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Tell me more ×
Answers OnStartups is a question and answer site for entrepreneurs looking to start or run a new business. It's 100% free, no registration required.
I have a customer who is demanding a refund for a purchase made in August 2009. Usually my approach is to give refunds without a quibble, even if they are outside of my 30 day no questions asked guarantee period. I'd like to give this guy a refund too but my payment processor doesn't allow refunding CC charges past 90 days so my hands are tied.
What should I do?
Edited to add: I am in Australia, they are in the USA.
share|improve this question
4 Answers
up vote 5 down vote accepted
If you want to send a refund just write him a check. Or use paypal. Or anything else.
Be creative. You can also offer to pay for a gift card to amazon.com or other vendor.
share|improve this answer
Try to give them the refund electronically instead of writing a cheque. An Australian cheque will take weeks to clear an American bank account and the bank could hold the funds until it clears.
share|improve this answer
Your hands are not tied, you just can't refund their credit card. This doesn't mean you can't refund in some other way.
You have added that you live in Australia, so sending a cheque is no good. You can refund the customer by Pay Pal, but I would speak to them and explain the situation and that you are willing to refund, but you need to know which payment method is convienient for the both of you.
Don't let rules like this determine your business practices. If there are restrictions then create a system to work around it. I personally find it infuriating when a company tells me they can't do something because of a policy they have. Standing out and going the extra mile is what makes you stand out from the crowd.
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How about just cut the customer a cheque?
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Not the answer you're looking for? Browse other questions tagged or ask your own question.
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1. Skip to navigation
2. Skip to content
3. Skip to sidebar
Source link: http://archive.mises.org/12613/what-next-for-treasury-bonds/
What Next for Treasury Bonds?
May 3, 2010 by
The government is not a wealth generator — it is completely at the mercy of the wealth generators in the private sector. This, of course, means that the US government must drastically cut its expenditures to prevent a serious economic disaster. FULL ARTICLE by Frank Shostak
Previous post:
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Add a Serial port to the LS MINI
From NAS-Central Buffalo - The Linkstation Wiki
(Difference between revisions)
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Revision as of 11:37, 8 September 2008
Linkstation Mini
LS MINI PCB frontside - high resolution
LS MINI PCB backside - high resolution
Contents
Background
Apparently there are two traces that have been interrupted which would allow serial port access.
These traces have been interrupted UNDER a SMD capacitor at position C54. Junker (see Yamasita's article/reference) discovered the way first[1]. Apparantly the pinheaders from the SCON-KIT/ PRO can be fit into the case quite easily as well[2].
Laitr Keiows and johnbock duplicated his efforts[3]
Method
C54
We need to fix these wires which go under C54:
Method 1: reconstruct the traces (on the backside)
This method requires absolutely no soldering.
Lay a layer of a scotch tape between holes, just not to cover them.
Use a strand of high flexible low oxygen copper wire.
1. thread it through both holes,
2. fix it with a scotch tape on the back side and then
3. cut remainders on the front side, leaving about 2 mm.
4. repeat with the second thread.
Be sure not to shorten anything else.
Holes marked in RED
Use a strand of high flexible low oxygen copper wire, thread it through both holes and fix it with a scotch tape on the back side
Cut remainders on the front side, leaving about 2 mm
Method 2: Bridge the traces (on the frontside)
Pinout of Port
Wire colors referenced in table
Pin Signal Wire Color
1 Transmit (TX) Green
2 Receive (RX) White
3 Power (3.3V)* none
4 Ground (GND) Red
Use a Level Shifter
The serial port signals from the processor are only 3.3V. For proper RS-232 12V signaling, an RS-232 level shifter needs to be added. These are very common in PDA serial cables also, but can be purchased
Models other than KuroPro
If you are attaching a serial header pin onto the main board, you may want to consider:
• Using the header pin unit with a 90 degree bend, or you might not be able to close the case
• Soldering it with the pins toward the interior, rather than toward the case. This allows easier access, since if the pins face the case side they would be very close to the metal side. This would make access is so tight that one might end up taking the board out to get plug fitted on the pins.
Build your own LVTTL/RS232 or LVTTL/USB interface
Buy your own TTL Level Shifter
Usage considerations for the TTL-232R-3V3
TTL-232R-3V3 USB to TTL Serial Converter Cable
A very similar TTL/USB converter cable that uses a chip by FTDI (the same chip is used in the SCON-KIT ) can be obtained, but the pinout at the connector end would need to be reassigned: Spec Sheet w/ pinout, wire colors & other info
Mouser Part # 895-TTL-232R-3V3 $20.00
Mouser Part # 517-929400-01-04 $0.32
A working/tested pinout/wire-color scheme is:
Color Pin Number Signal
yellow 1 TXD
orange 2 RXD
unused 3 VCC
black 4 GND
• Solder the 4-pin header to the board. Make sure you don't have shorts.
• You will need to switch wires on the TTL-232R-3V3 cable. Use a sharp object to lift the plastic tabs and carefully pull the wires out. Rearrange them according to the table above (black, empty, orange, yellow, empty, empty) and slide those wires back in. Tape the other wires to make sure they don't short anything.
• When plugging in the cable, make sure black aligns with GND, yellow with TXD, and orange with RXD.
• Connect the USB cable to your computer, start a terminal program with the right settings.
• Turn on the device, you should see output from the bootloader in couple seconds.
Serial Port Output
LS Mini: Serial Port Output - Boot-Log
References
1. シリアルコンソールのためのパッチ / patches for serial console:LS-WSGL/R1
2. シリアルコネクタの半田付け / soldering a serial connecter:LS-WSGL/R1
3. The Buffalo NAS hacking Forums:Serial access possible? YES!
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Information/LSPROOverview
From NAS-Central Buffalo - The Linkstation Wiki
Revision as of 22:50, 19 October 2006 by 209.94.50.66 (Talk)
Jump to: navigation, search
LS-GL ARM9 (LSPRO)
CPU MARVELL 88F5182 Media Vault Processor[1]
System on Chip(SOC)
CPU: ARM926EJ-Sid(wb) [41069260] revision 0 (ARMv5TEJ)
running @ 400Mhz
Orion[2] 1 streaming disabled
SysClock = 200Mhz , TClock = 166Mhz
RAM 128MB total: Two (2) NANYA NT5TU32M16AG or Elpida EDE5116AF DDR2 SDRAM
Flash ROM Flash: SST 256K CMOS Multi-Purpose
Other Two (2) 43DR39K Latch???
