banding may represent glycosylation or phosphorylation of the major band
Theoretical prediction is a primary antibody toward a single gene product should produce a single band. While this is common and in some cases to be expected, there are legitimate exceptions to the rule and other factors may be responsible. For example:
Factors that can produce multiple bands of variable molecular weight
• transcript variation
• multiple start/stop sights
• signal-dependent protein processing/shuttling (ie secretion)
• cell type/differentiation state specific variation
• endoplasmic reticulum and golgi-dependent alternative cofactor additions
Smearing effect for the band of interest
• post-translational modifications including glycosylation, nitrosylation, phosphorylation, methylation, acetylation, ubiquitination,
• ubiquitin-dependent protein degradation
Excess signal; dark exposure
Adjust blocking, 1ary, 2ary diluent all to 5% milk TTBS, and perform 10 shake rinses after the 2ary incubation to resolve overexposure of film
Adjust blocking, 1ary, 2ary diluent to 5% milk TTBS, titration of the primary, further washing after 2ary incubation, and adjusting exposure time can improve the signal:noise
How do I decrease the background on my blot?
The leading cause of excess background is cross-reactivity between blocking agent and primary or secondary antibody: this will result in an overall membrane staining. The best blocking/incubation buffer for your immunoassay is the one that gives you the most clean bands with minimal background noise.
Concentration of antibody may be too high or incubation time too long. Also, several short washing steps are better than one long one.
Additional considerations;
The primary antibody you purchased may be too sensitive for specific detection of the target protein. Contact the vendor and explain your results. Value your time and notify the vendor of your observations. Common feedback may include;
1. Further dilute out your HRP or AP conjugated secondary antibody.
2. Instead of primary antibody incubation overnight, try 2 hours at room temp.
3. Instead of 2 hours at room temp, try 1 hour are room remp or 1 hour at 37C.
4. Perform more wash steps between incubation steps. Try 5 shake rinses followed by 4 x5min washes in 1X TTBS. Several short washing steps are better than one long one.
5. Load less protein onto the gel;
whole cell lysate or tissue extract: 20-50 micrograms subcellular fractions (ie nuclear or cytosol extracts): 10-30 micrograms purified proteins (ie recombinant or eukaryotic expression): 5-50 nanograms
• Blocking of non-specific binding might be absent or insufficient. Increase the blocking incubation period and consider changing blocking agent. *The primary antibody concentration may be too high. Titrate the antibody to the optimal concentration, incubate for longer but in more dilute antibody (a slow but targeted binding is best).
• Incubation temperature may be too high. Incubate blot at 4°C.
• The secondary antibody may be binding non-specifically or reacting with the blocking reagent. Run a secondary control without primary antibody.
• Cross-reaction between blocking agent and primary or secondary. Add a mild detergent such as Tween20 to the incubation and washing buffer.
• Antibody detects the casein present in the milk. Use BSA as a blocking reagent instead of milk.
• Washing of unbound antibodies may be insufficient. Increase the number of washes.
• Your choice of membrane may give high background. Nitrocellulose membrane is considered to give less background than PVDF.
• The membrane has dried out. Care should be taken to prevent the membrane from drying out during incubation.
Ghost bands (reverse/white banding)
Ghost bands
Insufficient blocking
Ghost banding is the negative image of the proteins that have been transferred to the membrane.
Visualize in your mind; A 15 lane gel that has been run out and coommassie stained. Every lane will have a laddering appearance. Now imagine this same laddering band pattern being transferred to a PVDF or nitrocellulose membrane. The transfer of the proteins from the gel onto the surface of the membrane creates a protein fingerprint on the membrane. Blocking the membrane is an attempt to cover all other unbound sights.
Ghost banding occurs when there is residual background noise around where the protein fingerprint is present. This event suggests;
1. There is no detectable level of the target protein in the samples
2. The primary antibody is not recognizing the target protein
Excessive signal generated
Reduce the primary/secondary antibody dilution and lower the protein loading amount; Dilute HRP-conjugate at least 10-fold. High levels of specific antibody and an overabundance of protein can cause intense localized signals (typically a single band). Rapid and complete quenching of the substrate will produce no signal. Since there is no light production after the completion of the reaction, white bands are the result when exposed to film.
No signal
Actin or GAPDH control Western blot is an important control experiment to know your reagents and protocol are in line
• Run an antibody control: parallel Actin or GAPDH positive control western blot that corresponds to the same host species as your experimental primary antibody will conclusively indicate if the issue relates to your protocol on some level OR an issue with the primary antibody/protein expression level. This also validates that your secondary antibody is functional.
• Run a positive control: Running a sample that is known to express your protein of interest will conclusively indicate if the issue relates to the primary antibody.
• Antigen is not recognized by primary antibody & this can occur especially with monoclonal antibodies that were raised against a native protein. In some cases, a non-reducing gel system may need to be used. Otherwise contact the vendor technial service.
1. Reagent omitted or improperly prepared. A simple fix yet this becomes more and more rare with experience. Review the protocol.
2. Protein did not transfer from gel to membrane. Try a Ponceau S stain of the membrane to see if there are bands on the membrane.
3. Specificity of HRP secondary antibody not appropriate for primary antibody.
4. Correct orientation of membrane not maintained throughout procedure.
5. Presence of azide in buffer, inhibiting peroxidase activity. Horseradish peroxidase labeled antibodies should not be used in conjunction with sodium azide. A change in the blocking agent or incubation solution will solve this problem.
6. Detergent is too harsh: SDS, Nonidet P-40, and Triton X-100 disrupt binding between proteins. 0.01-0.05% Tween-20 is the most commonly used and recommended detergent for washing and incubation solutions.
Proteolytic breakdown of the antigen
If additional smear/ladder type banding is of lower apparent molecular mass than the full-length protein, then proteases may be active. The addition of fresh protease inhibitors such as PMSF, pepstatin or leupeptin can resolve this. Proteases can mediate degradation when samples are stored for prolonged time or samples are fractionated from starting cell or tissue preps.
Weak signal/poorly defined signal
Mulitple blank blots for different antibodies suggests there is a need to load positive controls in order to address sample loading amount and sample quality
First and foremost, the primary antibody may have low affinity for target protein. Antibody affinity may also change after denaturation of a cell/tissue sample with SDS.
1. Low antibody concentration. Increase the primary dilution.
2. Incubation time needs to be extended.
3. Insufficient protein loaded onto gel. Load more protein.
5. Exposure of film too brief. Try multiple exposures extending from 1 minute all the way to overnight.
6. Bald Spots: bubbles between gel and membrane: bubbles create points of high resistance that lead to low transfer efficiency, be sure to remove bubbles completely when putting together the transfer sandwich.
7. Incomplete Transfer.
One of several technical errors can be the source of incomplete transfer
• Proteins not completely eluted out of gel: this often occurs with high molecular weight proteins, especially when using a transfer buffer containing methanol. One way to overcome this phenomenon is by using nitrocellulose, which does not require methanol in the transfer buffer. Adding SDS to the transfer buffer as well as using higher field strengths also improves protein elution.
• Proteins have transferred through membrane: this may occur when working with proteins of very low molecular weight. Optimizing/shortening transfer times and using a double layer of membrane usually enables retention of small proteins.
• Inappropriate transfer buffer used: the most stable and commonly used buffers are Tris-Glycine based and contain methanol.
• Impurities in the transfer buffer: this will lead to a pattern on the membrane that mirrors the holes in the transfer cassette. Fresh buffer should be prepared prior to each transfer process.
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User:Etienne Robillard/Notebook/Chemtrails911 notebook/Agent Ecoli:Plasmid cloning vectors for gene therapy with phosphohistidine based oligos
From OpenWetWare
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Plasmid cloning vectors for gene therapy with phosphohistidine-based oligos
Contents
Artificial DNA promoters: phosphoramidate-based oligonucleotide synthesis
cDNA:
• N-6-benzoyl-deoxyadenosine phosphoramidite - Notice the P-N bound indicating the linkage of a phosphonate diester to a benzoyl atom :)
• N-3-oxo-hexanoyl-L-homoserine lactone - A light-inducible phosphohistidine-bound AHL ? A(denosine)TP/cAMP dependent.
• Reminder:
• NHC = (N heterocycle carbene) - Chemical compounds with a N chiral prodrug switch - highly enantioselective molecules
• N = indicates a Nitrogen atom
• P = a Phosphonate (inorganic state) - a compound for oligo synthesis using the nucleoside phosphoramidite method.
• P-N = phosphoramidate (a Nitrogen atom bound to a Phosphonate ester in nucleophilic substitution).
deoxynucleotide synthesis:
• cDNA synthesis building block = deoxynucleoside + 3'-phosphonate = synthetic nucleotide analog (dATP) 1
oligodeoxyribonucleotide synthesis:
• short 50-200(?) bp restriction endonucleases enzymes for cDNA catalysis/plasmid vector cloning in E. coli
• building blocks for oligonucleotides assembly with phosphoramidites method 1
• see also Oligonucleotide Synthesis
M13K07 cloning in E. coli:
• amino-acid sequence signature (Myc epitope tag) = EQKLISEEDL
References:
References
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I maintain that, if everyone knew what others said about him, there would not be four friends in the world. Pascal, Blaise
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Blaise Pascal (June 19, 1623August 19, 1662) was a French mathematician, physicist, and religious philosopher. Pascal was a child prodigy, who was educated by his father. Pascal's earliest work was in the natural and applied sciences, where he made important contributions to the construction of mechanical calculators and the study of fluids, and clarified the concepts of pressure and vacuum by expanding the work of Evangelista Torricelli. Pascal also wrote powerfully in defense of the scientific method.
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Journalist: a person without any ideas but with an ability to express them; a writer whose skill is improved by a deadline: the more time he has, the worse he writes. Kraus, Karl
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Karl Kraus (April 28, 1874 - June 12, 1936) was an eminent Austrian writer and journalist, known as a satirist, essayist, aphorist, playwright, and poet. He is generally considered one of the foremost German-language satirists of the 20th century, especially known for his witty criticism of the press, German culture, and German politics.
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My method is to take the utmost trouble to find the right thing to say, and then to say it with the utmost levity. Shaw, George Bernard
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George Bernard Shaw (July 26, 1856 November 2, 1950) was an Irish playwright and winner of the Nobel Prize for Literature in 1925.
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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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Faith. Belief without evidence in what is told by one who speaks without knowledge, of things without parallel. Bierce, Ambrose
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Rules of the Senate of the Federal Republic of Central America
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Item Metadata
dc.contributor.author Sosa, Juan Francisco de
dc.coverage.spatial Central America (general region)
dc.date.accessioned 2011-01-05T00:02:16Z
dc.date.available 2011-01-05T00:02:16Z
dc.date.issued 1825
dc.identifier.uri http://hdl.handle.net/1911/36223
dc.description Folio. 9 pp.
dc.format Translations
dc.format.medium Leaflets
dc.language.iso eng
dc.publisher Rice University
dc.relation.ispartof Finding Aid available at http://library.rice.edu/collections/WRC/finding-aids/manuscripts/0518
dc.relation.isversionof Original document is available at http://hdl.handle.net/1911/27047
dc.rights This work is licensed under a Creative Commons attribution 2.5 License
dc.rights.uri http://creativecommons.org/licenses/by/2.5/
dc.subject.lcsh Central America (Federal Republic: 1823-1840). Congreso Federal. Senado--Powers and duties
Central America (Federal Republic: 1823-1840)--Officials and employees
dc.title Rules of the Senate of the Federal Republic of Central America
dc.type Text
dc.digitization.specifications Images were captured using the TTI Better Light Super 8K2 digital scan-back system. Master Tiff images were scanned at 24-bit color, adobeRGB1998 color profile, at 600 dpi for graphically intense images and 400 dpi for text. Textual materials are marked up in TEI/XML standard (P5 version).
dc.contributor.funder Funding for the creation of this digitized text is provided by a grant from the Institute of Museum and Library Services.
dc.date.digital 2008-04-11
dc.contributor.translator Gauthereau-Bryson, Lorena
dc.format.xmlschema tei-americas-p5
dc.date.original December 28, 1825
dc.subject.local Constitutionalism
Development
Historiography
dc.source.collection Americas collection, 1811-1920, MS 518, Box 2 folder 9 Item 14, Woodson Research Center, Fondren Library, Rice University. Contact info: woodson@rice.edu
dc.identifier.original wrc51802090014
dc.identifier.digital aa00234tr
dc.source.provenance The Humanities Research Center at Rice University, under the direction of Dr. Caroline Levander, purchased this material from a manuscripts dealer in 2005. The Gilder Foundation funded the development of the physical archive. Original materials are housed at the Woodson Research Center, Rice University.
dc.pubplace Guatemala
dc.description.translation This document is an English translation of the "Reglamento del Senado de la República federal de Centroamérica." Translated by Lorena Gauthereau-Bryson. The language of the original document is Spanish.
dc.identifier.citation Sosa, Juan Francisco de. Rules of the Senate of the Federal Republic of Central America. Translated by Gauthereau-Bryson, Lorena. Leaflets. Guatemala, 1825. From Woodson Research Center, Rice University, Americas collection, 1811-1920, MS 518. http://hdl.handle.net/1911/36223.
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Xapi
From OpenStreetMap Wiki
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The OSM Extended API (or xapi, pronounced zappy) is a read-only API protocol, based on a modified version of the OSM main API, that provides enhanced search and querying capabilities. It offers search queries for some common simple use cases and helps to put load off the main API. In particular, it reimplements the standard map request such that it can be performed much faster. Xapi uses a REST style interface with X-path flavouring. More sophisticated queries can be handled with other read-only mirrors such as Overpass API which support a more powerful but more complex syntax
Xapi only ever deals with elements that are current and does not return any elements that are historical or deleted. The source database is a mirror of the main OSM database and is updated via the per-minute diff dumps. The data is normally no more than about 10 minutes behind the main database.
All responses are in the same format as the standard protocol, but with the addition of some namespaced extensions. Tag queries use an X-path like syntax to specify search terms. The visible attribute is excluded from the response because it always has a true value.
Contents
Implementations
There are several code/database implementation of the XAPI idea and several running deployments. These are listed below. You can also see various base URL options on the XAPI URL Builder (source code) display.
jXAPI
In January 2011 Ian Dees created a new Java version of XAPI backed onto postGIS. See his diary entry for details. Several people are now running this on different servers:
Note that bbox queries have a maximum of 10 square degrees.
pnorman's blog post on jXAPI setup has some information on tuning postgresql for a large dataset and speeding up the initial load of data.
Overpass API
Overpass API now has a XAPI Compatibility Layer. (status: Running normally). It supports the more common XAPI queries, as well as its own, more extensible query language. Details are explained in the section XAPI Compatibility Layer.
Xappy.js
Xappy.js is a reimplementation of the OSM XAPI in node.js (Java Script). Currently using Postgres and the PostGIS extension with the option to implement other backends.
The original XAPI
The original XAPI was created using GT.M (formerly MUMPS) by User:80n. There were multiple instances of the xapi service running on several different servers. Each server could be accessed directly or via a redirect which was used to direct the request to a suitable server of its choosing.
All of the original XAPI servers have been decommissioned or are otherwise no longer running.
Query Map
The Map query is identical to the main API map query and returns:
• All nodes that are inside a given bounding box and any relations that reference them.
• All ways that reference at least one node that is inside a given bounding box, any relations that reference them [the ways], and any nodes outside the bounding box that the ways may reference.
GET /api/0.6/map?bbox=left,bottom,right,top
where:
• left is the longitude of the left (westernmost) side of the bounding box, or minlon.
• bottom is the latitude of the bottom (southernmost) side of the bounding box, or minlat.
• right is the longitude of the right (easternmost) side of the bounding box, or maxlon.
• top is the latitude of the top (northernmost) side of the bounding box, or maxlat.
Example
http://www.informationfreeway.org/api/0.6/map?bbox=11.54,48.14,11.543,48.145
Notes
• Unlike the main API which restricts queries to 0.25 square degrees, XAPI allows much larger requests, up to 10,000,000 elements (this is still less than a third of California) or 100 square degrees, whichever is smaller.
• The map query is functionally identical to the tag query /api/0.6/*[bbox=left,bottom,right,top]
• There must not be spaces in the string of values defining the box.
Query Tags
Xapi implements queries for all three kinds of elements; nodes, ways and relations.
Nodes
A node request will return an xml document containing nodes and their associated tags. The URL for a node request takes the following form:
http://www.informationfreeway.org/api/0.6/node[...]
This will return a standard OSM API response containing nodes and tags. For example:
<?xml version='1.0' standalone='no'?>
<osm version='0.6' generator='xapi: OSM Extended API'
xmlns:xapi='http://www.informationfreeway.org/xapi/0.6'
xapi:uri='/api/0.6/node[amenity=hospital]'
xapi:planetDate='200803150826'
xapi:copyright='2008 OpenStreetMap contributors'
xapi:instance='zappy2'>
<node id='672180' lat='48.2111685091189' lon='16.3035366605548' timestamp='2006-09-11T16:28:25+01:00' version='1' changeset='10968'>
<tag k='amenity' v='hospital'/>
<tag k='name' v='Wilhelminenspital'/>
</node>
<node id='3596186' lat='53.4633699598014' lon='-2.22667910006381' timestamp='2007-06-21T17:10:58+01:00' version='2' changeset='2213'>
<tag k='amenity' v='hospital'/>
<tag k='name' v='Manchester Royal Infirmary'/>
</node>
...
</osm>
Ways
The URL for way requests has the following form:
http://www.informationfreeway.org/api/0.6/way[...]