NEC 500T 0536KX00???????
NIC MARVELL 88E1111 Gigabit Ethernet Transceiver.
USB 2 - USB 2.0 Max: 480 Mbps (HS Mode), Max: 12 Mbps (FS Mode)
SATA Controller Marvell Serial ATA Adapter - Internal drive is formatted as XFS file system
Drive Capacity 750GB, 500GB, 400GB, 300GB, 250GB or 160GB
Stock Firmware BUFFALO LS-GL U-Boot - U-Boot 1.1.1 (Jun 12 2006 - 10:32:00) Marvell version: 1.10.8
Linux version 2.6.12.6-arm1 (root@develop) (gcc version 3.4.4 (release) (CodeSourcery ARM 2005q3-2)) #75 Sun Jun 11 14:33:24 JST 2006 [3][4]
hddrootfs.img
initrd.img password
IeY8omJwGlGkIbJm2FH_MV4fLsXE8ieu0gNYwE6Ty
Buffalo has released a new version of the LinkStation[5]. based on a Mediabolic Reference Design[6] similar to the Maxtor shared storage II[7] device.
Contents
From the Forums
Firmware
http://www.buffalo-technology.com/linktheater/ls-gl_100-042.zip
if you unpack the zip-file you get the following files:
hddrootfs.img
initrd.img
linkstation_version.txt
LSUpdater.exe
lsupdater.ini
u-boot.buffalo.updated
uImage.buffalo
this is the password which can be used to unpack hddrootfs.img and initrd.img (=Ramdisk...this is the EM Mode Linux)
IeY8omJwGlGkIbJm2FH_MV4fLsXE8ieu0gNYwE6Ty
Features
• Simplified File Sharing For Home or Small Office Network
• Active Directory Support: Works as a client in an Active Directory domain allowing LinkStation Pro to utilize the domain users and groups.
• High Speed Processor, DDR-II Ram, and SATA Hard Drive Provide Ultra Fast Transfer Rates.
• Control Access With Group and User Level Security
• Access Data from any Windows or Macintosh Computer on Your Network
• Two or More LinkStations Can be Used to Back Up Each Other Over Your Network
• Easy Setup Does Not Require Drivers
• Scheduled Backup via USB 2.0 to External Storage
• Expand Storage by Adding a USB 2.0 Hard Drive
• Auto-MDIX10/100/1000 Base-T Gigabit Ethernet Port
• Gigabit JumboFrame Support (4k, 8k, 15k)
• Protect your Data with Memeo™ AutoBackup Software
• Minimal Power Consumption (~23W)
• Space-saving Compact and Aesthetic Design
This is from the Buffalo Site[8]
References
1. http://www.embedded.com/ - Marvell's Feroceon ARM-based CPU shifts to variable-length pipeline
2. Marvell: Media Vault Processors (Orion)
3. http://www.yamasita.jp/linkstation/0608/060808.html LS-160GL (dissasembled)] - From www.yamasita.jp
4. The Linkstation Community Forum / General Development / preview of the Linkstation Pro
5. Tom's Networking: BuffaloTechnology's LinkStation Pro: One Hot NAS!
6. Mediabolic: NAS Media Server Reference Designs
7. http://www.linuxdevices.com/ Maxtor shared storage II: Dual-drive NAS server runs Linux, supports DLNA
8. http://www.buffalotech.com/ LinkStation Pro Shared Network Storage 500GB
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Selectivity of Multi-wall Carbon Nanotube Network Sensoric Units to Ethanol Vapors Achieved by Carbon Nanotube Oxidation
Robert Olejnik, Petr Slobodian, Pavel Riha, Petr Saha
Abstract
Two kinds of multiwall carbon nanotubes (MWCNT) networks “Buckypaper” were made by the vacuum filtration method of MWCNT aqueous suspension. The first one was prepared from pure CNT and the second from its oxidized form. The CNT oxidation increase content of oxygen bonded to the surface of CNT. The sensitivity of MWCNT networks to organic solvent vapors (ethanol and heptane) has been investigated by resistance measurements. The solvents had different polarities given by Hansen solubility parameters and nearly the same volume fractions of saturated vapors at the condition of experiment. CNT oxidation significantly increases the sensitivity of CNT resistive sensoric unit to vapors of ethanol and decrease response to heptane vapors.
Full Text: PDF DOI: 10.5539/jmsr.v1n1p101
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Journal of Materials Science Research ISSN 1927-0585 (Print) ISSN 1927-0593 (Online)
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Tuesday, May 18, 2010
Oil Slick Enters the Loop Current
MODIS/Terra satellite image taken May 17, 2010
According to BP, it succeeded in intubating the riser pipe from the leaking Deepwater Horizon well.
At the oil-leak site, a tube five-feet long and four inches in diameter was pushed into a leaking riser that’s 21 inches in diameter _ the source of most of the spill. The inserted tube has three large flexible rubber diaphragms to keep it in the riser and block oil and water from mixing; however, BP officials said the riser is still leaking some oil.
The pipe is full of nitrogen, which is slowly being pulled back to let oil and gas flow in while keeping water from entering. Methanol, a kind of antifreeze, is also being pumped into the riser to stop crystals from forming that could block gas and oil from flowing to the ship. Crystals got in the way of a previous attempt to lower a 78-ton containment cap over the leak site.
The surface tanker will separate the oil, gas and water mixture for storage and eventual offloading. Overnight some of the collected gas was burned through a flare system on the tanker. BP officials weren't able to specify Sunday how much the tanker can hold.
The company says it is capturing about one fifth of the oil leaking though the pipe and hopes to raise that amount to three quarters. Meanwhile a significant amount of oil is still leaking into the gulf. It is not clear from reports exactly how many gallons are being captured and how many are still leaking. It is also not clear whether the proportions are the same whether the spill rate is closer to BP's estimate or that of independent experts. The next attempt to stop the spill will be a "top kill," which entails jamming mud and cement into the top of the well until the leak stops. That would be at best a temporary patch until a relief well is ready in August.
Meanwhile, satellite imagery shows that oil from the Deepwater Horizon spill has already entered the Loop Current, which circulates clockwise around the northern Gulf of Mexico. (See the image at the top of the post.) Within a few days, the Loop Current could carry oil to the Florida Keys:
This study implies that the greatest risk of land impacts by surface oil caught in the Loop Current is along the ocean side of the Florida Keys, and along the coast of Southeast Florida from Miami to West Palm Beach. Eddies breaking away from the Gulf Stream would also likely bring oil to northwest Cuba, the western Bahamas, and the U.S. East Coast as far north as Cape Hatteras, North Carolina, though at lesser concentrations. Southwest Florida cannot rest entirely, though--the "forbidden zone" is only true for surface waters, and there is onshore flow below the surface. Since recent ship measurements have detected substantial plumes of oil beneath the surface, southwest Florida might be at risk if one of these plumes gets entrained into the Loop Current. ... There are plans for the Hurricane Hunters to go out again tomorrow and drop more probes into the spill to attempt to get a better handle on where the oil is and where the currents are taking it.
It is possible that some of that oil has already arrived, and a major barrier reef could be at risk. The risk to the reef is magnified if you consider that there is far more oil present underwater than is visible on the surface. BP has used massive amounts of dispersants to break up the oil leaking from the riser pipe. As a result, most of the oil is not reaching the surface.
Scientists are finding enormous oil plumes in the deep waters of the Gulf of Mexico, including one as large as 10 miles long, 3 miles wide and 300 feet thick in spots. The discovery is fresh evidence that the leak from the broken undersea well could be substantially worse than estimates that the government and BP have given.
“There’s a shocking amount of oil in the deep water, relative to what you see in the surface water,” said Samantha Joye, a researcher at the University of Georgia who is involved in one of the first scientific missions to gather details about what is happening in the gulf. “There’s a tremendous amount of oil in multiple layers, three or four or five layers deep in the water column.”
The plumes are depleting the oxygen dissolved in the gulf, worrying scientists, who fear that the oxygen level could eventually fall so low as to kill off much of the sea life near the plumes.
Dr. Joye said the oxygen had already dropped 30 percent near some of the plumes in the month that the broken oil well had been flowing. “If you keep those kinds of rates up, you could draw the oxygen down to very low levels that are dangerous to animals in a couple of months,” she said Saturday. “That is alarming.”
What this means is that underwater ecosystems are probably at far greater risk than bird nesting colonies, in either Louisiana or the Florida Keys.
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All Topics
From eLinux.org
Revision as of 03:15, 2 September 2008 by Flakeman2 (Talk | contribs)
Jump to: navigation, search
Contents
Bootup Time
• Bootchart lite (lightning talk) – Shuuji Miyake (JJ16)
• Parallelizing Linux boot on CE Devices - Vitaly Wool (ELCE07)
• Evaluation and improvement of Bootchart - K. Yasui (JJ18)
• TP TimeMeasure, A tool to masure application software startup time - Yoichi Yuasa (JJ19)
• Instant Startup for Application Using Reducing Relocation Time and Rearrange Function - Min-Chan Kim (ELC08)
• Fast Booting of Embedded Linux - Ho-Jun Park (KTJ3) download pdf download demo
Browsers
• WebKit on Linux and How It Compares to Other Open Source Engines - Holger Freyther (ELCE07)
• Embedding a Mozilla Based Browser - Sampo Nurmentaus (ELCE07)
Distributions
• The PokyLinux Distribution: Mobile GNOME at Your Fingertips - Dodji Seketeli (ELCE07)
• Maemo Mobile Linux Platform, Current Status and Future Directions – Kate Alhola (ELC08)
• Roll-Your-Own Linux the Easy Way with LTIB – Stuart Hughes (ELC08)
• Building Custom Embedded Linux Distributions (using OpenEmbedded) – Matt Locke (ELC08)
• UME - Ubuntu Mobile and Embedded - David Mandala (ELC08)
File Systems
• JFFS2/YAFFS explanation and comparison of mounting time - K. Yano (JJ17)
• Improving JFFS2 RAM Usage and Performance - Alexey Korolev (ELCE07)
• Introduction to LogFS - Jörn Engel (ELCE07)
• YAFFS - Wookey (ELCE07)
• The Comparison of Flash File system performace - JFFS2, YAFFS, LogFS - Katsuki Uwatoko (JJ19)
• AXFS: Architecture and Results – Jared Hulbert (ELC08)
• Filesystem Support on Multi Level Cell (MLC) Flash in Open Source - Kyungmin Park (ELC08)
Graphics
• Writing DirectFB gfxdriver For Your Embedded System - Takanari Hayama (ELCE07)
• DirectFB Internals - Things You Need to Know to Write Your DirectFB gfxdriver - Takanari Hayama (ELC08)
• Adding Framebuffer support for Freescale SoCs - York Sun (ELC08)
• Gstreamer and OpenMAX IL: plug and play - Felipe Contreras (ELC08)
Memory Management