This returns an xml document containing ways that match the search terms. For each matching way the nodes referenced by that way are also returned. An example of the response from a way query looks like this:
<?xml version='1.0' standalone='no'?>
<osm version='0.6' generator='xapi: OSM Extended API'
xmlns:xapi='http://www.informationfreeway.org/xapi/0.6'
xapi:uri='/api/0.6/way[landuse=residential]'
xapi:planetDate='200803150826'
xapi:copyright='2008 OpenStreetMap contributors'
xapi:instance='zappy2'>
<node id='218963' lat='52.5611324692581' lon='-1.79024812573334' timestamp='2006-03-22T16:47:48+00:00' version='1' changeset='2211'>
</node>
<node id='331193' lat='53.7091237972264' lon='-1.50282510180841' timestamp='2007-03-31T00:09:22+01:00' version='1' changeset='2211'>
<tag k='highway' v='traffic_signals'/>
<tag k='source' v='Yahoo'/>
</node>
...
<way id='4958218' timestamp='2007-07-25T01:55:35+01:00' version='3' changeset='2211'>
<nd ref='218963'/>
<nd ref='331193'/>
...
<tag k='landuse' v='residential'/>
<tag k='source' v='landsat'/>
</way>
</osm>
Relations
The URL for relation requests has the following form:
http://www.informationfreeway.org/api/0.6/relation[...]
This returns an xml document containing relations that match the search terms. For each matching relation the nodes and ways referenced by that relation are also returned. An example of the response from a relation query looks like this:
<?xml version='1.0' standalone='no'?>
<osm version='0.6' generator='xapi: OSM Extended API'
xmlns:xapi='http://www.informationfreeway.org/xapi/0.6'
xapi:uri='/api/0.6/way[landuse=residential]'
xapi:planetDate='200803150826'
xapi:copyright='2008 OpenStreetMap contributors'
xapi:instance='zappy2'>
<node ...
<way ...
<relation id='2670' timestamp='2007-10-25T03:05:34Z' version='32' changeset='2211'>
<member type='way' ref='3992472' role=''/>
<member type='way' ref='3992524' role=''/>
<member type='way' ref='4253050' role=''/>
<member type='way' ref='4253053' role=''/>
<member type='way' ref='4266813' role=''/>
<member type='way' ref='10285106' role=''/>
<tag k='name' v='Fonnereau Way'/>
<tag k='network' v='Ipswich footpaths'/>
<tag k='type' v='route'/>
</relation>
</osm>
All Elements
All elements (nodes, ways and relations) that match the given filter predicates can be requested using the following URL:
http://www.informationfreeway.org/api/0.6/*[...]
This returns an xml document containing nodes, ways and relations that match the search terms. For each matching way the nodes and referenced by that way are also returned. Likewise, for each matching relation the ways and nodes referenced by that relation are also returned. An example of the response from this type of query looks like this:
<?xml version='1.0' standalone='no'?>
<osm version='0.6' generator='xapi: OSM Extended API'
xmlns:xapi='http://www.informationfreeway.org/xapi/0.6'
xapi:uri='/api/0.6/*[amenity=hotel]'
xapi:planetDate='200803150826'
xapi:copyright='2008 OpenStreetMap contributors'
xapi:instance='zappy2'>
<node id='218963' lat='52.5611324692581' lon='-1.79024812573334' timestamp='2006-03-22T16:47:48+00:00' version='1' changeset='2211'>
</node>
<node id='331193' lat='53.7091237972264' lon='-1.50282510180841' timestamp='2007-03-31T00:09:22+01:00' version='1' changeset='2211'>
<tag k='amenity' v='hotel'/>
</node>
...
<way id='4958218' timestamp='2007-07-25T01:55:35+01:00' version='1' changeset='2211'>
<nd ref='218963'/>
<nd ref='331193'/>
...
<tag k='amenity' v='hotel'/>
<tag k='building' v='hotel'/>
</way>
<relation id='123456' timestamp='2007-10-25T03:05:34Z' version='32' changeset='2211'>
<member type='node' ref='331193' role=''/>
<member type='node' ref='331194' role=''/>
...
<tag k='amenity' v='hotel'/>
<tag k='operator' v='Premier Inns'/>
<tag k='type' v='operators'/>
</relation>
</osm>
Predicates
Each API request can be suffixed with selection predicates which determine which elements to select. For example [amenity=hospital] will select all elements that have an amenity tag with a value of hospital. The full url to select all nodes that are tagged as hospitals would be:
http://www.informationfreeway.org/api/0.6/node[amenity=hospital]
A request can be suffixed with multiple predicates, each of which further constrains the results (currently limited to one tag predicate and one bbox predicate, though jXAPI and Overpass servers support multiple tag predicates). For example:
http://www.informationfreeway.org/api/0.6/node[amenity=hospital][bbox=-6,50,2,61]
this request will select and return all nodes with a tag of amenity=hospital within the bounding box that covers the whole of the England, Wales and Scotland.
Tag Predicates
A selection predicate must be of the form [key=value]. For example: node[amenity=hospital] will match any node that has an amenity key with a value of hospital, ie
<tag k="amenity" v="hospital"/>
.
A union operator may be used to select multiple values. For example to select all major roads:
• way[highway=motorway|motorway_link|trunk|primary]
The union operator can also be used with the key. For example to select golf courses:
• node[amenity|leisure=golf_course]
A wildcard can be used for the value (but not for the key), so predicates similar to the following examples are possible:
• way[construction=*]
• way[highway=*]
Key wildcards were supported in the past, but this is no longer maintained.
Note: The URL needs to be UTF-8 url encoded in case of non-ascii characters.
BBox Predicates
Another form of selection predicate is the bbox pseudo key. A selection predicate of the form [bbox=left,bottom,right,top] defines a bounding box that is used to limit the extent of the result document. Only elements that have some part within the bbox will be included in the result document.
Unlike the standard OSM API, the bbox predicate is not limited in size unless it is used without a tag predicate, in which case it is limited to 100 square degrees.
The default extent, if a bbox predicate is not specified, is the whole planet. This is equivalent to specifying [bbox=-180,-90,180,90].
Child Element Predicates
Items can be selected based on whether or not they have child elements. For example, ways can be selected that do not have any tags or do not have any nodes. This is achieved by using an XPath-like element test. Specifically the following are implemented:
• /api/0.6/way[nd] - selects ways that have at least one node
• /api/0.6/way[tag] - selects ways that have at least one tag
• /api/0.6/way[not(nd)] - only selects ways that do not have any nodes
• /api/0.6/way[not(tag)] - only selects ways that do not have any tags
• /api/0.6/node[way] - selects nodes that belong to at least one way
• /api/0.6/node[not(way)] - selects nodes that do not belong to any way
• /api/0.6/node[not(tag)] - selects nodes that do not have any tags
• /api/0.6/relation[node] - selects relations that have at least one node member
• /api/0.6/relation[way] - selects relations that have at least one way member
• /api/0.6/relation[relation] - selects relations that have at least one relation member
• /api/0.6/relation[not(node)] - selects relations that do not have any node members
• /api/0.6/relation[not(way)] - selects relations that do not have any way members
• /api/0.6/relation[not(relation)] - selects relations that do not have any relation members
Notes:
1. If using wget then parenthesis characters need to be escaped, so for negation predicates, use [not\(way\)] rather than [not(way)].
2. In the OSM xml schema nodes do not really have ways as child elements. However, there is, logically, a many-to-many relationship between nodes and ways, and so xapi implements this relationship and enables nodes to be selected based on whether or not they are members of a way. Of course, the output xml is the same as normal and does not include way elements within a node element.
Escaping
Values within predicates can be escaped by prefixing a backslash character. For example to retrieve elements with a tag value that contains a pipe character such as [route=46|46A] you would need to use [route=46\|46A].
The following characters can be escaped in this way: | [ ] * / = ( ) \ and space
Spaces in tag values do not normally need to be escaped but this is dependent on the client. In this case you need to use URL escaping which requires that each space be replaced by %20. So [route=46 46A] would become [route=46%2046A].
Tags
The main method of querying Xapi is using a tag/value combination in a predicate. In addition to all the normal tags that you expect to find, the following attributes can also be queried using /api/0.6/*[@attribute=value]
• @user - the username of the last person to change an element
• @uid - the user id of the last person to change an element
• @changeset - the changeset in which an element was changed
Usage
Xapi URLs can be used from within any web-browser, however a simple query can return several Mb of data which can overwhelm some browsers. It is recommended that a tool such as wget or curl be used with the output directed to a file. For example, the following command uses wget to select all hospitals and store the result document in a file named data.osm. Note that wget has a default timeout of 15 minutes which may be too short for some queries so be sure to add the --timeout=0 option to turn this off.
wget --timeout=0 http://www.informationfreeway.org/api/0.6/node[amenity=hospital] -O data.osm
Note: If you use curl, it will handle redirections automatically, so you need to query the host server directly or use the "--location" option. Also you need to use the "--globoff" option, otherwise it will try to interpret the brackets ("[", "]") as part of the command line:
curl --location --globoff "http://www.informationfreeway.org/api/0.6/node[amenity=hospital]" -o data.osm
If you use a script regularly to fetch data from Xapi it would be helpful to set the user agent string to something meaningful. This will help us understand more about how Xapi is being used.
Limitations
• Predicates. Currently each request is limited to one tag predicate and one bbox predicate. In the future it is hoped that more sophisticated conditions will be implemented. Multiple bboxes would be great for applications like GpsMid - they already implemented data retrieval over xapi in Osm2GpsMid for single regions which is very helpful.
• Request grammar. The request grammar is not formally defined and is not processed using a proper parser, so malformed requests may have unpredictable results. Caveat Emptor.
Proposed Future Extensions
• "Search by region": the ability to limit queries not by a bounding box, but by recognized regions (e.g. Countries, Counties, continents). Proposed Jan 2011.
• json output: We have this feature in xappy.js it might be used by setting the http content-type header to "application/json". Here some format infos: Xappy.js#JSON output
Implementation-specific differences
Some xapi implementations differ from the specification set out in this page.
Jxapi
Relations
pgsnapshot and jxapi relation support for relations by area is quirky. These quirks can result in a response that does disagrees with the documented Xapi API and are not backwards-compatible. Todo: list quirks.
Request Metadata
jxapi uses the format used by osmosis state.txt for xapi:planetDate, not the documented xapi format.
Bounds =
jxapi returns a bounds element, like the main API. This could cause issues with any programs expecting xapi output exactly as documented but any programs capable of parsing the normal API output should have no issues.
API element queries
jxapi supports the GET /api/0.6/[node|way|relation]/#id and GET /api/0.6/[nodes|ways|relations]?#parameters queries of [API v0.6]. It is not clear if this is part of the Xapi specification but if not the addition is backwards compatible.
Metadata queries
The standard instructions for setting up jxapi do not include the indexes required to optimize the @user, @uid and @changeset queries. They will run but may run very slowly if not restricted to a small region.
Overpass
Request Metadata
The request metadata returned from overpass differs from the xapi metadata. Todo: list how it differs
Metadata
Overpass does not return the metadata (version number and changeset) by default. An xapi request against the overpass xapi compatibility layer will not result in a .osm file that can be used for editing. See @meta below.
@meta
As a work-around to the above, [@meta] can be added to a request to have the metadata returned and an editable file.
Alternatives
See also
Personal tools
Namespaces
Variants
Actions
site
Toolbox
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Australian Bureau of Statistics
Celebrating the International Year of Statistics 2013
ABS Home > Statistics > By Release Date
1002.0 - Australian Statistics Advisory Council - Annual Report, 1998-99
Previous ISSUE Released at 11:30 AM (CANBERRA TIME) 30/08/1999
Page tools: Print Page Print All RSS Search this Product
• About this Release
ABOUT THIS RELEASE
Outlines the functions and activities of the Australian Statistics Advisory Council.
© 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
Statistics by Release Date
May, 1952
31/05/1952 Western Australian Year Book, 1948-1949 (cat no. 1300.5)
© 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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Research article
Tbx3 represses PTEN and is over-expressed in head and neck squamous cell carcinoma
Durmus Burgucu1, Kenan Guney2, Duygu Sahinturk3, Irem H Ozbudak4, Deniz Ozel5, Gulay Ozbilim4 and Ugur Yavuzer1*
Author Affiliations
1 Department of Physiology, School of Medicine, Akdeniz University, Antalya, 07058, Turkey
2 Department of Ear-Nose and Throat Head and Neck Surgery, School of Medicine, Akdeniz University, Antalya, 07058, Turkey
3 Life Sciences Research and Application Centre, Akdeniz University, Antalya, 07058, Turkey
4 Department of Pathology, School of Medicine, Akdeniz University, Antalya, 07058, Turkey
5 Department of Biostatistics and Medical Informatics, School of Medicine, Akdeniz University, Antalya, 07058, Turkey
For all author emails, please log on.
BMC Cancer 2012, 12:481 doi:10.1186/1471-2407-12-481
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2407/12/481
Received:28 June 2012
Accepted:17 October 2012
Published:19 October 2012
© 2012 Burgucu 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
Despite advances in diagnostic and treatment strategies, head and neck squamous cell cancer (HNSCC) constitutes one of the worst cancer types in terms of prognosis. PTEN is one of the tumour suppressors whose expression and/or activity have been found to be reduced in HNSCC, with rather low rates of mutations within the PTEN gene (6-8%). We reasoned that low expression levels of PTEN might be due to a transcriptional repression governed by an oncogene. Tbx2 and Tbx3, both of which are transcriptional repressors, have been found to be amplified or over-expressed in various cancer types. Thus, we hypothesize that Tbx3 may be over expressed in HNSCC and may repress PTEN, thus leading to cancer formation and/or progression.
Methods
Using immunohistochemistry and quantitative PCR (qPCR), protein and mRNA levels of PTEN and Tbx3 were identified in samples excised from cancerous and adjacent normal tissues from 33 patients who were diagnosed with HNSCC. In addition, HeLa and HEK cell lines were transfected with a Tbx3 expressing plasmid and endogenous PTEN mRNA and protein levels were determined via qPCR and flow cytometry. Transcription assays were performed to demonstrate effects of Tbx3 on PTEN promoter activity. Mann–Whitney, Spearman’s Correlation and Wilcoxon signed-rank tests were used to analyze the data.
Results
We demonstrate that in HNSCC samples, Tbx3 mRNA levels are increased with respect to their normal tissue counterparts (p<0.001), whereas PTEN mRNA levels are significantly reduced in cancer tissues. Moreover, Tbx3 protein is also increased in HNSCC tissue sections. Over-expression of Tbx3 in HeLa and HEK cell lines causes reduction in endogenous PTEN mRNA and protein levels. In addition, transcription activity assays reveal that Tbx3 is capable of repressing both the basal and induced promoter activity of PTEN.
Conclusions
We show that Tbx3 is up-regulated in tissue samples of HNSCC patients and that Tbx3 represses PTEN transcription. Thus, our data not only reveals a new mechanism that may be important in cancer formation, but also suggests that Tbx3 can be used as a potential biomarker in cancer.
Keywords:
Tbx3; PTEN; Cancer; Squamous cell carcinoma
Background
The T-box is a conserved DNA-binding and dimerization motif, which was first identified in the mouse protein Brachyury [1] and the genes encoding T-box containing proteins are collectively known as the T-box (TBX) family of genes. Tbx transcription factors family plays important roles in cell proliferation, fate and identity during development [2,3]. Based on their sequence similarities, five subfamilies have been identified in mouse and the Tbx2 subfamily is comprised of Tbx2, Tbx3, Tbx4 and Tbx5[4]. Through their T-box domains, each T-box factor binds to the “T-half-site” found in the promoters of the target genes and regulates gene expression by either activating or repressing transcription. Amongst the Tbx family of proteins, Tbx3 and Tbx2 are known to function generally as transcriptional repressors, although Tbx3 has also been shown to have an activation domain [5-7]. In humans, TBX3 mutations cause ulnar-mammary syndrome (UMS) which is characterized by mammary gland hypoplasia, abnormal limb development and various abnormalities of the heart and genitalia [8]. In addition to its key role in development, TBX3 expression has also been found to be amplified or over-expressed in many different cancer types including breast, cervix, ovary, pancreas, liver cancers and melanomas [9-14]. Research towards identifying the molecular mechanisms of Tbx3 in cancer formation revealed that Tbx3 interacts with proteins of several oncogenic pathways. In liver tumorigenesis for example, Tbx3 lies downstream of the Wnt-β-catenin pathway and is a regulator of β-catenin [12]. Tbx3 also represses E-cadherin which has been implicated in metastasis of epithelial tumours [13]. In breast cancer, FGF signalling regulates Tbx3 [15] and Tbx3 cooperates with c-Myc and Ras associated transformation [16,17]. Another well-defined pathway that Tbx3 takes part is the p14/19ARF-Mdm2-p53 pathway. Tbx3 represses the expression of the human tumour suppressor gene p14ARF and the murine homolog p19ARF[17-19]. In addition, Tbx3 directly represses the p21Cip1/WAF1 promoter [20]. The p14/19ARF-Mdm2-p53 pathway plays an important role in regulating cell senescence and protects the cells against oncogenic transformation. Repression of p14/19ARF or p21Cip1/WAF1 by Tbx3 seems to block this protective pathway and bypass cellular senescence via p53 dependent or independent ways, thus leading to uncontrolled cell proliferation. In the light of the available evidence, it seems that Tbx3 uses multiple pathways and mechanisms in driving tumorigenesis.
Head and Neck cancers originate on the mucosal surfaces of oral cavity, pharynx and larynx. Because 90% of these malignancies exhibit squamous cell characteristics, the head and neck cancers are commonly called “Head and Neck Squamous Cell Carcinomas” (HNSCC). Worldwide, HNSCC is the sixth most common cancer type, with extremely poor clinical outcomes [21,22]. Research during the last decade revealed some of the molecular mechanisms underlying the pathogenesis of HNSCC. Inactivation of many tumour suppressor gene products such as p53, p16INK4a, E-cadherin and PTEN [23-27] or activation of proto-oncogenes such as Cyclin D, EGFR and p63 [28-30] have been found to be implicated in HNSCC occurrence.