• Asymmetric NUMA: Multiple-Memory Management For The Rest of Us – Paul Mundt (ELCE07, JJ19)
• Implementation of Memory management method for embedded systems using CABI - Miyake (JJ18)
• Swap usage in embedded system (Korean) - Seung-Ho Park (KTJ2)
• Avoiding Out-Of-Memory on Embedded Linux Young-Joon Jang (KTJ2, ELC08)
• Dependable Memory management system for Embedded Linux (Japanese) - Yamamoto (JJ20)
Mobile Phone
• Development of Mobile Linux Open Platform (Android) - Junji Kondo (JJ18, ELC08)
Power Management
• A Power Management Architecture For Mobile Devices - Matthew Locke (ELCE07)
• Linux Suspend-to-Disk Objectives for Consumer Electronic Devices – Vitaly Wool (ELCE07)
• Linux Clock Management Framework - Siarhei Yermalayeu (ELCE07)
• A Dynamic Voltage and Current Control Interface for the Linux Kernel – Liam Girdwood (ELC08)
• Power Management Quality of Service and How You Could Use it in Your Embedded Application – Mark Gross (ELC08)
• Building Blocks for Embedded Power Management – Kevin Hillman (ELC08)
• Linux System Power Management on OMAP3430 - Richard Woodruff (ELC08)
Processor/Platform
• CELL BE - H. Machida (ELCE07)
• ARM procedure call standard – Hee Seo (KTJ2)
RealTime
• Recent new Features in NPTL - Hiroki Kumagai (JJ16)
• Covers priority inheritance mutexes
• CABI, CPU Resource Allocator development status - Y. Yuasa (JJ17)
• Status Overview of Real-Time – Thomas Gleixner (ELCE07)
• RT Patch for Cell EB - Patch Status and Performance Measurements - Tsutomu Owa (ELCE07)
• Using Real-Time Linux - Klaas van Gend (ELC08)
• Real-Time Virtualization Solutions for Linux - A Comparison of Strategies - Nicholas McGuire (ELC08)
• Adventures In Real-Time Performance Tuning - Frank Rowand (ELC08)
• The Completely Fair Scheduler - Thomas Gleixner (KTJ3) download pdf
• Designing a Realtime System with MV Linux- Seung-Ryong Kwon (KTJ3) download pdf
Security
• Knoppix 5.1.1 for Trusted Computing Geeks - K.Suzaki (JJ17)
• Trusted Secure Isolation For Embedded Linux – Hadi Nahari (ELCE07)
• Development of Embedded SELinu - Yuichi Nakamura (JJ18, ELC08)
• Performance evaluation of Secure OS using LSM - Naoto Matsuda (JJ18)
• Recent Security Features and Issues in Embedded Systems - KaiGai Kohei (ELC08)
• Avoiding Web Application Flaws in Embedded Devices – Jake Edge (ELC08)
• How to Analyze Your Linux's Behavior with TOMOYO Linux - Kentaro Takeda (ELC08)
Size
• Compressed Cache – (JJ16)
• Linux-tiny update – Satoru Ueda (for Tim Bird) (JJ17)
• Linux Tiny - The Diet Must Go On – Michael Opdenacker (ELCE07)
• Compressed Swap Solution for Embedded Linux - Alexander Belyakov (ELC08)
• Kernel Size Report, and Bloatwatch Update – Matt Mackall (ELC08)
• Linux Tiny - Penguin Weight Watchers – Thomas Petazzoni (ELC08)
Tools
• TimeDoctor - Francois Audeon (ELCE07)
• Using a JTAG for Linux Driver Debugging – Mike Anderson (ELC08)
• How GCC Works, An Embedded Engineer's Perspective – Gene Sally (ELC08)
• Embedded Linux Development with Eclipse - JT Thomas (ELC08)
• Scratch Box on cross compile environment (Japanese) – Kobayashi (JJ20)
• Scratch Box on cross compile environment - part 2 (Japanese) – Fuse (JJ21)
Tracing
• KFT on PPC – Tsutomu Owa (JJ16)
• OProfile porting on MIPS architecture - Takehiko Nagano (JJ16)
• Episodes of LKST for Embedded Linux Systems - Hirohisa Iijima (ELC08)
• Function-Call Backtracing based on MIPS architecture Linux System - Jong-Sung Kim (KTJ3) download pdf
Tutorials/Development tips
• Dynamic Linking 3 – Tetsuyuki Kobayashi (JJ16)
• Learning Kernel Hacking from clever people – Hugh Blemings (ELC08)
Advice/Tips for Acting within Community
• To Go Along with Community – Shibata (3-JJ17) (4-JJ18)
• Experiences Posting Patches to the Community - Nakamura (JJ16)
• Free Software, Licensing and Business Processes - Shane Martin Coughlan (ELCE07)
• Methods to Protect Proprietary Components in Device Drivers – Matt Porter (ELCE07)
• From the world of Community
• David Woodhouse (JJ19, KTJ2)
• The Relationship Between kernel.org Development and the Use of Linux for Embedded Applications - Andrew Morton (ELC08)
• Appropriate Community Practices: Social and Technical Advice - Deepak Saxena (ELC08)
• The Discrimination Method of GPL License Violation on Embedded Products - Kyung-Ae Kim (KTJ3)
Advocacy
• Advantage of Linux for use of Embedded systems (JJ18)
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PRUSSv2 Interrupt Controller
From eLinux.org
Revision as of 19:50, 4 December 2011 by Scribe (Talk | contribs)
Jump to: navigation, search
The PRUSS Interrupt Controller sits on the SCR 32-bit bus that interconnects elements of the PRUSS. It also has a direct outgoing connection to the ARM Interrupt Controller, EDMA and TSC_ADC Event triggers, allowing interrupts to these units to be dispatched by various components of the PRUSS. The controller also has a direct incoming connection, allowing it to receive events from various SoC external peripherals.
Important Note: It is vital to clear all system interrupts before the PRU is halted, else the PRUSS will not power down.
Contents
Features
A list of 64 possible interrupt events.
10 interrupt channels (Channel-0 to Channel-9), allowing for 10 separate active triggers, which may be triggered by one or more specified interrupts from the above list.
If more than one interrupt arrives at the same time, those assigned to a lower channel number will be given priority. If more than one interrupt arrives at the same time on the same channel, again, the interrupt with the lowest interrupt number from the above table is given priority.
10 host channels (Host-0 to Host-9), allowing for one or more interrupt channels to be directed to up to 10 different locations, either within or outside of the PRUSS.
The first two channels, Host-0 and Host-1, always directly point to Register R31 bit 30 and bit 31 respectively of the two PRU units, enabling PRUs to receive interrupts by checking these register bits.
Other locations a host channel may point to will typically be local peripherals, external components such as the EDMA for triggering a DMA transfer and the ARM Interrupt Controller for interrupting an operating system, allowing for software intervention.
Enabling the Interrupt Controller
Instruction Location Name Location Number
1. Globally enable interrupts by setting the Global Enable Register (GER) to 1 PRUSS_INTC + GER 0x0002_0000 + 10h
2. Set polarity of all incoming events through the System Interrupt Polarity Registers (SIPR0 and SIPR1) to Active High (set all bits to 1) PRUSS_INTC + SIPR0
PRUSS_INTC + SIPR1
0x0002_0000 + D00h
0x0002_0000 + D04h
3. Set the type of all incoming events through the System Interrupt Type Registers (SITR0 and SITR1) to 'pulse' (set all bits to 0) PRUSS_INTC + SITR0
PRUSS_INTC + SITR1
0x0002_0000 + D80h
0x0002_0000 + D84h
Although the Interrupt Controller supports settings for individual interrupt polarities and types, in the AM335X (BeagleBone) processor, these settings are ALWAYS Active High and Pulsed and as such can be configured as part of the global set-up as opposed to configuration for individual interrupts.
Configuring and enabling an Interrupt
Instruction Location Name Location Number
1. Map the chosen system event to an interrupt channel by inserting the channel number into the appropriate Channel Map Register (CMR0::15 - each register represents 4 system interrupts) PRUSS_INTC + CMR0 ...
PRUSS_INTC + CMR15
0x0002_0000 + 400h ...
0x0002_0000 + 43Ch
2. Map the configured interrupt channel to the chosen host channel by inserting the host channel number into the appropriate Host Map Register (HMR0::2 - each register represents 4 interrupt channels)
It is recommend to assign interrupt channel X to host channel X (Interrupt Channel 1 -> Host Channel 1 etc.)
PRUSS_INTC + HMR0 ...
PRUSS_INTC + HMR2
0x0002_0000 + 800h ...
0x0002_0000 + 808h
3. Clear the system interrupt's status by setting the appropriate bit in the System Interrupt Status Register to 1 (SECR0::1 - each register represents 32 interrupts) PRUSS_INTC + SECR0
PRUSS_INTC + SECR1
0x0002_0000 + 280h
0x0002_0000 + 284h
4. Enable the individual host channel by writing the host channel number to the Host Interrupt Enable Indexed Set Register (HIEISR)
Individual interrupts can be disabled by following the above step but by instead writing to the Host Interrupt Enable Indexed Clear Register (HIDISR)
PRUSS_INTC + HIEISR 0x0002_0000 + 34h
5. Enable the individual system interrupt (system event) by writing the interrupt number to the System Interrupt Enable Indexed Set Register (EISR)
Individual system interrupts can be disabled by following the above step but by instead writing to the System Interrupt Enable Indexed Clear Register (EICR)
PRUSS_INTC + EISR 0x0002_0000 + 28h
Servicing (clearing) an Interrupt
Instruction Location Name Location Number
1a. Clear the interrupt's status by setting the bit at the location of the interrupt number in the System Interrupt Status Enabled/Clear Register (SECR0::1 - for example, to clear Interrupt 12, write 1 to bit 12 in SECR0). PRUSS_INTC + SECR0
PRUSS_INTC + SECR1
0x0002_0000 + 280h
0x0002_0000 + 284h
1b. Alternatively, clear the interrupt's status by writing the interrupt number to the System Interrupt Status Enabled Indexed Clear Register (EICR). PRUSS_INTC + EICR 0x0002_0000 + 2Ch
Interrupt Nesting
Interrupt nesting allows various priorities of interrupts to be disabled when an interrupt event, with nesting configured, is received. Disabled interrupts are then re-enabled by the user writing to the ISR register.
There are three types of supported nesting:
Nesting of all host channels of the same or lower priority when an interrupt event is received
The nesting level can be set by placing the channel number in the Global Nesting Level Register (GNLR).
Nesting of an individual host channel, the individual host may not be interrupted by interrupt events on interrupt channels of the same or lower priority
The nesting level can be set individually by placing the channel number in the Host Interrupt Nesting Level Registers (HINLR0::1)
Software nesting, whereby the software disables all host channels on receipt of an interrupt, proceeded by enabling/disabling individual host channels and finally re-enabling all host channels, allowing only those manually enabled to continue processing interrupts. The changes are reversed once the interrupt request has been serviced by the software.
Requires the most CPU intervention and should be avoided if either of the first two nesting solutions are applicable.
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PandaBoard
From eLinux.org
Revision as of 12:48, 22 May 2012 by Esky-sh (Talk | contribs)
Jump to: navigation, search
The PandaBoard is an OMAP4430 (Cortex-A9) based low cost development platform.
Contents
Hardware
• OMAP4 (Cortex-A9) CPU based open development platform.
• OMAP4430 Application processor
• 1GB low-power DDR2
• Display HDMI v1.3 Connector (Type A) to drive HD displays, DVI-D Connector (can drive a 2nd display, simultaneous display; requires HDMI to DVI-D adapter), LCD expansion header
• 3.5" audio in/out and HDMI Audio out
• Full size SD/MMC card
• Built in 802.11 & Bluetooth v2.1+EDR
• Onboard 10/100 Ethernet
• Expansion: 1xUSB OTG, 2xUSB HS host ports, General purpose expansion header (I2C, GPMC, USB, MMC, DSS, ETM)
• JTAG, UART/RS-232, 2 status LEDs, 1GPIO button
More details can be found here
• PandaBoard EA1 Front
A hi resolution picture of the PandaBoard EA1 front is available here: http://elinux.org/images/d/d4/Panda_front.jpg
• PandaBoard EA1 Back
Availability
PandaBoard are in production and can be ordered from Worldwide distributors. You can also easily identify the board you have using Board revision id
Rev A3
Latest version of the board.