The gene phosphatase and TENsin Homolog (PTEN) encodes a tumour suppressor which is mostly inactivated in many cancers. PTEN is the main negative regulator of the phosohatidylinositol-3-Kinase (PI3K) signalling pathway. PI3 kinases that are activated by either receptor tyrosine kinases (RTK) or G-protein coupled receptors (GPCR), catalyze conversion of phosohatidylinositol 4,5 phosphate (PIP2) to phosohatidylinositol 3,4,5 phosphate (PIP3), thereby activate AKT kinase and subsequent downstream components [31]. PTEN is a lipid and protein phosphatase and inhibits PI3K mediated signals involved in cellular growth, proliferation and survival by dephosphorylating PIP3 at the plasma membrane [32]. Although PTEN was found to be down-regulated in many different cancer types, this is not necessarily due to somatic mutations of the PTEN gene. Indeed, in a group of HNSCC tumour samples, it was demonstrated that down-regulation of PTEN was not due to its allelic loss or point mutations within the gene [26,27], indicating that the reduced expression of PTEN might be as a consequence of either transcriptional or post-transcriptional regulations.
The role of Tbx3 in regulation of pathways involved in cell proliferation, especially tumour suppressors such as E-cadherin and p53, which have also been found to be inactivated in HNSCC, prompted us to analyze the Tbx3 status in this particular type of cancer. To this end, in a period of 2 years, tissue samples were collected from patients undergoing operation with the diagnosis of HNSCC. During operations, samples were excised from both the seemingly cancerous areas and also from the normal-looking tissue surrounding the lesion site. Both kind of tissues (cancer and normal) were examined pathologically and then analyzed for expression of Tbx3 mRNA and protein levels. In addition, PTEN mRNA was also measured as it has been shown to be down-regulated in most of the samples of HNSCC. In this paper we report that in HNSCC samples both the mRNA and protein levels of Tbx3 are increased with respect to their normal tissue counterparts, whereas PTEN mRNA levels are decreased in cancer tissues as it has been reported before [33]. We also demonstrate that in two different cell lines, over expression of Tbx3 causes reduction in endogenous PTEN mRNA and protein levels. In addition, using transcription activity assays we show that Tbx3 is capable of repressing both the basal and induced promoter activity of PTEN.
Methods
Tissue samples
In a two-year period, surgical resection specimens from 33 patients who underwent partial or total laryngectomy for HNSCC in the Ear-Nose and Throat Head and Neck Surgery Department of Akdeniz University, School of Medicine, were collected. In compliance with the principles of the Declaration of Helsinki, the study was approved by the Ethical Committee of the University (No: 04.12.09/011398) and written informed consents were obtained from patients who accepted to participate in the study. During operation, samples were collected from both the cancerous area and the adjacent normal tissues. Before sending the tissues for pathological examination, about 10 mg from each of the tissue (cancer and normal) was spared and immediately placed in RNAlater TissueProtect Tubes (Qiagen GmbH, Cat No: 76163) to prevent degradation of RNA. The specimens were examined by the Pathology Department of the same University. Following routine paraffin embedding, sections in 5μm thicknesses were prepared and stained with haematoxylin/eosin (H&E) for histopathological evaluation. Pathological features of the patients were examined according to the American Joint Committee on Cancer (AJCC) [34]. Upon confirmation of tissues as cancerous and normal, the samples that were spared for RNA analyses were sent to the Physiology Department and stored at -80°C till usage.
RNA analysis
Frozen tissues were disrupted and homogenized by MagNa Lyser Instrument (Roche, GmbH) and total RNA was isolated by using RNeasy Mini Kit (Qiagen GmbH, Cat No: 74124) according to the manufacturer’s instructions. RNA (1μg) was then reverse transcribed using the Transcriptor High Fidelity cDNA synthesis kit according to the manufacturer’s instructions (Roche GmbH, Cat No: 508195500). For real-time PCR, LightCycler 1.5 Instrument was used. The primer pairs for amplification of Tbx3 [GenBank:NM_005996.3], PTEN [GenBank: NM_000314.4] and human β-actin [GenBank:NM_001101.3] were designed using the Universal Probe Library (UPL) Assay Design Center ( http://www.roche-applied-science.com webcite). The human β-actin gene was used as an internal standard to correct sample-to-sample variations within a PCR run. Hydrolysis (TaqMan) probes; Probe 47 (Roche GmbH, Cat no: 04688074001), Probe 48 (Roche GmbH, Cat no: 04688082001) and Probe 64 (Roche GmbH, Cat no: 04688635001) from the UPL were used for detection and quantification of Tbx3, PTEN and human β-actin mRNAs. The cDNA from each gene was amplified by PCR using the appropriate primer sets and probes with the TaqMan Master Mix (Roche GmbH, Cat No: 04735536001) according to the manufacturer’s instructions. The data was analyzed using the analysis module for absolute quantification of LightCycler Software 4.1.
Construction of the PTEN promoter reporter plasmids
The PTEN promoter region [GenBank No: AF067844.1] between positions −1895 to + 400 (Extended promoter – EP-PTEN) was amplified from genomic DNA by PCR using the primers (F1) 5′-agacagatctGTGGGGTGCGGGGTAGGAGT and (R1) 5′-agacaagcttGACGAAGAGGAGGCGAGA. For the amplification of the core promoter region (CP-PTEN) lying between −1477 and −710, the primer pair (F2) 5′-agacagatctGGCTTGCTCTTAGGGTAG and (R2).
5′-gcgtaagcttCGTGAACACATAGCCGT was used. The deletion mutant (Δmut CP-PTEN) between positions −1345 and −710 was amplified from genomic DNA via PCR using the F3 (5′- agacagatctCCAGTTCCCCAAGCGCCAG) and R2 primer pair. The sequences in lowercase are present to facilitate cloning by placing Bgl II and Hind III restriction enzyme recognition sequences (depicted in bold and underlined). The EP-PTEN (2295 bp), the CP-PTEN (767 bp) and the Δmut CP-PTEN (635 bp) PCR products were digested by Bgl II/ HindIII and cloned into a pGL3.1-Basic plasmid (Promega), which was linearized using the same restriction endonucleases. All constructs were verified by DNA sequencing. The Tbx3 and USF expression plasmids were kindly provided by Prof. Colin R. Goding (Ludwig Institute for Cancer Research, Oxford, UK).
Cell culture and transcriptional activity assays
The HeLa and HEK cell lines were used for transcriptional activity assays as these cell lines are well known for being easy to grow and readily transfectable. In addition both cell lines express PTEN and do not contain genetic mutations of p53. The cell lines were maintained at 370C with 5% CO2 in Dulbecco’s Modified Eagle Medium (DMEM) supplemented with 10% fetal calf serum (FCS) and 1% penicillin/streptomycin. Cells were plated on 96-well dishes and co-transfected with 0.5μg/well PTEN pGL3.1 reporter plasmids and Tbx3 and/or USF expression plasmids (0.2 to1.0 μg/well) using FuGene HD (Roche, Cat no: 04709691001) according to the manufacturer’s instructions. After 48 hours, cells were harvested and lysed by using the One-Glo Luciferase Assay System (Promega, Cat no:E6110). The lysates were then analyzed on a luminometer (Luminoskan Ascent, ThermoScientific). The experiments were repeated at least five times before establishing the final data. For each construct, values from 5 different experiments were obtained; average values were calculated and the data was presented as “% Promoter Activity” relative to the promoter activity of CP-PTEN (100%). Flow cytometry and western blots were performed in parallel to confirm the basal and over-expressed Tbx3 protein levels for each experiment and one representative western blot was shown in the relevant figures. To measure the endogenous PTEN mRNA levels, HeLa and HEK cell lines were transfected with a Tbx3 expressing plasmid in different concentrations and cells were harvested 48 hours following transfection. From transfected and untransfected cell lines, RNA was isolated and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed as described above. For endogenous PTEN protein determination, both of the cell lines were seeded onto 6-well dishes and transfected with Tbx3 expressing plasmid as described before. Forty-eight hours following transfection, cells were harvested and flow cytometry was performed as mentioned below.
Immunohistochemistry and immunoblots
Parafin embedded, 5μm thick tissue sections were stained for Tbx3 protein using a monoclonal anti-Tbx3 antibody (ABCAM, Cat no: ab89220). The sections were analysed using standard avidin-biotin immunohistochemical methods according to the manufacturer’s instructions (Vector Laboratories, Burlingane, California). An anti IgG-antibody was used as control.
For immunoblots; transfected and untransfected cells were harvested and lysed in lysis buffer (150 mM NaCl, 50 mM Tris pH 8.0, 1.0 % NP40) and the protein content was determined by Bradford method. Equal amounts of protein was loaded onto 10% SDS-PAGE and separated by electrophoresis (80V, 2hr). This was followed by blotting onto nitrocellulose membranes. Immunoblotting was performed using anti-Tbx3 antibody at a dilution of 1:100. Immunoreactive bands were revealed by an ECL kit (Amersham) according to the manufacturer’s instructions.
Flow cytometry
Transfected and untransfected cell lines were harvested and washed twice with phosphate buffered saline (PBS). BD Biosciences Cytofix/CytopermTM Kit (Cat no: 554714) was used for fixation and permeabilization of cells according to manufacturer’s instructions. Cells were incubated for 30 min. at room temperature with anti-Tbx3 (ABCAM, Cat no: ab89220) and anti-PTEN (BD™ Phosflow 560002, labelled with PE-A) antibodies simultaneously, which were diluted in BD Biosciences Perm/Wash Buffer in 1:50 and 1:10 ratios, respectively. Following the washing steps, cells were incubated with a secondary antibody (DyLight 488, ABCAM, Cat no: ab96879) at a dilution of 1:2000 to enable detection of Tbx3. Analyses were performed on a BD FACS Canto II and protein expression of both Tbx3 and PTEN were measured in a total of 10,000 cells.
Statistical analysis
The Statistical Package for the Social Sciences (SPSS) 18.0 software was used. Comparison of the mRNA levels between the tumour and normal tissues were performed using the Wilcoxon signed-rank test. Spearman’s Correlation test was used for evaluation of PTEN mRNA levels in response to over-expressed Tbx3. Mann–Whitney test was employed for interpretation of the in vitro transcriptional activity assays. Data are means of ±SDs of five independent experiments and p<0.05 was considered statistically significant.
Results
Tbx3 mRNA and protein expression is increased in HNSCC
A total of 33 patients (32 males and 1 female), with a median age of 53 years, were analyzed. The majority of patients (85%) had HNSCC originated from larynx (n=28), 6% from tongue (n=2) and in 3 patients from oropharynx, submandibular gland or tonsils (3% each). The clinical stage was IV in 73% of patients, whereas 27% of patients were at stage III. In the sample group only one patient was at stage II. The mRNA expression of Tbx3 was found to be significantly increased in cancer samples (min-max: 22–7100, median: 242) with respect to the normal tissue (min-max: 12–1460, median: 5.38) obtained from the same individuals (p<0.001) (Figure 1A). Although generally PTEN mRNA expression was rather low in tissues, still there was a statistically significant reduction in expression in cancer tissues (min-max: 0–5.62, median: 0.0085) when compared to the normal tissue (min-max: 0–13.10, median: 0.5, p<0.001) (Figure 1B). Neither the clinical stage nor the origin of cancer exhibited a statistically significant difference in Tbx3 mRNA levels. In order to determine whether the increase in Tbx3 mRNA level correlates with protein level in HNSCC tissue samples, paraffin embedded cancer and normal tissue sections were stained with anti-Tbx3 antibody. As seen in Figure 1C, tumour sections (c) exhibited significantly stronger cytoplasmic and nuclear Tbx3 staining with respect to the normal tissues (d). We were not able to detect PTEN protein in HNSCC tissue samples, possibly due to low levels of PTEN mRNA in these tissues. As a consequence western blotting was not sensitive enough to detect such small amounts of protein. Nevertheless, these results demonstrated for the first time that both mRNA and protein levels of Tbx3 are increased in HNSCC tissue samples.
Figure 1. Tbx3 mRNA and protein levels are increased in HNSCC tissues. Tissues from cancerous and adjacent normal areas were excised from patients who were diagnosed with HNSCC. RNA was isolated and mRNA levels of Tbx3 (A) and PTEN (B) were quantified using TaqMan probes. Results were normalized to β-Actin mRNA levels. The sign “*”denotes for statistically significant increase and decrease with respect to the normal tissue mRNA levels (p<0.001). (C) Laryngeal squamous cell carcinoma tissue sections stained with haemotoxcylin/eosin (HE) (a) and anti-IgG antibody (b) as an isotypic control. Squamous cell carcinoma sections (c) exhibited stronger cytoplasmic and nuclear staining with anti-Tbx3 antibody with respect to the normal epithelium (d) (magnification 100x).
Endogenous PTEN mRNA and protein levels are reduced in response to Tbx3 expression
The inverse correlation of Tbx3 and PTEN mRNA levels in HNSCC samples prompted us to analyze whether Tbx3 would cause a reduction in endogenous PTEN mRNA levels. To this end, HeLa and HEK cell lines were used as both of these cell lines are known to express PTEN and relatively low levels of Tbx3. The cell lines were transfected with a plasmid carrying a cDNA that expresses Tbx3. Three different plasmid DNA concentrations (as measured by a spectrophotometer) were used in transfections (0.2, 0.5 and 1 μg). Forty-eight hours following transfection, RNA was isolated from the transfected and untransfected cells and PTEN mRNA levels were quantified using TaqMan probes. As seen in Figure 2A, transfection of a Tbx3 expressing plasmid in increasing amounts caused a gradual decrease in PTEN mRNA levels in both of the cell lines. Spearman’s Correlation test revealed a significant negative correlation between the amounts of transfected Tbx3 expression plasmid and PTEN mRNA levels (r = −0,858 and p<0.05). In order to verify that transfection of a Tbx3 expressing plasmid causes over expression of Tbx3 protein in the cells, flow cytometry was employed. In addition, using a differentially labelled (PE-A) anti-PTEN antibody, PTEN protein levels were analysed in the same cell lines to determine whether over-expressed Tbx3 protein affects the PTEN protein level. In untransfected cells endogenous Tbx3 and PTEN levels were rather low (Figure 2B, panels a and c). Transfection of 1 μg of Tbx3 expressing plasmid caused an increase in Tbx3 protein levels (b) with respect to untransfected cells (a), demonstrating that Tbx3 protein was over-expressed in transfected cell lines (Figure 2B, panels a and b). Interestingly, cells transfected with a Tbx3 expressing plasmid displayed a reduction in PTEN protein levels with respect to the untransfected cells (Figure 2B, panels d and c, respectively). Thus, these results indicate that transfection of a Tbx3 expressing plasmid causes over expression of Tbx3 protein within the cells and the over-expressed Tbx3 protein results in reduction of both endogenous mRNA and protein levels of PTEN.
Figure 2. Tbx3 represses endogenous PTEN mRNA levels. (A) Different amounts of plasmid DNA (0.2, 0.5 and 1.0 μg) that expresses Tbx3 was transfected into HeLa and HEK cell lines. RNA from untransfected and transfected cell lines was isolated and PTEN mRNA levels were determined using TaqMan probes. Results were normalized to β-Actin mRNA levels. Spearman’s Correlation test revealed a significant decrease in PTEN mRNA levels with increasing amounts of Tbx3 expressing plasmid (r= −0.858 and p<0.05). (B) Cells transfected with 1μg of Tbx3 expressing plasmid and untransfected cells were analysed by flow cytometry using differentially labelled antibodies against Tbx3 (Labelled with DyLight 488) and PTEN (labelled with PE-A) for determination of Tbx3 and PTEN protein levels. Left panels (untransfected cells, a and c) display the endogenous Tbx3 and PTEN protein levels, which are shown in P6 and P3, respectively. Upon transfection, Tbx3 protein is increased (b) within the cells. In cells, where Tbx3 is over expressed, PTEN protein is decreased (d) with respect to that seen in untransfected cells (c).
Tbx3 Represses PTEN promoter activity
The schematic diagram of the PTEN promoter region is given in Figure 3A. The analysis of the PTEN promoter [GenBank: AF067844.1] revealed that PTEN has a TATA-less and GC-rich promoter. The start codon (ATG) is preceded by a 1030 bp long leader sequence within the first exon. The core promoter of PTEN lies between positions −1344 to −745 with respect to the beginning of the first exon (0) [35]. This region contains binding sites for transcription factors USF, Sp1 and EGR1 and has been shown to govern maximum promoter activity [36-38]. The minimal promoter is also localized within this region between positions −958 to −821. In order to assess the role of Tbx3 in regulation of PTEN transcription, the PTEN promoter region between positions −1895 to +400 (EP-PTEN) and also a smaller region between −1477 and −710, encompassing the core promoter, were cloned into a luciferase reporter plasmid (CP-PTEN) (Figure 3B). Thus, the CP-PTEN encompassing the core promoter region extends about 100 bp upstream and 35 bp downstream from the core promoter of PTEN. Both of the PTEN promoter reporter plasmids were then transfected into the HeLa and HEK cell lines either on their own or together with a plasmid expressing Tbx3 (Figure 4A). In order to confirm over-expression of Tbx3, western blotting and flow cytometry were performed in parallel. As shown in Figure 4A, the promoter activity of CP-PTEN was 2-fold stronger than the EP-PTEN [35,39] and co-transfection of a Tbx3-expressing plasmid resulted in a 4-fold and a 2- fold reduction in the EP-PTEN and CP-PTEN promoter activities, respectively. Importantly, transfection of a Tbx3 expressing plasmid in increasing amounts, which causes over-expression of Tbx3 within the cells, resulted in progressive decrease in the PTEN promoter activity (Figure 4B). In both HeLa and HEK cell lines, a statistically significant decrease in the basal promoter activity of CP-PTEN was observed when 0.5 or 1 μg of Tbx3 expressing plasmid was transfected (p<0.05). However, especially in HeLa cells the CP-PTEN promoter did not exhibit a linear repression with increasing amounts of transfected DNA. In correlation with this, western blots did not demonstrate a linear accumulation of Tbx3 protein either. This could be due to inefficient translation process. In other words, probably every single transfected DNA molecule was not successfully translated into protein. Nevertheless, these results demonstrate that over-expression of Tbx3 within the cells results in repression of PTEN promoter activity.