Rev A1/A2
Details
Rev EA1/EA2
These were limited number of 'Early Adopter' boards that built prior to production versions. more details
Rev ES
There is now a PandaBoare-ES http://pandaboard.org/content/pandaboard-es which includes an OMAP 4460 at up to 1.2GHz. Several important differences make it important (at the present time) that the MLO/u-boot/kernel be specifically crafted for the 4460. The thermal management is not in the mainline 4430 code as yet and could cause unwanted thermal problems. So BEWARE of running any code built for the non -ES PandaBoard on the -ES model.
Accessories
Recommended Reading Material
How To's
Older How To's
Community
Website: http://pandaboard.org
IRC: #pandaboard @irc.freenode.net
Mailing List: pandaboard@googlegroups.com
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"warc_filename": "<urn:uuid:0ceeecef-ec06-44f1-8878-a1cae43d8d65>",
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Maryland CemeteriesEdit This Page
From FamilySearch Wiki
Revision as of 00:08, 12 July 2012 by Dianekay (Talk | contribs)
United States Maryland Cemeteries
Contents
Websites
The following websites will help you find cemetery records, transcriptions, and headstone photographs currently available online:
Resources at the Maryland State Archives
• Tombstones and Cemetery Records. A bibliography for each county in Maryland is listed on this site. Other resources are also available.
• Funeral Home Records are closely related to a search for cemetery records. The Maryland State Archives website maintains a list of funeral homes and identifies where some of the records are located.
National Cemeteries in Maryland
African American Cemeteries in Maryland
Cemetery records at the Family History Library
Click here to see the full list of cemetery records available at the Family History Library for Maryland: Maryland cemetery records at the Family History Library. A few examples from this list include:
• FHL book 975.2 V22r Historic graves of Maryland and the District of Columbia : with the inscriptions appearing on the tombstones in most of the counties of the state and in Washington and Georgetown}} You can review this book while visiting the Family History Library, or order a copy of the microfilm through FamilySearch.
• FHL film 285059 A List of Ohioan's killed during the Civil War : buried at National Cemetery, Andersonville, Georgia; Antietam cemetery, Maryland, and miscellaneous cemeteries] (This is a microfilm that can be ordered at FamilySearch.
• FHL book 975.2 V34d Directory of Maryland burial grounds. This is a book that was published in 1996. A microfilm copy is not available.
• FHL 151717 D.A.R. genealogical records A book containing the Daughters of the American Revolution (DAR) compiled cemetery records for Maryland is available at the Library and a microfilm copy can also be order through FamilySearch.
Maryland Cemetery Message Boards and Online Mailing Lists
If you need help finding the cemetery where your ancestor was buried in Maryland, an online message board or mailing list might be helpful:
Maryland counties
See the individual county pages for a list of cemeteries within each county and links to available records:
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).
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An unofficial blog that watches Google's attempts to move your operating system online.
Send your tips to gostips@gmail.com.
January 28, 2011
Google Image Search Indexes SVG Files
Last year, Google announced that it started to index SVG files, but the results were only returned by the web search engine. "SVG is an open, XML-based format for vector graphics with support for interactive elements. We're big fans of open standards, and our mission is to organize the world's information, so indexing SVG is a natural step. We index SVG content whether it is in a standalone file or embedded directly in HTML," explained Google at that time.
Now you can find SVG files in Google Image Search by restricting the results to this filetype in the advanced search page or by using the filetype operator. Here's an example: [molecule filetype:svg]. If you restrict the results to Wikipedia, Google returns 57,300 SVG files.
Most browsers can render SVG markup, but there are at least two important exceptions: Internet Explorer (IE9 will add support for SVG) and Android's built-in browser.
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[Date Prev][Date Next][Thread Prev][Thread Next][Date Index][Thread Index]
[libreoffice-users] Re: Question about Calc
Am 29.06.2012 11:10, Ian Whitfield wrote:
Morning All
Can you help me out - I've done this before but now can not get it to
work!!
I'm working in Calc (latest) on PCLinuxOS (latest) and have a multi-page
spreadsheet.
I have my dates in SHEET 1.Col 'C' with the matching data in the same
ROW. Lower down I use a dropdown box to select which date I want. I then
use a MATCH function to find out which ROW that date is on. So far so
good... this works fine and - for example - I get a returned value of
'14' which tells me that the data for the date selected is on ROW 14 of
the spreadsheet.
=INDEX($ListSheet.$A$1:$X$999 , MATCH(value , array , 0) , column_number)
--
For unsubscribe instructions e-mail to: users+help@global.libreoffice.org
Problems? http://www.libreoffice.org/get-help/mailing-lists/how-to-unsubscribe/
Posting guidelines + more: http://wiki.documentfoundation.org/Netiquette
List archive: http://listarchives.libreoffice.org/global/users/
All messages sent to this list will be publicly archived and cannot be deleted
Follow-Ups:
Re: [libreoffice-users] Re: Question about CalcIan Whitfield <whitfield@telkomsa.net>
References:
[libreoffice-users] Question about CalcIan Whitfield <whitfield@telkomsa.net>
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{
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"provenance": "cccc-CC-MAIN-2013-20-0000.json.gz:25248",
"uncompressed_offset": 207841907,
"url": "quotationsbook.com/quote/gift/5752/",
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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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"provenance": "cccc-CC-MAIN-2013-20-0000.json.gz:25249",
"uncompressed_offset": 207847408,
"url": "quotationsbook.com/quote/gift/9686/",
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"warc_filename": "<urn:uuid:0ceeecef-ec06-44f1-8878-a1cae43d8d65>",
"warc_url": "http://quotationsbook.com/quote/gift/9686/"
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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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Help Wikitravel grow by contributing to an article! Learn how.