Figure 3. Schematic diagram of PTEN promoter. (A) Core promoter of PTEN localized between −1345 to −745 is shown. The beginning of exon 1 is designated as (0) and the start codon “ATG” within the first exon is indicated. A 1030 bp long leader sequence (LS) is found between the beginning of the first exon and the ATG site. The gray area between −958 and −821 is the minimal promoter of PTEN. Binding sites for the main transcription factors within the core promoter region are shown. (B) The EP-PTEN, CP-PTEN and Δ mut. CP-PTEN promoter constructs used in this study are shown. All promoter regions were cloned into the luciferase expressing plasmid pGL3 (Luc).
Figure 4. Tbx3 represses PTEN promoter activity. (A) EP-PTEN and CP-PTEN reporter plasmids were transfected into HeLa and HEK cell lines with (1μg) or without Tbx3 expressing plasmid. Using a luminometer, promoter activities of both plasmids were measured by means of luciferase activity. pGL3 control and pGL3 Basic plasmids were transfected into both of the cell lines as positive and negative controls, respectively. In both of the cell lines, expression of Tbx3 caused 3- to 4-fold reduction in the promoter activities of EP-PTEN and CP-PTEN reporter plasmids. Over expression of Tbx3 protein upon transfections was confirmed by western blots (WB) using an antibody against Tbx3 protein. (B) CP-PTEN reporter plasmid was transfected into both HeLa and HEK cell lines together with increasing amounts of a Tbx3 expressing plasmid. Promoter activity of CP-PTEN was then measured via luciferase assays using a luminometer. The sign “*”denotes for statistically significant decrease (p<0.05) in the PTEN promoter activity with respect to the basal activity of CP-PTEN as measured in the absence of Tbx3 expressing plasmid (100%). Expression of Tbx3 has been demonstrated by western blots (WB) using an anti-Tbx3 antibody.
The positive acting transcription factor USF has been demonstrated to bind to a region within the core promoter of PTEN and induce the transcriptional activity of PTEN promoter [36]. In order to determine whether Tbx3 would have an effect on induced PTEN promoter activity, a USF expressing plasmid was transfected into HeLa and HEK cell lines. As expected, over-expression of USF caused 1.5-fold increase in the promoter activity of CP-PTEN (Figure 5). USF also increased the EP-PTEN promoter activity (data not shown). However, as shown in Figure 5, when Tbx3 was over-expressed alongside USF, it was still capable of repressing the induced transcriptional activity by 2.5- and 3-fold in HeLa and HEK cell lines, respectively (p<0.05). Thus, this data demonstrate that Tbx3 represses both the basal and induced PTEN promoter activity and that this repression is specific as similar patterns of repression was observed in two different cell lines.
Figure 5. Tbx3 represses induced PTEN promoter activity. HeLa and HEK cell lines were transfected with the CP-PTEN reporter plasmid. Luciferase activity of CP-PTEN was measured in response to over expressed USF with or without Tbx3. USF is capable of inducing the transcriptional activity of CP-PTEN by 1.5-fold and Tbx3 is capable of repressing the induced transcription activity by 3-fold (p<0.05). pGL3 control and pGL3 Basic plasmids were transfected into both of the cell lines as positive and negative controls, respectively. The sign “*” denotes for statistically significant difference in PTEN promoter activity with respect to the basal activity (100%).
Tbx3 represses PTEN through a 132 bp DNA region within the PTEN promoter
Since both the EP-PTEN (−1895/+400) and CP-PTEN (−1477/-710) were repressed by Tbx3, we reasoned that the DNA region that is responsive to Tbx3 must be downstream of position −1477. In order to narrow down the Tbx3-responsive DNA region, we generated a third plasmid construct spanning between positions −1345 to −710 (Δ mut-CP-PTEN), in which 132 bp were deleted downstream of position −1477 (Figure 3A). This was then transfected into HeLa cells along with the two other PTEN reporter plasmids, EP-PTEN and CP-PTEN. As shown in Figure 6, basal activity of Δ mut-CP-PTEN was weaker compared to EP-PTEN or CP-PTEN, suggesting that the deleted 132 bp contains binding sites for positive acting factor/s. Interestingly however, although Tbx3 was capable of repressing EP-PTEN and CP-PTEN, the deletion mutant was not repressed by Tbx3. Analysis of this 132 bp DNA region did not reveal the presence of a canonical Tbx3 binding site. These results suggest that the PTEN promoter region between positions −1477 to −1345 contains binding sites for possible positive acting factors and Tbx3 represses PTEN promoter through this particular DNA region.
Figure 6. A 132 bp DNA region is responsible for repression of PTEN promoter by Tbx3. 132 bp from the 5-end of CP-PTEN was deleted to generate the Δ mut. CP-PTEN. All three reporter constructs were transfected into HeLa cell line and promoter activities were determined in the absence or presence of 1μg Tbx3 expressing plasmid. As has been shown before, Tbx3 was capable of repressing promoter activities of both the EP-PTEN and CP-PTEN, whereas no repression by Tbx3 was detected in Δ mut. CP-PTEN. Western blot (WB) shown below was performed by an anti-Tbx3 antibody and displays the Tbx3 protein in untransfected and transfected cells.
Discussion
It is now believed that pathways that are critical for physiological development may also play a role in tumorigenesis. In support of this, many signalling pathways such as Wnt and Notch1 or transcription factors like Sox2, Tbx2 and Tbx3, all of which are important in embryologic development, were also shown to be involved in tumorigenesis [40]. Although Tbx3 exhibits an abnormal expression pattern in various cancers, molecular mechanisms underlying the role of Tbx3 in cancer are not yet entirely revealed [9-12,14]. Nonetheless, it is now clear that Tbx3 is one of the major proteins involved in pathways regulating cellular proliferation and senescence. In addition, accumulating evidence suggests that Tbx3 plays an essential part in metastasis [11,13,41]. This latter role seems to be very important as success in cancer treatment strategies largely depends on the capacity of primary tumour cells to metastasize.
In terms of prognosis, squamous cell cancer of head and neck constitutes one of the worst cancer types, despite advances in diagnostic and treatment strategies. Research towards identifying molecular mechanisms of HNSCC revealed that many oncogenes and tumour suppressors are involved in formation and progression of this particular type of cancer. Although these research allowed establishment of new treatment regimes targeting these signalling pathways, the prognosis is still rather poor due to the aggressive metastatic capacity of this cancer [42,43]. Metastasis of primary cancer cells to distant organs is believed to be governed by induction of a program called epithelial-to-mesenchymal transition (EMT) [44]. Recently, a microarray analysis performed on a panel of HNSCC cell lines demonstrated that in EMT-like HNSCC cell lines Tbx3 was one of the strongly up-regulated gene besides a set of 145 genes [45]. Although these results were obtained from cell lines, nevertheless they are in perfect agreement with our data presented in this paper which demonstrates that both the mRNA and protein levels of Tbx3 are increased in tissues obtained from patients with HNSCC. Humtsoe et al. [45] also showed that Tbx3 over-expression has resulted in EMT-like cell survival, while inhibition of Tbx3 by siRNA has suppressed cell invasion. These results indicate that Tbx3 expression in HNSCC cell lines induce metastasis and raise the possibility that Tbx3 may be an important diagnostic marker in HNSCC progression. However, in our study group neither the clinical stage nor the origin of cancer exhibited a correlation with the Tbx3 mRNA levels. This could simply be due to the relatively small sample size and the fact that in our samples the majority of HNSCC samples originated from larynx (85%) and the patients were at clinical stage IV (73%) or III (27%). It will be important to analyze Tbx3 mRNA and protein levels in larger groups and also in earlier stages of the disease.
Previously several mechanisms have been identified which Tbx3 uses during cancer formation and progression [12,16-20]. However, regulation by Tbx3 has not been demonstrated before for PI3K/PTEN/AKT signalling pathway, which plays very important roles in cancer formation, development and cancer cell metabolism. The protein kinase AKT is in the centre of PI3K/PTEN/AKT signalling pathway and induces cellular proliferation by regulating protein synthesis, cell metabolism and apoptosis. Activation of AKT is dependent on enhanced activity of PI3K or decreased activity of PTEN. Indeed, after p53, PTEN is the second most altered tumour suppressor in cancers. However, although a reduced expression of PTEN is observed in most of the solid tumours, genetic mutations of PTEN are rather rare in most cancer types, except in glioblastome multiforme and endometrial cancer [46]. In HNSCC, mutations or amplifications of the genes encoding PI3K or AKT2 have been identified [47-49], but although a reduced protein expression of PTEN has been reported [27,50-52], rather low rates of mutations (8%) within the PTEN gene were found [53]. Therefore, one of the reasons for the loss of PTEN activity or protein expression observed in HNSCC or other types of cancer could be through down-regulation of PTEN via transcriptional regulation. The core promoter of PTEN located at positions −1344 to −745 was found to be capable of governing the maximum promoter activity [35]. Several studies performed on PTEN promoter clearly revealed the presence of negative regulators located both upstream and downstream of the core promoter, however these regions were not analyzed further as they were not within the scope of the respective papers [35,36,39]. In this paper we demonstrated that Tbx3 is one of the repressors as it was capable of repressing the transcription activity of PTEN promoter in both HeLa and HEK cell lines. In addition, when the PTEN core promoter activity was induced by over-expressing USF, Tbx3 was again able to overcome the transcriptional activity and repress the induced PTEN promoter activity. The repression of the induced PTEN promoter activity by Tbx3 could be due to the binding of Tbx3 and USF to the PTEN promoter simultaneously. However, it is also entirely possible that over-expressed Tbx3 could have down-regulated USF expression. Even so, these results and the fact that increasing amounts of Tbx3 causes a gradual decrease in the promoter activity of PTEN imply that Tbx3 is capable of repressing PTEN and that this repression is specific.
How and where within the PTEN promoter Tbx3 binds to, is not yet clear. Since the deletion mutant (Δ mut CP-PTEN) was not repressed by Tbx3, it can be argued that the Tbx3 responsive DNA region within the PTEN promoter is localized between positions −1477 and −1345. Unfortunately, search for a Tbx3-protein binding site within this 132 bp region did not reveal a consensus binding site. However, it is known that although many of the Tbx-family of proteins bind to brachyury site [54] either using the whole palindrome or to half-sites only, there can be some variations within the consensus sequence [55]. It is also noteworthy to mention that DNA-binding may not necessarily be an intrinsic determinant for specificity for Tbx-family of proteins. Indeed, accumulating evidence indicates that for Tbx family of proteins, DNA target specificity is dictated by interactions with other transcription factors and specific chromatin determinants [56-58]. Thus, identification of Tbx3 binding site within the PTEN promoter or any possible interactions of Tbx3 with the chromatin structure around the PTEN promoter require further research.
We demonstrated repression of PTEN transcription by Tbx3, both by using in vitro transcriptional activity assays and also by quantitative PCR, where we measured endogenous PTEN mRNA levels in response to over expressed Tbx3. As has been demonstrated by flow cytometry analyses, over expression of Tbx3 also caused a reduction in endogenous PTEN protein levels. Although reductions in endogenous PTEN mRNA and protein levels in response to over-expressed Tbx3 strongly suggest that this repression may occur in vivo, we were not able to demonstrate direct binding of Tbx3 to PTEN promoter in vivo. However, considering that Tbx3 has been implicated in metastasis of cervix, breast, head and neck squamous cell carcinomas, as well as melanomas [11,13,41,45], it is tempting to speculate that this repression may take place in vivo as well, especially during metastasis. Metastasis is the main cause of death in the majority of human cancers and in order to survive, cancer cells must overcome the challenges that metastatic processes present, such as apoptosis either due to cellular detachment or cell shape change [59]. Although resistance to apoptosis enables tumour cells to survive, it leads to a period of tumour dormancy, as growth in the metastatic sites is installed temporarily [60]. Anoikis is the term used to describe apoptosis due to cellular detachment. Role of PTEN in anoikis has been reported before [61] but direct effect of PTEN on anoikis and tumour dormancy has been demonstrated in mammary epithelial cell lines by disruption of PTEN expression using homologous recombination, which resulted in growth factor independent proliferation and resistance to anoikis [62]. Interestingly, in HNSCC cell lines showing EMT-like features in which Tbx3 was found to be over-expressed, it was also demonstrated that these cell-lines exhibited resistance to anoikis [45]. Therefore, it is possible that repression of PTEN by Tbx3 may account for resistance to anoikis observed in cancer cells.
Conclusions
We have shown that Tbx3 is up-regulated in tissue samples obtained from patients with HNSCC. In addition, we demonstrated that Tbx3 is capable of repressing PTEN transcription. This repression may have implications in progression and metastasis of cancer cells. In this scenario, over-expression of Tbx3 may render the cancer cells to gain the metastatic capacity and by inhibiting PTEN, may enable cells to resist apoptosis, therefore giving them the chance to survive and migrate to distant sites.
Abbreviations
DNA: Deoxyribonucleic acid; mRNA: Messenger ribonucleic acid; PCR: Polymerase chain reaction; bp: Base-pair.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
DB carried out all molecular biology experiments and participated in statistical analysis. KG participated in the design of the study, carried out diagnosis and operations of the patients and sample collection during operations. DS carried out RNA extractions. IHO and GO carried out the pathological examinations and immunohistochemistry. DO performed the statistical analysis. UY designed and coordinated the study, analyzed the data and wrote the manuscript. All authors read and approved the final manuscript.
Acknowledgement
We thank Prof. Colin R. Goding (Ludwig Institute for Cancer Research, Oxford, UK) for providing the USF/ Tbx3 expression plasmids and for reading and editing the manuscript. This work was supported by grant provided by The Scientific and Technological Research Council of Turkey (TUBITAK), project no: 109S348.
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J Cell Sci 2001, 114(Pt 13):2375-2382. PubMed Abstract | Publisher Full Text
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Pre-publication history
The pre-publication history for this paper can be accessed here:
http://www.biomedcentral.com/1471-2407/12/481/prepub
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Research article
The generalised anxiety stigma scale (GASS): psychometric properties in a community sample
Kathleen M Griffiths1*, Philip J Batterham2, Lisa Barney1 and Alison Parsons2
Author Affiliations
1 Depression & Anxiety Consumer Research Unit, Centre for Mental Health Research; The Australian National University, Acton, Canberra, ACT, Australia
2 Centre for Mental Health Research, The Australian National University, Acton, Canberra, ACT, Australia
For all author emails, please log on.
BMC Psychiatry 2011, 11:184 doi:10.1186/1471-244X-11-184
Published: 22 November 2011
Abstract
Background
Although there is substantial concern about negative attitudes to mental illness, little is known about the stigma associated with Generalised Anxiety Disorder (GAD) or its measurement. The aim of this study was to develop a multi-item measure of Generalised Anxiety Disorder stigma (the GASS).
Methods
Stigma items were developed from a thematic analysis of web-based text about the stigma associated with GAD. Six hundred and seventeen members of the public completed a survey comprising the resulting 20 stigma items and measures designed to evaluate construct validity. Follow-up data were collected for a subset of the participants (n = 212).
Results
The factor structure comprised two components: Personal Stigma (views about Generalised Anxiety Disorder); and Perceived Stigma (views about the beliefs of most others in the community). There was evidence of good construct validity and reliability for each of the Generalised Anxiety Stigma Scale (GASS) subscales.
Conclusions
The GASS is a promising brief measure of the stigma associated with Generalised Anxiety Disorder.
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Select computer software
From FamilySearch Wiki
(Difference between revisions)
m
Revision as of 21:07, 16 November 2012
User:Ccsmith/sandbox/wiki2 User:Ccsmith/sandbox/beginners User:Ccsmith/sandbox/computers Back to Main Page
Choosing computer software
Many genealogists start out with a paper based system. After becoming more involved, you may move to a computer based genealogy program. The advantages of recording your genealogy on a computer are many. Here a just a few:
• The ease of searching for a particular person to add information is far easier than leafing through a large number of pedigree charts or family group sheets.
• Can easily install photographs of ancestors on the pedigree and family group charts so as to give faces to the names on the forms.
• Making changes to spellings or dates, etc. are considerably easier with a computer. Sheets stay neat and clean without smudges.
• Paper copies can be printed for those who want to have paper copies of genealogy material.
• Your genealogical findings can easily be sent to another person with a computer.
• Work on research with others who have the same interest in a common pedigree can easily be coordinated via computers.
• You will find many genealogical data bases with billions of names that are easily available via computer and many are free such as FamilySearch.org.
• Putting your put your genealogy on these data bases which allows others to see what you have opens up the possibility of coming across others working on the same lines. You can either share what you have or acquire information you may have been searching for a long time.
• There are many associations and family history groups that you can join up with and not have to live near by to get involved.
There are many types of programs available for both the Apple operating systems and the Windows operating systems. There are also programs for tablet computers and smartphones. Below is information on software for PCs and Macs.
Free Genealogy Software for Microsoft Windows
Commercial Genealogy Software for Microsoft Windows
Genealogy Programs for Microsoft Windows Certified for New FamilySearch
FamilySearch Certified Products and Services
• Ancestral Quest - Access, Helper, Ordinance Reservation, Ordinance Request, Multi-Language, PAF Add-in, Print, Sync, Update
• Ancestral Quest Basics - Access, Ordinance Reservation, Ordinance Request, Multi-Language, PAF Add-in, Print, Sync, Update
• FamilyInsight - Access, Helper, Ordinance Reservation, Ordinance Request, Multi-Language, PAF Add-in, Sync, Update
• Gaia Family Tree - Access, Print, Sync, Update
• Get My Ancestors - Access, Multi-Language
• Legacy FamilyTree 7.5 - Access, Helper, Ordinance Status, Ordinance Reservation, Ordinance Request, PAF Import, Print, Sync, Update
• MagiKey Family Tree - Access, Helper, Ordinance Status, Ordinance Reservation
• Ordinance Tracker - Access, Ordinance Status, Ordinance Request
• RootsMagic 4 - Access, Helper, Ordinance Reservation, Ordinance Request, Print, Sync, Update
• RootsMagic 4 Essentials - Access, Helper, Ordinance Reservation, Ordinance Request, Print, Sync, Update
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Regimented Potential Incident Examination Report
From Forensics Wiki
Revision as of 18:08, 6 May 2007 by Pdxsharkey (Talk | contribs)
Jump to: navigation, search
Please help to improve this article by expanding it.
Further information might be found on the discussion page.
The Regimented Potential Incident Examination Report (RPIER or RAPIER) is script based incident response tool released under the GPL by Intel. It is a modular framework.
See Also
List of Script Based Incident Response Tools
External Links
Personal tools
Namespaces
Variants
Actions
Navigation:
About forensicswiki.org:
Toolbox
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"url": "www.go4expert.com/forums/splitting-single-file-multiple-data-file-t28205/",
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splitting a single file into multiple data file
Newbie Member
17Apr2012,02:00 #1
Hi,
I am working on a batch script which can work on my following scenario.
I have a source file as lets say A.csv with header and huge amount of data.
I want to split the csv file A.csv into multiple csv files of 20000 record each and having header in each csv.
Thanks
aadi
Go4Expert Member
17Jul2012,19:20 #2
I've seen this functionality with WinRAR.
Have you considered it?
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About this Journal Submit a Manuscript Table of Contents
ISRN Analytical Chemistry
Volume 2012 (2012), Article ID 801607, 16 pages
doi:10.5402/2012/801607
Review Article
Food Analysis: Present, Future, and Foodomics
Laboratory of Foodomics, Institute of Food Science Research (CIAL), CSIC, Nicolas Cabrera 9, Campus de Cantoblanco, 28049 Madrid, Spain
Received 12 September 2012; Accepted 24 October 2012
Academic Editors: A. Golcu, A. M. Haji Shabani, and I. Miksik
Copyright © 2012 Alejandro Cifuentes. 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
This paper presents a revision on the instrumental analytical techniques and methods used in food analysis together with their main applications in food science research. The present paper includes a brief historical perspective on food analysis, together with a deep revision on the current state of the art of modern analytical instruments, methodologies, and applications in food analysis with a special emphasis on the works published on this topic in the last three years (2009–2011). The article also discusses the present and future challenges in food analysis, the application of “omics” in food analysis (including epigenomics, genomics, transcriptomics, proteomics, and metabolomics), and provides an overview on the new discipline of Foodomics.
1. Food Analysis: A Brief Historical Perspective
Analysis of foods is continuously requesting the development of more robust, efficient, sensitive, and cost-effective analytical methodologies to guarantee the safety, quality, and traceability of foods in compliance with legislation and consumers’ demands. The old methods used at the beginning of the 20th century based on the so-called “wet chemistry” have evolved into the current powerful instrumental techniques used in food laboratories. This improvement has led to significant enhancements in analytical accuracy, precision, detection limits, and sample throughput, thereby expanding the practical range of food applications. As mentioned by McGorrin [1] “the growth and infrastructure of the modern global food distribution system heavily relies on food analysis (beyond simple characterization) as a tool for new product development, quality control, regulatory enforcement, and problem-solving.” Besides, currently, there is also a huge interest in the health-related properties of foods as a result of an increasing public concern on how to improve health through the so-called functional foods, functional ingredients, and nutraceuticals. Thus, there is no doubt on the importance and current need of analytical techniques developments able to face all these demands.
Traditionally, analytical techniques have been classified according to their working principle. For example, they can be spectroscopic (e.g., mass spectrometry (MS); nuclear magnetic resonance (NMR); infrared (IR); atomic spectroscopy (AS)), biological (polymerase chain reaction (PCR); immunological techniques; biosensors), electrochemical (including also biosensors here), for separation (e.g., high-performance liquid chromatography (HPLC); gas chromatography (GC); capillary electrophoresis (CE); supercritical fluid chromatography (SFC)), for sample preparation (e.g., solid phase extraction (SPE); supercritical fluid extraction (SFE); headspace (HS); flow injection analysis (FIA); purge and trap (PAT); microwave-assisted extraction (MAE); automatic thermal desorption (ATD)), hyphenated (e.g., putting together separation and spectroscopic techniques), and so forth. Every technique provides specific information on the sample or components under study based on a specific physical-chemical interaction, and all have their own advantages and drawbacks when applied to food analysis as will be discussed below. A description of the huge number of analytical techniques commonly used in food analysis is out of the scope of this work. An additional idea on the complexity of the number of techniques currently involved in food analysis can be obtained developing a little more one of the above subdisciplines. Considering the case of immunological techniques, they include the following ones: enzyme immunoassay (EIA), enzyme-linked immunosorbent assay (ELISA), immunodotting, radioimmunoassay (RIA), solid-phase RIA, liquid-phase RIA, immunoradiometric assay (IRMA), fluorescence: fluorescence immunoassay, enzyme-linked fluorescent immunoassay, fluorescence polarization immunoassay (FPIA), time-resolved fluorescence immunoassay (TRFI), and chemiluminescence immunoassay (CIA), up to 27 techniques can be associated to immunological techniques.
The present paper will focus on recent developments and applications of modern instrumental analytical techniques to detect compounds of significance to food science and technology, with a special emphasis on the literature published from January 2009 to January 2012. Namely, the present work will focus on modern analytical instrumentation, the development of new methods and their application in food science and technology including the new field of Foodomics [2], as well as recent works on quality control and safety, nutritional value, processing effects, storage, bioactivity, and so forth. The analysis of a large variety of food-related molecules with different chemical properties, including amino acids, peptides, proteins, phenolic compounds, carbohydrates, DNA fragments, vitamins, toxins, pesticides, additives, and chiral compounds, is also described below. Besides, a global picture on the evolution of the principal analytical techniques employed in food analysis will be provided through a comparison between the number of works published on food analysis in the first ten years of this 21st century (2001–2011) with the number of works published in the last ten years of the past 20th century (1990–2000) on the same topic.
2. Food Analysis: Current State of the Art, Methodologies, and Applications
A large number of works have directly focused on the analytical technique used in food analysis, while others have focused on the type of food, compound, or process investigated. Regarding specific analytical techniques applied to solve different problems in food analysis, one of the more active areas is the development of sample preparation techniques, in good agreement with the complex nature of foods. Sample preparation is one of the key steps for the development of any new analytical methodology; as a result, research on new sample preparation procedures is one of the most active areas in analytical chemistry. Advances in sample preparation aim to minimize laboratory solvent use and hazardous waste production, save employee labor and time, and reduce the cost per sample, while improving the efficiency of the analyte isolation. This includes the development and application of molecularly imprinted polymers in food sample analysis [3], the use of monoliths in sample preparation and analysis of milk [4], the development of porous monolith microextraction techniques for determination of veterinary residues in food matrices by [5], the use of the so-called QuEChERS (quick, easy, cheap, effective, rugged, and safe) methodology for determining pesticide residues in food matrices [6], the application of immunoaffinity column clean-up techniques in food analysis [7], the development of solid-phase microextraction (SPME) techniques for quality characterization of food products [8], the application of ultrasound-assisted extraction to the determination of contaminants in food and soil samples [9], and the use of liquid phase microextraction in food analysis [10]. Besides, some papers have focused on the description of sample preparation strategies used for the analysis of aflatoxins in food and feed [11], antibacterial residues in foodstuffs [12], or the determination of pesticides in foods [13]. At present, new green sample preparation methods are being studied; among them, supercritical fluid extraction (SFE) and subcritical water extraction (SWE, also called accelerated solvent extraction) are among the more promising processes in food science, not only in food analysis [14] but also for obtaining new functional food ingredients. These extraction techniques based on pressurized fluids provide higher selectivities, shorter extraction times, and are environmentally friendly.
Following with the description based on specific analytical techniques, separation techniques continue as one of the more active areas in food analysis. Separations based on liquid chromatography (LC) are the most numerous as can be deduced from the many works published on the use of different formats of LC [15, 16], including hydrophilic interaction liquid chromatography (HILIC) [17, 18], nano-LC [10], or high-speed counter-current chromatography [19], just to name a few. Other techniques as gas chromatography (GC) still have an important role in food analysis, for instance, for the analysis of volatile fractions or fatty acids in foods [20]. Electrodriven separation techniques such as capillary electrophoresis (CE) or microchip capillary electrophoresis have found important applications in food analysis as can be deduced from the many review works devoted to this topic [21, 22], including the detection of genetically modified organisms [23, 24], nucleosides and nucleotides in foods [25], analysis of contaminants in emerging food safety issues and food traceability [26], and food-borne pathogens [27].
It is also interesting to realize how mass spectrometry (MS) has evolved in the last years in food analysis. In the 1990s, MS was mostly used as GC detector to confirm the identification of analytes. During the last decade, MS has mainly been used for direct identification and quantification of food compounds typically coupled to other separation techniques like LC and, in a less extent, CE. Single quadrupole MS has been restricted to screening purposes since these instruments do not meet the more recent criteria set by food regulators as FDA or EFSA, especially those regarding the requested number of identification points. As a result, tandem MS has become a general tool for the identification and quantification of analytes (mainly contaminants) in food analysis. The enhanced selectivity afforded by tandem MS detection may also contribute to the simplification of the extraction procedure if attention is paid to ion suppression phenomena. At this point, the use of triple quadrupole, ion trap, and more recently time of flight MS analyzers coupled to uni- or bidimensional separation techniques have been widely reported in the scientific literature in food analysis [28, 29]. Other MS applications include analysis of pesticides and their metabolites in food and water matrices [30, 31], analysis of food proteins and peptides [32], MS-based analytical methodologies to characterize genetically modified crops [33], MALDI-TOF MS analysis of plant proanthocyanidins [34], or multistage mass spectrometry in quality, safety, and origin of foods [35]. It is expected that new developments on ionization techniques prior to MS analysis can make even broader its application in food analysis [36].
Spectroscopic techniques are based on the principle that molecules and atoms can interact with electromagnetic radiation. Structural, physical-chemical, and/or qualitative-quantitative information of the compounds under study can thus be obtained. This information is provided by the wavelength or frequency detected in the emitted or absorbed energy spectrum. Spectroscopic techniques have found in food analysis a large use due to that they are fast, give direct measurement of the food constituents, do not use toxic reactants and solvents, can be used in process line, are not destructive and noninvasive, and some of them can detect several compounds simultaneously [37]. Nowadays, spectroscopic techniques based on infrared region are one of the most numerous in the food analysis. Thus, infrared spectroscopy is frequently used for quality control of food including analysis of honey [38] or muscle food [39]. Spectroscopic techniques based on the near infrared (NIR) spectrum have also been used to identify transgenic foods [40] or for measuring bioactive compounds in foods [41]. The use of the midinfrared region has been applied to study the secondary structure of food proteins [42] or to study intact food systems exploring their molecular structure-quality relationships [43], while raman spectroscopy has also found a number of applications in agricultural products and food analysis [44]. Another spectroscopic technique such as nuclear magnetic resonance (NMR) has been used for the rapid analysis of oil and fact content in agrifood products [45], or in the mode 31P NMR to solve different problems in food analysis [46]. Other topics currently under development are the application of chemiluminescence in food analysis [47] or the use of chemiluminescence as detection in LC [48] or CE [49]. Other spectroscopic techniques like fluorescence [50] or modern electrothermal atomic absorption spectrometry have also found interesting applications in food analysis [51].
Hyphenated techniques have found a huge number of possibilities in food analysis. This is the case of liquid chromatography online coupled to mass spectrometry (LC-MS) or tandem MS (LC-MS/MS) which have been extensively applied to ensure food safety [52, 53], particularly to analyze antimicrobials residues in food of animal origin [54], antibiotics in food samples [55], clenbuterol residues [56], food allergens [57], and so forth. Other hyphenated techniques such as gas chromatography-mass spectrometry (GC-MS) or capillary electrophoresis-mass spectrometry (CE-MS) have also found interesting applications to analyze essential oils [58] or food contaminants [59].
Biological techniques employ living organisms or some of their products such as enzymes, antibodies, and DNAs, to identify and analyze foods. Although biological-type techniques such as the classical enzymatic or microbiological analysis will not be specifically covered in this paper, their use is still a must in many microbiological and food laboratories. The main developments in this area have been brought about by the important advances in the following.(i)DNA-based techniques and molecular methods have allowed the fast and sensitive detection of Salmonella in foods [60], the detection of fraudulent seafood species substitution [61], or the microbial composition of different foods [62, 63]. The detection of multiple genetically engineered crops [64] is still an important topic in which the effect of food processing on plant DNA degradation and PCR-based analysis of transgenic foods has also been studied [65]. These DNA-based methods also allow the authenticity determination of meat and meat products [66], the identification of animal species in food products [67], as well as the authentication of maize [68].(ii)Biosensors are analytical devices composed of a biological recognition element (e.g., enzyme, antibody, and microbe) coupled to a chemical or physical transducer that converts the chemical signal into an electrical response. Biosensors provide a continuous or semicontinuous electronic signal proportional to an analyte or group of analytes. Biosensors have been developed for determining major and minor food components, preservatives, food colors and sweeteners, toxins, pesticides, antibiotics, and hormones [69]. They have also found use in tracking microbial contamination [70], to follow food safety [71], processing, and to certify food quality and control including the development of the so-called electronic nose [72] or electronic tongue [73] that have a large impact on flavor analysis. The advantages of these methods are the rapid response time, the high degree of specificity and sensitivity, and the possibility of being used for inline processes monitoring food manufacturing. (iii)Other developments include the use of peptide nucleic acid (PNA)-based technologies for food analysis and food authentication [74] or the development of new immunoassay methodologies for analyzing veterinary drug residues in foods and food products [75] or to characterize plant food allergens [76].
On the other hand, many other works—instead of focusing on a given analytical technique for food analysis as above—have studied specific food constituents for whose analysis different analytical techniques and methods have been developed. One of the main topics is the case of contaminants in foods whose analysis is a must for ensuring human exposure to noxious residues though diet does not exceed acceptable levels for health. As mentioned above, the everyday more exigent demands on food safety are bringing about a tremendous development in analytical instruments and methodologies to analyze foodborne pathogens [77] and contaminants [7880], or the effect of food processing on pesticide residues in fruits and vegetables [81]. Good examples of the tremendous work devoted to these issues are the analysis of mycotoxins in foods [82, 83], the analysis of other toxin-like compounds as, for instance, sterigmatocystin, a toxic metabolite closely related to aflatoxins, and produced by the fungi Aspergillus nidulans and A. versicolor that has been found in different foods [84]. Another important issue is the analysis of antibiotics in foods [85], including different legal aspects related to their determination and subsequent validation of the analytical methodologies [86]. Robust analytical methods are continuously under development in order to improve the figures of merit (analysis speed, resolution, and sensitivity), allowing the fast and sensitive analysis of other food contaminants as well as possible dangerous compounds generated during food processing as acrylamide [87, 88], melatonin [89], N-nitrosamines [90], dioxins and dioxin-like PCBs [91], polycyclic aromatic hydrocarbons [92], Sudan dyes [93], food taints and off-flavours [94], thiols in wine [95], and sulphites in food and beverages [96].
Currently there is an important amount of work devoted to the study of food not only considered as source of energy, but also as a natural source of valuable ingredients than can provide additional health benefits. Following this trend new terms as functional foods, functional ingredients, or nutraceuticals are now in use in many laboratories that investigate links between the composition of food and its health benefits. This has been the case of isoflavones that has been largely analyzed in food and biological fluids based on their claimed health benefits supposedly due to their antioxidant activity [97, 98], a point that is now under controversy. Similar approach has been applied for the advanced analysis of food anthocyanins, isoflavones, and flavanols [99], flavonoids [100], phenolic compounds [101, 102], carotenoids [103, 104], and other phytochemicals in foods [105]. Many times these studies focus on the biological properties of other compounds, as fatty acids [106] or glucosinolates [107] that can have other sources different than plants. The analysis of nutraceuticals is a key issue for which advanced analytical techniques will play a key role [108] as well as for global research in nutrition and dietetics [109]. In this regard, other important topics are the determination of bioactive compounds in cranberry [110] or the determination of amino acids in grape-derived products [111]. Some compounds have also attracted much attention due to their beneficial rheological properties, this is the case of the analysis of the gelling carrageenans [112], or the determination of the degree of N acetylation of the polymers chitin and chitosan [113].