Montérégie
From Wikitravel
(Redirected from Monteregie)
Jump to: navigation, search
Montérégie is the region of Quebec immediately east, south and west of Montreal, extending to the borders of Ontario and New York State. The South Shore of the St. Laurent River, across from Montreal, is a series of suburbs serving the city proper. Further out, the flat valley of the St. Laurent provides for pleasant, airy farmland and countryside.
[edit] Cities
• Longueuil — the largest city on the South Shore
• Brossard
• Chambly — home to Fort Chambly, a French fort built in the 1700s.
• Hudson — a small, scenic town in the Vaudreuil region, west of Montreal.
• Huntingdon — small village on the Chateauguay river.
• Mont-Saint-Hilaire — a scenic town near Montreal with a mountain, river and foliage.
• Rigaud — a mountain town in Vaudreuil county that attracts skiers, hikers, maple syrup enthusiasts and Catholic religious tourists.
• Rougemont — a small town known primarily for its apple (and apple cider) production, and sugar shacks.
• Saint-Constant — home of the Canadian Railway Museum
• Saint-Jean-sur-Richelieu — small town on the Richelieu river. Host of the Hot Air Ballon festival in July.
• Salaberry-de-Valleyfield — town located to the south-west of Montreal.
[edit] Other destinations
• Kahnawake Mohawk Reserve, just across Montreal's Mercier bridge, is a suburban native reserve. Not too many tourist attractions (except during the powwow in July-- see below), but close to Montreal if you want to say that you've visited one of Canada's native reserves.
• Akwesasne Mohawk Reserve is in the extreme southwest of Quebec. The reserve extends across the St. Lawrence river into Ontario and New York State. The Quebec portion of Akwesasne is much easier accessed from Ontario or New York (unless you have a boat), since there are no roads linking the Akwesasne reserve to the rest of Quebec. Its main tourist attraction, the casino, is located on the Ontario side.
[edit] Understand
The Montérégie, named after the mountains that sporadically pop out of the St.Lawrence River valley, is a sort of "catch-all" tourism region rather than a distinct geographical or cultural area. The region is a mixture of Montreal suburbs and rural farming areas near the edges of Quebec.
In spite of this, a few generalization can be made about the region:
• In the 18th and 19th century, it was a military buffer region. Capturing Montreal was an American objective in the American Revolution and the War of 1812. Several battles were fought in the Montérégie, and the ancient forts that remain are interesting tourist attractions.
• As a mixture of suburban and rural areas, it is a swing political district. If you want to know which way the political wind is blowing in Quebec, ask people in the Montérégie.
• While most of the area is economically and culturally integrated with Montreal, the more rural towns were once isolated farming areas with their own traditions. If one digs hard enough, one can still find cultural relics from this era, such as the Brome County Fair.
[edit] Talk
The majority of the people living in the Montérégie speak French. There are significant English-speaking populations in some towns. Most people can speak English to some degree; a lost tourist will almost always be able to get directions in English, although not always from the first person they ask. Traffic signs are in French, but are designed (with pictures and symbols) so that people who speak only English can easily figure them out.
Kahnawake and Akwesasne Reserves have made efforts to increase the use of the Mohawk language, offering language classes and using it on community radio and in some public events. Most people on the reserves speak English, and French to a lesser extent.
Some people may speak a third language, especially near Montreal, but outside native reserves it is uncommon to hear them spoken on the street. A working knowledge of French or English will be almost essential to communicate with locals.
[edit] Get in
By car If entering the Montérégie from Montreal, remember that weekdays from about 4:30-6:30pm weekdays is rush hour (often a 30 minute delay to cross a bridge). If entering the Montérégie from the United States, remember that the border inspection is most crowded on Sunday nights; you might wait in line for an hour or more. The rest of the time, it usually takes 5-10 minutes.
From New York: Drive north on Interstate 87. The Montérégie begins at the Canadian border.
From Vermont: Drive north on Interstate 89. The Montérégie begins at the Canadian border.
From Montreal:
• Autoroute 138 crosses the Mercier Bridge to the Kahnawake Mohawk Reserve
• Autoroute 15/20/10 crosses the Champlain Bridge to Brossard
• Highway 112 crosses the Victoria Bridge to Saint-Lambert
• Autoroute 134 crosses the Jacques Cartier bridge to Longueuil
• Autoroute 25 follows the Lafontaine Tunnel through to Boucherville.
From Quebec City: Autoroute 20 leads into the northeastern part of the Montérégie.
From Ottawa: Take Highway 417 eastbound. The Montérégie begins at the Quebec border.
From Toronto: Take Highway 401 eastbound. The Montérégie begins at the Quebec border.
From Sherbrooke: Autoroute 10 westbound takes you to the Montérégie.
By Train The Agence Metropolitaine de transport[[1]] has three commuter train lines that connect Montreal to some towns in the Montérégie near the city. (Blainville to Saint-Lambert, Candiac to Chateauguay, and Rigaud to Vaudreuil). Trains go toward Montreal in the morning; away from Montreal at night.
By subway Montreal's metro (subway) trains have one stop in the Montérégie, called "Longueuil-Université-de-Sherbrooke" [[2]]. This is located on the yellow line, which begins at the Berri-UQAM metro station in Montreal. Longueuil-Université-de-Sherbrooke metro station is connected to the main bus terminal of the Reseau de Transport de Longueuil[[3]], which serves much of the South Shore.
By bus There are a number of regional public bus systems (known as "CIT"s) that serve distinct parts of the Montérégie, linking closeby towns together and connecting them with Montreal. Most of them focus on getting people to Montreal on weekday mornings and getting them back to the Monteregie on weekday nights.
• CIT La Presqu'Ile [4] serves Hudson and Vaudreuil.
• CIT Valle Richelieu [[5]] serves McMasterville, St-Hyacinthe, Beloeil, and Saint-Hilaire.