Other more specific applications in food analysis have also seen a great development as a result of the combination of several analytical advances that have been put together. A good example is the study of the geographical origin of foods via the analyses of stable isotope ratio of light elements [114] or the meta-analysis of the effects of pasteurization on milk vitamins [115]. This is also the case of the analysis of the volatile fraction of foods, which is known to have a crucial effect on food quality and acceptance. The study of the volatile fraction of food or beverage requires analytical methods and technologies able not only to evaluate its composition exhaustively but also to monitor variations of its profile and to detect trace components characterizing the food being investigated. The strategies of analysis have changed significantly over the last 15–20 years because of the introduction of new approaches, in particular: (i) solventless sample preparation techniques; (ii) fast gas chromatography and related techniques; (iii) new analytical techniques, such as comprehensive gas chromatography (GC); (iv) new operative strategies based on approaches developed for other fields and applied to food analysis; (v) data elaboration strategies producing a higher level of information [116]. Chiral analysis has also seen an important growing in food analysis, since chiral methods can be used to study and characterize foods and beverages through the enantiomeric separation of different food compounds such as amino acids, pesticides, and polyphenols [117]. Another example is the investigation on food texture in which physical characteristics perceived by the senses are investigated. Research in this area has evolved tremendously in the last decade based on multidisciplinary approaches that encompass chemistry, physics, physiology, and psychology, to study fracture of food, the sounds it makes during biting and chewing, its microstructure, muscle movements during mastication, swallowing, and acceptability, and so forth [118, 119].
Several books have also been printed in this period focusing on molecular techniques for detection and characterization of foodborne pathogens [120, 121], molecular biological and immunological techniques for food chemists [122], mass spectrometry in food safety [123], food analysis instruments [124], dairy food analysis [125], grains identity preservation and traceability [126], food contaminants [127], antibiotic residues in food [128], and fortified foods with vitamins [129].
Also, several book chapters have focused on the use of FTIR for rapid authentication and detection of adulteration of food [130], time-domain NMR applied to food products [131], or biosensors for functional food safety and analysis [132]. Readers interested in this topic can also take resort of several special issues published by different journals on food analysis [133], advanced separation methods in food analysis [134], allergens in foods [135], natural bioactive compounds and nutrigenomics [136], food and beverage analysis [137] and advanced food analysis [138].
Table 1 provides information on the number of works published in the period 2001–2011 found through a search in the database Food Science and Technology Abstracts (FSTA) using as key terms the names of the analytical technique indicated in each case.
Table 1: Number of works published in the period 2001–2011 found through a search in the database Food Science and Technology Abstracts (FSTA) using as key terms the names of the analytical technique indicated in each case.
There are some important conclusions that can be extracted from the results of Table 1 when they are compared to the results from a similar search published by our group at the end of the 20th century summarizing the works published on food analysis in the period 1990–2000 [139]. The most important trend is the huge increase in biological and sample preparation techniques as compared with the previous period and the important decrease in the use of radiochemical and thermal techniques, probably due to the specific information that those techniques provide and the need for high-throughput techniques widely based on new and advanced technologies able to provide more information of better quality. Thus, it is not strange that techniques such as thermal and radiochemical have decreased by half (compared to the previous period) and others such as spectroscopic, biological, and sample preparation techniques have increased two, three, and four times, respectively. Other well-established techniques such as separation techniques continue to be used in a high extend, but nowadays they are not the most widely used (as in the period 1990–2000), since spectroscopic techniques have gained importance and at present are the most extensively used in food analysis.
3. Present Challenges in Food Analysis
Currently there are a good number of challenges to be solved in food analysis. The variety of toxic residues in food is continuously increasing as a consequence of industrial development, new agricultural practices, environmental pollution, and climate change. A critical issue will be how to detect untargeted compounds and determine their identity in foods, for which the development of advanced analytical techniques is expected to play a crucial role [140]. This increasing number of food contaminants is bringing about the development of everyday more powerful, sensitive, and fast analytical methodologies able to detect emerging contaminants in food-like industrial organic pollutants, nanomaterials, pharmaceutical residues antibiotics, and coccidiostats or emerging groups of marine biotoxins [141]. In spite of these important developments, still hundreds of foodborne infection cases occur around the world, and up to one third of the population in industrialized nations suffers from foodborne illness each year. Microbiologists have developed over the last decades reliable culture-based techniques for pathogens detection in foods. These methods are considered to be the “gold-standard”; however, they remain cumbersome and time consuming. The introduction of genetic-based technologies makes feasible developing sensitive and specific screening tests for the detection of microbial pathogens. Microarray-based technologies represent an advance in nucleic acid testing methods whose main features include miniaturization, ability to parallelize sample processing, and ease of automation [142, 143]. Despite the advent of these rapid detection methods based on molecular techniques (or immunoassays), it is suggested that reduction and/or elimination of cultural enrichment will be essential in the quest for truly real-time detection methods. As such, there is an important role for the so-called preanalytical sample processing that in this case would include bacterial concentration and purification from the sample matrix as a step preceding detection [144]. In this regard, one analytical challenge that still remains in food safety is to present reliable results with respect to official guidelines, as fast as possible without impairing method properties such as recovery, accuracy, sensitivity, selectivity, and specificity [78].
It is also now under discussion the way in which the toxicity of food chemical contaminants is addressed. It seems it should be optimized considering food cooking, processing and eating habits, parameters that usually are neglected [145]. In addition, there is also a need of new and alternative (in vivo) toxicity tests as well as new detection tools for testing the effects of food chemical contaminants, moving away from the mouse bioassay for food toxin analysis [146]. To achieve this goal, the use of noncarcinogenic functional cell models, of alternative animal models like zebrafish embryos, and a toxicogenomic approach, seem to be the most promising strategies for the future toxicity assessment of food chemical contaminants [147].
There is also a good amount of discussion on how to ensure food safety around the globe and the many roles of risk analysis including microbial risk assessment [148, 149]. In this regard, benefit-risk assessment in food and nutrition weighs the beneficial and adverse effects that a food (component) may have, in order to facilitate more informed management decisions regarding public health issues. Although benefit-risk assessment is now in its infancy, and its exact scope is yet to be defined, benefit-risk assessment can be a valuable approach to provide the best possible science-based answer to complicated questions with a large potential impact on public health [150]. To achieve these goals it will be necessary to develop new and more powerful tools for the performance assessment and improvement of food safety following a global approach [151]. For instance, a good topic to evaluate through benefit-risk assessment will be the use of nanomaterials in food science. Nanotechnology and nanomaterials have remarkable potential to enhance the food supply through novel applications, including nutrient and bioactive absorption and delivery systems; microbial, allergen, and contaminant detection and control; food packaging properties and performance; improved colors and flavors. Based on these multiple applications, exposure to nanomaterials in the human food chain may occur not only through intentional uses in food manufacturing, but also via uses in agricultural production and carry over from use in other industries. New analytical methods are, therefore, needed to fully detect and characterize nanomaterials incorporated into foods and in other media. Moreover, there is also a need for additional toxicology studies on different types of nanomaterials to understand how they can affect food safety [152]. Besides, nanomaterials are also expected to play a crucial role in the miniaturization of analytical systems [153] including newly emerging technologies able to offer platforms with greater automation and multiplexing capabilities [154] or in the development of new nanomaterial-based biosensors for food analysis applications [155]. These multiplexed bioanalytical techniques are expected to provide control agencies and food industries with new possibilities for improved, more efficient monitoring of food, and environmental contaminants. In this regard, developments in planar-array and suspension-array technologies have demonstrated their potential in detecting pathogens, food allergens and adulterants, toxins, antibiotics, and environmental contaminants [156]. In this context, microfluidics technology has also shown interesting applications for food analysis although more effort has to be put on the development of multipurpose microfluidic platforms that integrate multiple unit operations for real food sample analysis [157]. Miniaturized systems and their applications are expected to keep growing in food analysis.
More suitable analytical techniques are still required for the detection of allergens in foods because minute amounts of the allergen can have critical consequences in sensitized persons. Although immunological methods are currently preferred, the determination of allergenic proteins by LC-MS has advanced in recent years, and it is now frequently used for the identification and quantitation of food allergens [57]. In spite of these advances, confirmatory alternatives are still needed to be able to face other additional problems originated, for example, by food matrix interferences or food processing, which may not influence allergenicity but do impair allergen detection.
Regarding comprehensive and multidimensional chromatography methods (e.g., LC × LC; GC × GC), an important point to consider is that nowadays these multidimensional techniques require dedicated laboratories, equipment, and highly trained personnel, what can explain the relatively low number of applications of these techniques [159161]. In order to improve the simplicity and speed of analysis provided by these techniques, keeping the cost of analysis as low as possible, important instrumental developments have to be achieved. They include the improvement of the connection of the two systems to overcome the relatively costly operation conditions in GC × GC or the loss in sensitivity in LC × LC. In the coming years, new solutions should appear in order to facilitate these couplings as well as to further increase the orthogonality of the systems and, consequently, their separation power and applications in food analysis [159].
Nowadays, food laboratories are being pushed to exchange their classical procedures for modern analytical techniques that allow them to give an adequate answer to global demands on food safety, quality, and traceability. Besides, the Montreal Protocol has had a major impact also on food laboratories that have been pushed to develop more environmental-friendly methods. An important challenge is the implementation of Green Analytical Chemistry [162] also in food analysis laboratories [163] including, for instance, the greening of sample preparation techniques (with the use of new green solvents, miniaturization, or employment of solventless techniques) and the combination with new (and cleaner) separation techniques.
4. Food Analysis in the Postgenomic Era: Omics Approaches and Foodomics
The sequencing of nearly the whole human genome at the beginning of 21st century is considered the beginning of the so-called postgenomic era. The advances observed in this period have made feasible to count on analytical instruments and methodological developments that were unthinkable few decades ago. As a result, researchers in food science and nutrition are being pushed to move from classical methodologies to more advanced strategies usually borrowing methods well established in medical, pharmacological, and/or biotechnology research. In this context, we coined and defined Foodomics as a discipline that studies the food and nutrition domains through the application of advanced omics technologies to improve consumer’s well-being, health, and knowledge [2, 21, 164]. The main idea behind the use of this new term has been not only to use it as a flag of the new times for food analysis, but also to highlight that the investigation into traditional and new problems in food analysis in the postgenomic era can find exciting opportunities and new answers through the use of epigenomics, genomics, transcriptomics, proteomics, and metabolomics tools. A description on the basis of these omics approaches is given next.
Epigenomics studies the mechanisms of gene expression that can be maintained across cell divisions, and thus the life of the organism, without changing the DNA sequence. The epigenetic mechanisms are related to changes induced (e.g., by toxins or bioactive food ingredients) in gene expression via altered DNA methylation patterns, altered histone modifications, or noncoding RNAs, including small RNAs. The global analysis of gene expression as approached by transcriptomics offers impressive opportunities in Foodomics (e.g., for the identification of the effect of bioactive food constituents on homeostatic regulation and how this regulation is potentially altered in the development of certain chronic diseases). Two conceptually different analytical approaches have emerged to allow quantitative and comprehensive analysis of changes in mRNA expression levels of hundreds or thousands of genes. One approach is based on microarray technology, and the other group of techniques is based on DNA sequencing. Next, typically real-time-PCR is applied to confirm the up- or downregulation of a selected number of genes. In proteomics, the huge dynamic concentration range of proteins in biological samples causes many detection difficulties due to that many proteins are below the sensitivity threshold of the most advanced instruments. For this reason, fractionation and subsequent concentration of the proteome are often needed. Besides, the use and development of high-resolving separation techniques as well as highly accurate mass spectrometers are nowadays essential to solve the proteome complexity. Two fundamental analytical strategies can be employed: the bottom-up and the top-down approach. Both methodologies differ on the separation requirements and the type of MS instrumentation. New proteomic approaches based on array technology are also being employed. Metabolome can be defined as the full set of endogenous or exogenous low molecular weight metabolic entities of approximately <1000 Da (metabolites), and the small pathway motifs that are present in a biological system (cell, tissue, organ, organism, or species). Unlike nucleic acid or protein-based omics techniques, which intend to determine a single chemical class of compounds, metabolomics has to deal with very different compounds of very diverse chemical and physical properties. Moreover, the relative concentration of metabolites in the biological fluids can vary from millimolar level (or higher) to picomolar, making it easy to exceed the linear range of the analytical techniques employed. No single analytical methodology or platform is applicable to detect, quantify, and identify all metabolites in a biological sample. Two analytical platforms are currently used for metabolomic analyses: MS- and NMR-based systems. These techniques either stand alone, or combined with separation techniques (typically, LC-NMR, GC-MS, LC-MS, and CE-MS), can produce complementary analytical information to attain more extensive metabolome coverage. There are three basic approaches that can be used in metabolomics: target analysis, metabolic profiling, and metabolic fingerprinting. Target analysis aims the quantitative measurement of selected analytes, such as specific biomarkers or reaction products. Metabolic profiling is a nontarget strategy that focuses on the study of a group of related metabolites or a specific metabolic pathway. Meanwhile, metabolic fingerprinting does not aim to identify all metabolites, but to compare patterns of metabolites that change in response to the cellular environment.
Due to the huge amount of data usually obtained from omics studies, it has been necessary to develop strategies to convert the complex raw data obtained into useful information. Thus, bioinformatics has become also a crucial tool in Foodomics. Over the last years, the use of biological knowledge accumulated in public databases by means of bioinformatics allows to systematically analyse large data lists in an attempt to assemble a summary of the most significant biological aspects. Also, statistical tools are usually applied, for example, for exploratory data analysis to determine correlations among samples (which can be caused by either a biological difference or a methodological bias), for discriminating the complete data list and reduce it with the most relevant ones for biomarkers discovery, and so forth
The application of advanced omics technologies as proposed by Foodomics has already found application in different topics in food science and nutrition. Some examples are given below. Proteomics and metabolomics represent powerful analytical strategies to acquire more detailed and complete information on food composition even beyond the traditional food component analysis. Following this idea, proteomic methods have already been applied to several issues related to food safety [165], as well as the optimization of processing and quality control of food of animal origin [166], to investigate the milk proteome [167, 168], the rice proteome [169], or to study allergy and intolerance to wheat products [170]. Transcriptomic, proteomic, nd metabolomic approaches are also valuable tools to distinguish between similar food products and to detect food frauds (adulteration, origin, authenticity, etc.), food-borne pathogens, toxic species, food allergens, and so forth. For instance, in the context of food safety and transcriptomics, several DNA microarray chips have already been developed for the detection of food-borne pathogens, toxigenic microorganisms, GMO analysis, and so forth. Proteomic and metabolic changes also occur during crops growing conditions, food processing/preparation (fermentation, baking, boiling, etc.), and food conservation/storage (freezing, smoking, drying, etc.). These tools have already been demonstrated to be very useful for getting a deeper understanding of molecular details of foods and food related matrices [171173] including the analysis of GM foods. In this later case, the use of omics approaches able to provide useful fingerprints of GM foods (e.g., for GM detection, composition monitoring, traceability, study of unintended modifications, and labelling issues) has already been recommended by the European Food Safety Authority [33, 174176]. In this context, metabolomics (via GC-MS, LC-MS, CE-MS, or NMR) has potential to add significant value to crop and food science, raw material quality and safety, food storage, shelf life, and postharvest processing [177]. There are also other topics in which Foodomics can play a crucial role including the comprehensive assessment of food safety, quality and traceability ideally as a whole [164]; the investigation on the global role and functions of gut microbiome, a topic that is expected to open an impressive field of research [178, 179]; the stress adaptation responses of food-borne pathogens to ensure food hygiene, processing and preservation [180], or the molecular basis of biological processes with agronomic interest and economic relevance, such as the interaction between crops and its pathogens, as well as physicochemical changes that take place during fruit ripening [181].
Currently, a main area of research in food science is the connection between food and health. Today, food is considered not only a source of energy but also an affordable way to prevent future diseases. The number of opportunities (e.g., new methodologies, new generated knowledge, new products, etc.) derived from this trend are impressive, and it includes, for example, the possibility to account for food products tailored to promote the health and well-being of groups of population identified on the basis of their individual genomes. Interaction of modern food science and nutrition with disciplines such as pharmacology, medicine, or biotechnology provides impressive new challenges and opportunities. As a result, advanced analytical methodologies, “omics” approaches, and bioinformatics—frequently together with in vitro, in vivo, and/or clinical assays—are applied to investigate topics in food science and nutrition that were considered unapproachable few years ago demonstrating the huge possibilities of Foodomics in this important area of research [182]. However, food scientists and nutritionists have to face a large number of challenges to adequately answer the new questions emerging from this new field of research. One of the main challenges is to improve our limited understanding of the roles of nutritional compounds at molecular level (i.e., their interaction with genes and their subsequent effect on proteins and metabolites) for the rational design of strategies to manipulate cell functions through diet, which is expected to have an extraordinary impact on our health. The problem to solve is huge, and it includes the study of the individual variations in gene sequences, particularly in single nucleotide polymorphisms (SNPs), and their expected different answer to nutrients. Moreover, nutrients can be considered as signalling molecules that are recognized by specific cellular-sensing mechanisms [183]. However, unlike pharmaceuticals, the simultaneous presence of a variety of nutrients, with diverse chemical structures and concentrations and having numerous targets with different affinities and specificities, increases enormously the complexity of the problem [184]. Therefore, it is necessary to look at hundreds of test compounds simultaneously and observe the diverse temporal and spatial responses. Besides, several of the health benefits assigned to many dietary constituents are still under controversy as can be deduced from the large number of applications rejected by the European Food Safety Authority about health claims of new foods and ingredients [185]. More sounded scientific evidences are needed to demonstrate or not the claimed beneficial effects of these new foods and constituents. In this sense, the advent of new postgenomic strategies as Foodomics seems to be essential to understand how the bioactive compounds from diet interact at molecular and cellular level, as well as to provide better scientific evidences on their health benefits. The combination of the information from the three expression levels (gen, protein, and metabolite) can be crucial to adequately understand and scientifically sustain the health benefits from food ingredients. A representation of an ideal Foodomics strategy to investigate the effect of food ingredient(s) on a given system (cell, tissue, organ, or organism) is shown in Figure 1. Following this Foodomics strategy, results on the effect of food ingredient(s) at genomic/transcriptomic/proteomic and/or metabolomic level are obtained, making possible new investigations on food bioactivity and its effect on human health at molecular level [186].
Figure 1: Scheme of an ideal Foodomics platform to investigate the health benefits from dietary constituents on a given biological system (cell, tissue, organ, or organism), including analytical methodologies used and expected outcomes. Modified from [158] with permission from Elsevier.
However, in spite of the significant outcomes expected from global Foodomics strategies, there is still a long way to go since practically there are no papers published in literature in which results from the three expression levels (transcriptomics, proteomics, and metabolomics) are simultaneously presented and merged being the number of review papers on this topic higher than the number of research papers. To our knowledge, only two papers have presented results from the three expression levels simultaneously following a global strategy [158, 187]. Figure 2 shows the results from one of these global Foodomics studies on the chemopreventive effect of dietary polyphenols against HT29 colon cancer cells proliferation [158]. Figure 2 shows the genes, proteins and metabolites that were identified (after transcriptomic, proteomic, and metabolomic analysis) to be involved in the principal biological processes altered in HT29 colon cancer cells after the treatment with rosemary polyphenols, showing the huge potential of this global strategy.
Figure 2: Foodomics identification of the genes, proteins and metabolites involved in the principal biological processes altered in HT29 colon cancer cells after their treatment with rosemary polyphenols. In red: up-regulated; in green: down-regulated. Modified from [158] with permission from Elsevier.
However, Foodomics still needs to overcome some important gaps and limitations in order to demonstrate all its great analytical potential. Analytical strategies used in Foodomics have to face important difficulties derived, among others, from food complexity, the huge natural variability, the large number of different nutrients and bioactive food compounds, their very different concentrations, and the numerous targets with different affinities and specificities that they might have. In this context, epigenomics, transcriptomics, proteomics, and metabolomics represents powerful analytical platforms developed for the analysis of gene expression, proteins, and metabolites. However, “omics” platforms must be integrated in order to understand the biological meaning of the results on the investigated system (e.g., cell, tissue, organ) ideally through a holistic strategy as proposed by Systems Biology. Thus, Systems Biology can be defined as an integrated approach to study biological systems, at the level of cells, organs, or organisms, by measuring and integrating genomic, proteomic, and metabolic data [188]. Systems Biology approaches might encompass molecules, cells, organs, individuals, or even ecosystems, and it is regarded as an integrative approach of all information at the different levels of genomic expression (mRNA, protein, and metabolite). Data interpretation and integration when dealing with such complex systems are not straightforward and have been detected as one of the main bottlenecks. In the future, the combination of Foodomics and systems biology can provide crucial information on, for example, host-microbiome interactions, nutritional immunology, food microorganisms including pathogens resistance, farm animal production, or to fully understand postharvest phenomena through a global approach that links genetic and environmental responses and identifies the underlying biological networks. In this regard, it is expected that the new omics technologies combined with systems biology, as proposed by Foodomics, can lead postharvest research into a new era [181]. Besides, it is foreseen the emerging of other innovative approaches as, for example, green Foodomics, green systems biology [189], the human-gutome, and so forth.
Acknowledgments
This work was supported by AGL2011-29857-C03-01 (Ministerio de Ciencia e Innovación, Spain) and CSD2007-00063 FUN-C-FOOD (Programa CONSOLIDER, Ministerio de Educación y Ciencia, Spain) projects.
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About this Journal Submit a Manuscript Table of Contents
Journal of Metallurgy
Volume 2012 (2012), Article ID 762125, 10 pages
doi:10.1155/2012/762125
Research Article
Surface Modification of Light Alloys by Low-Energy High-Current Pulsed Electron Beam
1Key Laboratory of Materials Modification, Department of Materials Engineering, Dalian University of Technology, Dalian 116024, China
2Laboratoire d'Etude des Microstructures et de Mécanique des Matériaux (LEM3), CNRS UMR 7239, Université Paul Verlaine-Metz, Ile du Saulcy, 57045 Metz, France
3Shanghai Engineering Research Center of Mg Materials and Applications, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
4School of Materials Science and Engineering, Shenyang University, Shenyang 200240, China
Received 16 February 2011; Revised 17 August 2011; Accepted 9 December 2011
Academic Editor: Stefano Gialanella
Copyright © 2012 X. D. Zhang et al. 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
This paper reviews results obtained by the research groups developing the low-energy high-current pulsed electron beam (LEHCPEB) in Dalian (China) and Metz (France) on the surface treatment of light alloys. The pulsed electron irradiation induces an ultra-fast thermal cycle at the surface combined with the formation of thermal stress and shock waves. As illustrated for Mg alloys and Ti, this results in deep subsurface hardening (over several 100 μm) which improves the wear resistance. The analysis of the top surface melted surface of light alloys also often witnesses evaporation and condensation of chemical species. This phenomenon can significantly modify the melt chemistry and was also suggested to lead to the development of specific solidification textures in the rapidly solidified layer. The potential use of the LEHCPEB technique for producing thermomechanical treatments under the so-called heating mode and, thus, modify the surface crystallographic texture, and enhance solid-state diffusion is also demonstrated in the case of the FeAl intermetallic compound.
1. Introduction
Light alloys, such as Mg-, Al-, and Ti-based alloys, have attracted increasing attention in the past few decades owing to their low density and, correspondingly, their high strength/ductility ratio. Because of this, light alloys are increasingly used to replace steels in industrial components. However, these light alloys are all facing some serious surface-related disadvantages such as poor wear or corrosion resistance that have strongly limited their potential for some specific industrial applications. Therefore, surface treatment techniques should be applied on these light alloys in order to improve their global performance.
The low-energy high-current pulsed electron beam (LEHCPEB) process is a fairly new surface modification technique [1, 2]. The LEHCPEB sources have been first developed for surface treatment of materials by Proskurovsky and Ozur in Tomsk (Russia) [13]. As one kind of high-power charged particle beam, LEHCPEB exhibits essential advantages over pulsed laser and ion beams by its high efficiency, simplicity, and reliability. The pulsed electron irradiation induces (i) a rapid heating and cooling of the surface together with (ii) the formation of thermal stress and stress waves [4, 5]. As a result, improved surface properties of the material, often unattainable with conventional surface treatment techniques, can be obtained fairly easily. This is particularly true for tribological [2, 4, 6, 7] and corrosion properties [710]. Proskurovsky et al. [14] have carried out pioneer investigations of the LEHCPEB treatment on a series of Al- and Ti-base alloys and the results obtained showed an increase of corrosion and strength properties for the treated alloys. The group in Dalian University of Technology (China) has more recently done research on various light materials such as pure Al [11, 12], pure Ti [13], pure Mg [14, 15], and Mg alloys [6, 16, 17]. In particular, though collaboration with the University of Metz (France), they have detailed the microstructure evolution of LEHCPEB treated alloys and their corrosion properties [1823]. Also, the group has investigated the LEHCPEB treatment of a FeAl intermetallic compounds [24, 25], which can be used to replace refractory steels for high-temperature weight saving applications. This paper reviews the main results obtained from their studies on light alloys treated with LEHCPEB in connection to improvements in wear and corrosion resistances as well as specific features related to texture and microstructure modifications, deep hardening, and evaporation phenomenon.
2. The Surface Treatment System
The samples investigated in the present manuscript were treated in Dalian using a “Nadezhda-2” system. A schematic diagram of this LEHCPEB source is given in Figure 1. The “Nadezhda-2” electron-beam source can produce electron beams with the parameters as follows: electron energy 10–40 keV, peak current 102–103 A/cm2, pulse duration 0.5–5 μs, energy density 0.5–40 J/cm2, beam cross-section area 10–50 cm2, and repeating pulse interval 10 s. The electron beam is generated by an explosive emission graphite cathode. Spark plasma sources are placed evenly in a circle behind the anode, providing anode plasma that conducts the beam to the collector where the specimen to be treated is placed. An external magnetic field is applied to confine the beam to prevent the beam from pinching and dispersing. The accelerating voltage, magnetic fields intensity, and anode-collector distance control the beam energy density. They are simple and reliable in operation.
Figure 1: Schematic diagram of the LEHCPEB source based on vacuum spark plasma. 1: cathode, 2: anode, 3: collector, 4: vacuum chamber, 5: cathode plasma, 6: anode plasma, 7: solenoid, 8: spark plasma sources, 9: specimen, 10: plasma sheath, 11: electron beam [4].
3. Improvement of Wear and Corrosion Resistances
The pulsed electron irradiation generated by this surface treatment technique induces rapid melting of the surface followed by extremely fast solidification. This process leads to the dissolution of second-phase particles and, after sufficient number of pulses, to the formation of 2-3 μm thick homogeneous melted surfaces [18, 22, 26]. The so-formed homogeneous layers were demonstrated to improve the corrosion properties of dual-phase alloys such as the 316L stainless steel [7, 21] and the D2 steel [18] as well as NiTi shape memory alloys [20]. The LEHCPEB treatment also often induces in steels the formation of nanoscale structures formed by rapid solidification in the melted layer [18, 21, 27, 28]. Some extent of grain refinement was also observed in the subsurface that remained solid of a D2 steel because of the heavy deformation induced by the thermal stress wave accompanying the very fast thermal cycles [29]. In steels, these finer grains together with the strain hardening imparted by the thermal stresses are believed to be the major contributors to surface/subsurface hardening and associated wear resistance improvement [7]. In the following section, we present some results obtained on light alloys in terms of wear and corrosion resistances.
3.1. Mg and Its Alloys
The AZ31 (Mg-3Al-0.5Zn-0.5Mn) is a commercial α (Mg) single-phase Mg alloy while the AZ91 (Mg-8.9Al-0.5Zn-0.2Mn-0.04Si) one consist of a two-phase α (Mg) + -Mg17Al12 mixture. The LEHCPEB surface treatments were carried out for 5, 10, and 15 pulses using electron beam energy densities of 2.5 J/cm2 and of ~3 J/cm2 for the number AZ31 and AZ91 alloys, respectively. Wear tests were carried out without lubricant using a ball (WC-Co)-on-flat apparatus. Figure 2 gives the evolution of the wear rate with the number of pulses for the AZ31 alloy while the wear volume and the friction coefficients for the AZ91 alloy are shown in Figure 3. For both alloys, the wear mechanism was abrasive wear and the wear tracks were much wider for the untreated samples than for the treated ones. This indicates that a hardening effect occurred due to the LEHCPEB treatment.
Figure 2: Evolution of the wear rate with the number of pulses for the AZ31 Mg alloy [6].
Figure 3: Evolution of the wear volume and the friction coefficient with the number of pulse for the AZ91 Mg alloy [17].
For the AZ31 alloy, the wear rate decreases when increasing the number of LEHCPEB pulses and the best wear resistance was obtained after 15 pulses of treatments. This corresponds to an improvement in wear resistance by a factor of 6.7.
As illustrated in Figure 3, there is also a general trend for both the wear volumes and the friction coefficients of the AZ91-treated samples to decrease after the LEHCPEB treatment. However, the best wear resistance was obtained for the sample treated for 10 pulses only.
In terms of corrosion resistance, it is also the 10 pulsed treated sample that displayed the best behavior. This is illustrated in Figure 4 that gives the evolution of the corrosion rate with the number of pulses for the AZ91 alloy. The immersion corrosion experiments were performed in a 5% NaCl solution for 72 h on both the intial and LEHCPEB-treated AZ91 samples. The corrosion results indicated that the average corrosion rate decreased after the LEHCPEB treatment with the 10-pulsed sample showing the best corrosion resistance (the lowest corrosion rate). It is, therefore, clear that both the best wear and corrosion resistance are obtained after 10 pulses and not after the highest number of pulses (15 pulses). As will be discussed later in the text, this is likely due to some evaporation phenomena taking place more significantly after 15 pulses.
Figure 4: Evolution of the corrosion rate with the number of pulses [16].
Such improvements of the wear and corrosion resistance can be attributed to the formation of an extended graded structure (a nanograined MgO layer and a melted layer) at the surface layer of the irradiated AZ91 Mg alloy after the LEHCPEB treatment. The thin nanograined MgO layer present on the top surface played an important role of lubricant during wear tests and a protective layer during corrosion test. The melted layer formed beneath the oxide layer consists of Al oversupersaturated α (Mg) solid solution due to the solute trapping effect during the fast solidification process. Such a melted layer is favorable for the formation of a homogenous passive film during the corrosion test and thereby protects the substrate.
3.2. Ti and Its Alloys
LEHCPEB treatments were performed on the commercially pure Ti (CP-Ti) samples [13] with the accelerating voltage 25.2 kV and pulse times 15 and 25. Electrochemical corrosion tests for both the initial and treated samples were carried out using the conventional three-electrode cell in a 5% NaCl water solution.
Figure 5 shows the potentiodynamic polarization curves. There is a significant improvement in corrosion resistance after the LEHCPEB treatments evidenced by a shift of the whole polarization curve towards the region of lower current density and higher potential. The improvement in corrosion performance can be ascribed to two major factors. Firstly, it is well established that ultrafine structures in CP-Ti lead to improved corrosion resistance. This is due to the redistribution of impurities that segregate at grain boundaries and higher reactivity to form a protective oxide layer. Secondly, the LEHCPEB technique is very effective for removing top surface contaminants or self-purification helping to form more homogeneous protective layers.
Figure 5: Potentiodynamic polarization curves of CP-Ti samples before and after LEHCPEB treatments [9].
4. Deep Hardening Effects
The hardness of a material depends on several factors: the grain size via the Hall-Petch hardening, the alloying elements via the solid solution, and/or precipitation hardenings, the presence of structural defects such as vacancies or dislocations as well as the residual stress state. The understanding of hardening in iron and steels treated by LEHCPEB has already been investigated in detail recently. Two interesting behaviours are generally reported in steels concerning the hardness evolution on the LEHCPEB-treated samples. First, a modification of the hardness is obtained in the melted layer (hardening or softening) [7, 30]. Second, below this melted layer, the hardened subsurface—which extends over slightly more than 100 micron—consists in fact of two successive hardened zones. It is well established that the high dislocation density in the surface layer of the target material usually increases dramatically after the LEHCPEB treatment [31, 32]. For example, Valyaev et al. have shown the dependence of hardness on dislocation densities in pure iron treated by pulsed electron beam treatment [31, 32]. The LEHCPEB irradiation also induced vacancy type of defects that should also favour the increased hardness in steels [33, 34]. The first hardness peak was attributed essentially to the quasi-static thermal stress and the repeated action of the beam induced the formation of microdeformation bands. The second peak—of lower intensity—was related to deeper hardening induced by the thermal stress wave [7]. In some cases, the tensile stress that is created in the rapidly quenched melted layer has been suggested to induce a top surface softening over the top first few microns. For example, Rotshtein et al. [30] and Zou et al. [7] have also observed a decrease in hardness at the top surface layer of a 316LS steel. They considered that this was due to the residual tensile stress generated by the LEHCPEB treatment [7, 30].
Figure 6 gives the evolution of the cross-section microhardness with depth for the LEHCPEB-treated Mg alloys AZ31 and AZ91, pure Mg, and pure Al. Although the hardness was measured from different light alloys treated with different LEHCPEB parameters, the hardness profiles often show some common characteristic features: an overall increase in subsurface hardness with the possibility of some local sharp increase. It is interesting to notice that the increase in hardness is generally obtained over a depth of more than 100 μm for the LEHCPEB-treated samples, sometimes reaching a depth of nearly 500 μm (Figure 6(a)). These increases in hardness must be attributed to the action of the stress waves which can propagate far beyond the heat affected zone (HAZ). Hence, deformation occurs below the HAZ and the hardness can be increased due to the work-hardening effect [6, 14]. In fact, such deformation induced by thermal stress wave propagation was revealed by TEM observations in LEHCPEB treated pure Al. Figure 7 gives a TEM bright field image showing the deformation marks (stacking fault-like contrast) about 1 μm beneath the surface having orientations of about 45° with respect to the surface. Moreover, a direct experimental proof of the existence of the stress far below the surface is illustrated in the TEM image of Figure 8, where two wave fronts are observed about 0.5 mm beneath the surface.
Figure 6: Evolution of cross-section microhardness with depth for the LEHCPEB-treated samples: (a) AZ31 Mg alloy (27 kV, 10 pulses); (b) AZ91 Mg alloy (27 kV, 10 pulses); (c) pure Mg (27 kV, 10 pulses); (d) pure Al (28 kV, 1 pulse).
Figure 7: The stacking faults-like contrast about 1 μm beneath the surface melted layer [11].
Figure 8: Two wavy fronts approximately 0.5 mm beneath and perpendicular to the treated surface. They are parallel to a grain boundary [15].
It is usually accepted that the increase in hardness plays the major role for improving the wear resistance of LEHCPEB-treated samples. It is the subsurface hardening that is in fact responsible for the improved wear behaviour and diminution of the wear volumes depicted in Figures 2 and 3.
5. Microstructure Evolution and Evaporation Phenomena
The LEHCPEB surface treatment on light alloys is normally accompanied by significant surface evaporation of chemical species. Under intensive evaporation, a special surface morphology is observed after LEHCPEB treatment. Figure 9 shows a typical SEM surface micrograph of pure Mg irradiated by LEHCPEB with an energy density of about 3 J/cm2. Two distinct features can be clearly observed. The first one is the wavy aspect of the surface consisting of a succession of hills and valleys at the sample surface, which is different from common feature of many LEHCPEB treated metal surfaces. The second feature is the presence of many isolated particles on the surface, which is due to the condensation of the Mg vapor.
Figure 9: SEM micrographs showing typical surface morphology of pure Mg after evaporation treatment, energy density 3 J/cm2, 5 pulses [16].
After treatment in evaporation mode, it is expected that the selective evaporation taking place on the surface results in composition changes. Figure 10 gives the electron probe microanalyzer (EPMA) line scan analysis of the melted layer present locally at the surface of the AZ31 Mg alloy samples. The results clearly indicated a depletion of the Mg element and a corresponding increase of Al element in the melted layer. Such a selective evaporation of Mg over Al element is clearly the consequence of the LEHCPEB treatment operating in the evaporation mode at the sample surface.
Figure 10: EPMA line scan analysis of the melted layer present locally at the surface of the samples after the LEHCPEB treatment 15 pulses [6].
Results of SNMS (sputter neutral mass spectrometry, VG instrument) analysis are shown in Figure 11 where the evolution of the amount of the major elements—Ti and Al—is plotted as a function of the distance from the surface for the near α titanium TA15 samples treated with 23.4 kV. Chemical modifications are clearly visible at the top surface of the melted layers: the Ti concentrations increase while the Al concentrations decrease when approaching the surface. For the 5 pulsed sample (Figure 11(a)), starting from a depth of about 250 nm, the Ti content can reach about 88.5 at%, slightly higher than the average concentration in matrix (87.7 at%). Comparatively, the Al concentration decreases to about 10.5 at% instead of the initial 11.3 at%. For the 10 pulsed sample (Figure 11(b)), the chemical modifications in the surface layer are more pronounced. They start from a depth of about 400 nm and the Ti content reaches the maximum value at about 89 at% at the top surface while the Al concentration decreases to about 9.8 at%. Numerical calculation also confirmed that the Al element is more prone to evaporate than the Ti element. The evaporation of Al is more pronounced at higher number of pulses indicated that more energy input can generate a more significant evaporation phenomenon. This more pronounced change in chemistry modification in terms of magnitude and depth with increasing number of pulses when the evaporation mode is taking place is consistent with previous results on a NiTi alloy [20].
Figure 11: SNMS composition profiles in Ti and Al for the TA15 near α titanium alloy. Experimental conditions are (a) 23.4 KeV 5 pulses; (b) 23.4 KeV 10 pulses.
6. Modification of Surface Crystallographic Textures
An interesting effect of the LEHCPEB surface treatment is the modification of the surface crystallographic texture without changing the macroscopic shape of the sample. In a classical manner, this can be done when the top surface that has been melted resolidifies by the nucleation and growth of new grains. The growth of the new grains follows the major thermal gradient (perpendicular to the surface) along which some preferred orientations can grow more rapidly; creating thereby a solidification texture. As previously stated, it is also well established that evaporation can become significant at high energy densities [2, 35]. This phenomenon was suggested to lead to a modification of the atomic attachment along the growing solidification interface leading to the development of specific solidification textures in the rapidly solidified layer [20]. Another interesting phenomenon reported recently is the modification of crystallographic surface texture by treating the material below the onset of melting (the so-called heating mode) [24, 25].
Figure 12 shows the EBSD analysis of the surface of an FeAl alloy before and after the LEHCPEB treatment. The standard triangle is shown inset. The initial extruded bar was obtained from milled powder and the initial sample was cut perpendicular to the extrusion axis. The EBSD map in Figure 12(a) shows that a majority of grains have a green color. This illustrates that the as-extruded bar is characterized by a <110> fiber texture along the extrusion axis [36]. This is typical of extruded body-centered cubic metals. Figure 12(b) shows an EBSD map obtained from the surface of a sample treated for 20 pulses of LEHCPEB under the heating mode [25]. The fraction of large angle grain boundaries (LAGBs) is increased quite substantially due to the creation of new subgrains inside the initial grains, as witnessed by the presence of numerous LAGBs (in white) visible in Figure 12(b). These LAGBs must have been formed by the effect of the thermomechanical treatment associated with the LEHCPEB irradiation. Indeed, the material adjacent to the zone of energy transfer is rapidly heated, leading to the formation of a nonequilibrium temperature field coupled with dynamic stress fields propagating into the material. The maximum amplitude of thermal stress during treatment can reach values much higher than the yield strength of the material [5]. From the comparison of the maps in Figure 12, it is clear that many of the initially green grains (Figure 12(a)) have changed their colour, thereby indicating that the texture at the top surface has also been modified by the LEHCPEB treatment. The blue colour in the map—see the colour code in the inset standard suggests that the orientation of most of the grains has rotated towards <111> // the normal direction (ND) or in its vicinity. This modification is due to the heavy deformation and thermal cycles generated during each pulse that also lead to a complex combination of dynamic recovery and strain-induced grain boundary migration. Clearly, the thermomechanical treatment associated with the LEHCPEB treatment in the heating mode has drastically changed the surface texture and microstructure and, contrary to many processes involving plastic deformation, this is done without changing the macroscopic shape of the sample.
Figure 12: EBSD analysis showing the evolution of microstructure and texture of a FeAl alloy: (a) in the as-received state (extruded) and (b) after 20 pulsed of LEHCPEB treatment.
The treatment under the heating mode also modified the mechanical properties of the surface. Indeed, even after only 2 pulses, an increase of about 50 HV in hardness was associated with the LEHCPEB treatment at the surface of the FeAl sample (initially at 300 Hv). This was attributed to the formation of quenched-in vacancies, structural defects such as dislocation and subgrains, as well as the combination of grain refinement and texture modification toward the much stiffer <111> orientation [25]. In addition, LEHCPEB carried out on samples having their surface covered by graphite powder also demonstrates solid-state surface hardening and rapid solid-state surface alloying effects. This led to an increase of more than 100 HV (about 30%) associated with the thermally enhanced solid-state diffusion of C [25]. A final interest of the treatment under the heating mode is that the surface is free of any crater. Thereby, the corrosion resistance remains almost unchanged while other properties such as texture, grain size, and hardness can be modified to a significant extent [24].
As attested by the increasing number of papers published recently from different research groups [3746], the LEHCPEB surface treatment technique is now spreading worldwide seeking for additional new applications including, for example, surface cleaning, surface alloying [14, 32, 41, 42], surface strengthening, polishing, perforating, homogenization, and pre- or posttreatment.
7. Summary and Conclusion
This article deals with the application of the low-energy high-current pulsed electron beam surface treatment technique on light alloys, such as pure Mg and Ti, Mg and Al alloys as well as FeAl.
The pulsed electron irradiation induces an ultra-fast thermal cycle at the surface combined with the formation of thermal stress and shock waves. The LEHCPEB-modified layer is usually divided into three successive regions having different orders of penetration depth: (i) a melted and rapidly solidified layer on the top surface (~1 μm), (ii) a heat-affected zone where solid state phase transformation, deformation and recrystallization may occur (~10 μm), and (iii) a stress-wave-affected zone that can be hardened (~100 μm).
The detailed analysis of Al and Mg alloys revealed that the plastic deformation associated with the imparted stresses results in deep subsurface hardening that can extend over several 100 μm. To this hardening is associated a significant improvement in the wear resistance.
The analysis of the top surface melted surface of light alloys also often witnesses evaporation and condensation of chemical species. This evaporation phenomenon can significantly modify the melt chemistry. Through second-phase dissolution and microstructure refinement in the melted layer, significant corrosion improvement can also be obtained.
Crystallographic texture modifications are also revealed by detailed analysis of the top surface of LEHCPEB-treated samples. The evaporation process was, for example, suggested to lead to the development of specific solidification textures in the rapidly solidified layer. Comparatively, as demonstrated by the analysis of FeAl samples, the potential use of the LEHCPEB technique for producing thermomechanical treatments under the so-called heating mode modifies the surface crystallographic texture without any melting of the surface or any macroscopic change of the sample size.
An additional interest of the heating mode is that the surface is free of any crater. Thereby, the corrosion resistance remains almost unchanged while other properties such as texture, grain size, and hardness can be modified to a significant extent.
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Int. J. Mol. Sci. 2011, 12(10), 6733-6742; doi:10.3390/ijms12106733
Review
The Role of microRNAs in the Biology of Rare Diseases
National Centre for Rare Diseases, Istituto Superiore di Sanità Viale Regina Elena, Rome 299-00161, Italy These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 2 September 2011; in revised form: 21 September 2011 / Accepted: 30 September 2011 / Published: 11 October 2011
(This article belongs to the Special Issue Advances in Molecular Diagnostics)
Download PDF Full-Text [183 KB, uploaded 11 October 2011 13:53 CEST]
Abstract: Rare diseases (RD) are characterized by low prevalence and affect not more than five individuals per 10,000 in the European population; they are a large and heterogeneous group of disorders including more than 7,000 conditions and often involve all organs and tissues, with several clinical subtypes within the same disease. Very often information concerning either diagnosis and/or prognosis on many RD is insufficient. microRNAs are a class of small non-coding RNAs that regulate gene expression at the posttranscriptional level by either degrading or blocking translation of messenger RNA targets. Recently, microRNA expression patterns of body fluids underscored their potential as noninvasive biomarkers for various diseases. The role of microRNAs as potential biomarkers has become particularly attractive. The identification of disease-related microRNAs is essential for understanding the pathogenesis of diseases at the molecular level, and is critical for designing specific molecular tools for diagnosis, treatment and prevention. Computational analysis of microRNA-disease associations is an important complementary means for prioritizing microRNAs for further experimental examination. In this article, we explored the added value of miRs as biomarkers in a selected panel of RD hitting different tissues/systems at different life stages, but sharing the need of better biomarkers for diagnostic and prognostic purposes.
Keywords: microRNA; rare disease; biomarker; hepatoblastoma; multiple osteochondromas; Sezary syndrome; Hailey-Hailey disease; Rett syndrome
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MDPI and ACS Style
Salvatore, M.; Magrelli, A.; Taruscio, D. The Role of microRNAs in the Biology of Rare Diseases. Int. J. Mol. Sci. 2011, 12, 6733-6742.
AMA Style
Salvatore M, Magrelli A, Taruscio D. The Role of microRNAs in the Biology of Rare Diseases. International Journal of Molecular Sciences. 2011; 12(10):6733-6742.
Chicago/Turabian Style
Salvatore, Marco; Magrelli, Armando; Taruscio, Domenica. 2011. "The Role of microRNAs in the Biology of Rare Diseases." Int. J. Mol. Sci. 12, no. 10: 6733-6742.
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Shreffler:CFSE Labeling
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[[Category:ShreffLab]]
[[Category:Protocol]]
[[Category:Protocol]]
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[[Cateogory:Immunology]]
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[[Category:Flow cytometry]]
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[[Category:Immunology]]
Current revision
Contents
Overview
CFSE is used to fluorescently label live cells in order to track them. 5,6-CFDA/SE is membrane permeable, but trapped in the cell when converted by intracellular esterases. CFSE is equally partitioned to daughter cells during division and can be used to measure cell proliferation.
Materials
• 15 mL polypropylene tubes
• PBS
• 5,6-CFDA/SE Invitrogen C1157 dissolved in DMSO at 5 mM and stored at -20°C.
Procedure
1. Suspend PBMCs at 10x106 cells/mL in PBS alone.
2. Ensure that cells are uniformly suspended when CFSE is added.
3. If CFSE negative control is needed, remove cells now.
4. Make '2X' concentration (10 μM) in PBS
• For example: add 5 mL PBS + 10 μL 5 mM CFSE
5. Combine 1:1 PBMC cells + CFSE (e.g. 5 mL PBMCs + 5 mL CFSE) in 15mL tube and mix completely.
6. Place in 37°C H2O bath x 10 min.
7. Wash in 10 mL complete medium.
8. Resuspend in medium at desired density
Discussion
discuss this protocol
References
1. Lyons AB and Parish CR. . pmid:8176234. PubMed HubMed [Lyons]
Contact
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Template:SBB-Protocols Enz1
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EcoRI/BamHI Digest of Wobble Products
For wobble products, you will digest the entire extension reaction-worth of DNA Since you started with 50uL of extension reaction, you should now have 50uL of eluted DNA in water.
• Set up the following reaction in a PCR tube:
50uL eluted DNA
5.7uL NEB Buffer 2
0.5uL EcoRI
0.5uL BamHI
• Mix thoroughly by slamming the tube upside down on the table, and then a quick spin to move the liquid to the bottom of the tube.
• Incubate the reaction at 37 degrees on the thermocycler
• Proceed to another Zymo small fragment cleanup
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"url": "www.werelate.org/wiki/Place:L.B._Nagar%2C_Andhra_Pradesh%2C_India",
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Place:L.B. Nagar, Andhra Pradesh, India
Watchers
NameL.B. Nagar
TypeCity or town
Located inAndhra Pradesh, India
the text in this section is copied from an article in Wikipedia
Lal Bahadur Nagar,well known as L.B.Nagar, is a commercial and residential hub in Hyderabad, India. It was once a Municipality in Ranga Reddy District in the Andhra Pradesh but later got merged into the Greater Hyderabad Municipal Corporation.
Research Tips
This page uses content from the English Wikipedia. The original content was at L.B. Nagar. The list of authors can be seen in the page history. As with WeRelate, the content of Wikipedia is available under the Creative Commons Attribution/Share-Alike License.
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Mowat-Wilson syndrome
(Redirected from Mowat-Wilson Syndrome)
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Mowat-Wilson syndrome
Mowat-Wilson Syndrome, clinical features of Patient 2 at age: (A) 1 year and 6 months; (B-C) 3 years and 5 months; (D-E) 8 years and 1 month.
OMIM 235730
DiseasesDB 32975
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Mowat Wilson syndrome is a rare genetic disorder that was clinically delineated by Dr. D. R. Mowat and Dr. M. J. Wilson in 1998.[1]
Presentation
Mowat-Wilson Syndrome, clinical features of Patient 1 at age: (A) 1 year and 6 months; (B-C) 5 years; (D-E) 13 years and 8 months; (F-G) 18 years.
The disorder is characterized by a number of health defects including Hirschsprung's disease, mental retardation, seizure disorder, delayed growth and motor development, congenital heart disease, genitourinary anomalies and absence of the corpus callosum. Distinctive physical features include microcephaly, narrow chin, cupped ears with protruding lobes, deep and widely set eyes, open mouth, wide nasal bridge and a shortened philtrum.
Causes
The disorder is an autosomal dominant disorder resulting from new mutations or deletions of the ZFHX1B (SMADIP1) gene on chromosome 2q22. However, some of those affected by the disease do not have abnormalities of this gene that are currently detectable.
Prognosis
There is no cure for this syndrome. Treatment is supportive and symptomatic.
References
1. Hirschsprung disease, microcephaly, mental retardation, and characteristic facial features: delineation of a new syndrome and identification of a locus at chromosome 2q22-q23 -- Mowat et al. 35 (8): 617 -- Journal of Medical Genetics. Retrieved on 2007-08-23.
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Australian Bureau of Statistics
Celebrating the International Year of Statistics 2013
ABS Home > Statistics > By Catalogue Number
4509.0.40.001 - Crime and Safety, Australia: Supplementary National and Standard Tables, 1998
Latest ISSUE Released at 11:30 AM (CANBERRA TIME) 05/10/1999
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• About this Release
ABOUT THIS RELEASE
Contains state and territory wafers of most tables included in 4509.0 and additional national tables to those contained in 4509.0
© 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
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6203.0 - The Labour Force, 1970
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• About this Release
Presents detailed results of the monthly Labour Force Survey including tables showing the civilian population aged 15 and over by sex, labour force status, age (single years for persons aged 15-24 years), marital status, States and Territories, capital cities, attendance at school or tertiary education institution, country of birth, year of arrival in Australia, industry, occupation, hours worked, average hours worked, full-time/part-time workers, participation rates, whether looking for full-time or part-time work (unemployed), duration of unemployment, changes in labour force status using matched records, relationship in household, families. Most issues contain an article on a special labour force topic.
Continued by: The Labour Force, Australia
This publication has been scanned from the paper version using character recognition software. This provides a full-text searching capability once downloaded.
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Australian Bureau of Statistics
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8755.0 - Building Activity, Building Work Done, Australia, Preliminary, Mar 1999
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ABOUT THIS RELEASE
Presents preliminary statistics for the value of construction work done in Australia. Separate data is shown for building work done and for engineering work done for both the private and public sectors. The building work done data is further dissected into new residential, alterations and additions to residential and non-residential work. Original, seasonally adjusted and trend estimates for Australia, as well as some original state and territory data, are provided in current prices and chain volume measures terms. This is the major source of data used to compile the national accounts estimates for private gross fixed capital formation on dwellings, and other buildings and structures.
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5372.0.55.001 - International Merchandise Trade: Confidential Commodities List, Mar 2010
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PREFACE
This document details all import and export commodities which have been subject to confidentiality restrictions since 1 January 1988. The data cube containing the details of the confidentialisation is referred to as the Confidential Commodities List (CCL).
The CCL is available from the Downloads tab of this document. The data cube presents information under the following four headings:
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Australian Bureau of Statistics
Celebrating the International Year of Statistics 2013
ABS Home > Statistics > By Release Date
Statistics by Release Date
July, 1970
31/07/1970 Balance of Payments, Quarterly Summary, Jun 1970 (cat no. 5302.0)
23/07/1970 Report on Food Production and the Apparent Consumption of Foodstuffs and Nutrients in Australia, 1968-69 (cat no. 4306.0)
13/07/1970 Summary of Vital and Population Statistics, Dec 1969 (cat no. 3212.0)
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