• CIT Haut-Richelieu [[6]] serves Saint-Jean-sur-Richelieu
• CIT Sorel-Varennes [[7]] serves Sorel-Tracy, Contrecoeur, Verchères and Varennes
• CIT Sud-Ouest [[8]] serves Chateauguay, Kahnawake, Valleyfield and Vaudreuil
• CIT Le Richelain [[9]] serves Candiac, La Prairie and Saint-Philippe
• CIT Rousillon [[10]] serves Delson, Candiac and Saint-Constant
• CIT Chambly-Richelieu-Carignan [[11]] is self-explanatory
• CIT Haut-Saint-Laurent [[12]] serves Huntingdon and Ormstown
Greyhound busses [13] also leave from Montreal's Bus Station (de Maisonneuve and St-Denis Streets) and serve various cities in the Montérégie.
In addition, the Reseau de transport de Longueuil [[14]] operates bus routes between Montreal and some of its South Shore suburbs (Longueuil, Brossard, Saint-Lambert). These busses leave from the basement of 1001 de la Gauchetiere in Montreal or from Longueuil metro station.
[edit] Get around
By car The major highways through the Montérégie are:
• Autoroute 15, connecting Montreal with U.S. Interstate 87 to New York
• Autoroute 10, connecting Montreal to Sherbrooke and the Eastern Townships
• Autoroute 20, conecting Quebec City to Montreal through the eastern section of the Montérégie, and then reappearing in the westernmost section of the Montérégie on the way to Toronto
• Autoroute 30, a new toll route which bypasses the Island of Montreal and connects Vaudreuil with the south shore of the St. Lawrence River. [Map]
Public transport Public transportation within the Montérégie region is quite limited, as most of its public transport is designed to get commuters to and from Montreal, rather than around the Montérégie region.
• The Reseau de transport de Longueuil [[15]] operates bus routes in Longueuil and neighbouring suburbs to the south of Montreal.
• Check with the trains and busses coming to and from Montreal (see the "Get In" section) to see where they stop along the way through the Montérégie.
[edit][add listing] See
Driving through the Montérégie two unusual geographical features will strike you:
• The farmland is divided into long, thin strips, rather than large squares like everywhere else in North America. This is a legacy of Quebec's French colonial past. Farmhouses were built at the edges of these strips, along rows called "rangs".
• The otherwise completely flat region has isolated mountains popping out of the ground at near regular intervals. This is what gives the region its name ("Mountain region"). One of the prettiest is Mont-Saint-Hilaire; its mixture of mountain, river, forest, and farms make it picturesque, especially when the leaves change colour in October. There are paths to go hiking on the mountain.
A few other features of Montérégie are pleasant to visit on a daytrip from Montreal:
• Fort Chambly. A French fort dating from 1711 to protect against the British. [16]
• Fort Lennox. A British fort dating from 1819 to protect against the Americans. [17]
• Lac Brome. A pretty lake [18]
• Fort Coteau-du-Lac, 308 A Chemin du Fleuve, Coteau-du-Lac (Exit 7 on autoroute 20), [19]. Ruins of a fort along the St-Lawrence River. edit
[edit] Itineraries
[edit][add listing] Do
• Brome County Fair, 345 Stagecoach Road, Brome (Autoroute 10 Exit 73 - route 241 south, left on route 104, right on route 215), 1 450 242 2870, [20]. September 4-7, 2009. Since 1856, a large agricultural fair. edit
• Parc Safari, 850, Route 202, Hemmingford (Autoroute 15 Exit 6, route 202 west), (450) 247-2727. Late spring to early autumn. African safari and kids amusement park. edit
• Granby Zoo, 300, boul. David-Bouchard, Granby (about 84km from Montreal; see website for details), 1 877 472- 6299, [21]. The closest zoo to Montreal. edit
• Intrnational Hot Air Balloon Festival (Festival international de montgolfières), 5, chemin de l'Aéroport, St-Jean-sur-Richelieu, 1-450-347-9555. Aug 8-16, 2009. Annual hot air balloon festival held every August. edit
• Ormstown Fair (Expo Ormstown), Ormstown, Quebec (Off highway 138), 1 (450) 829-2776, [22]. June 11-14, 2009. An agricultural fair in a small town. edit
• Kahnewake Powwow, Kahnawake Mohawk Territory (Just 10 miles south of Montreal Routes 132 & 138 (off Mercier Bridge)), (450) 632-8667, [23]. Anually, in July. Pow Wows offer a time for Native Americans from a variety of different tribal nations to get together and participate in visiting, singing, and dancing. It is also a chance for non-Indian friends and families to take part in inter-tribal dancing as a Powwow is considered a cultural sharing event for all to learn about Native Americans and share ideas and information. $7. edit
[edit][add listing] Eat
As maple trees grow in the area, maple syrup is popular and plentiful in March and April. Some maple farms operate as "sucreries" or "cabanes a sucre" (aka sugar shacks), where tourists can see how the maple syrup is collected, and taste some for themselves. These are also one of the few places in Quebec where tourists can get a traditional rural meal. (Most locals only eat traditional meals on special occasions such as Christmas Eve, due mostly to its high fat content and association with traditional ways.) Traditional meals include:
• tourtiere, a pork and beef pie
• yellow split pea soup
• pancakes
• ham with maple syrup
• maple sugar pie
• "pouding chomeur", a light sweet cake, (literal translation: "pudding for the unemployed")
• taffee (maple syrup poured into snow, which freezes onto a popsicle stick)
Fine dining in the Montérégie is some of the best value for money in North America. Almost every town in the region has one or two good restaurants, usually with lower prices than those of Montreal. Usually, asking a local to point you to the most expensive restaurant in town will get you to the right place.
If a quick lunch is what you are after, the ever-present "Saint-Hubert" chain of chicken restaurants is surprisingly good.
• Sucrerie de la Montagne (Mountain Sugar Shack), 300 Ch St Georges, Rigaud (Rigaud Mountain), 1-450-451-5204, [24]. Maple syrup farm with a year-round traditional-style restaurant, hayrides, and demonstrations on maple syrup production. edit
[edit][add listing] Drink
[edit] Stay safe
The Montérégie is generally a low-crime area. Almost the whole area is served by the emergency number "911", which you can call to contact police, fire or ambulance services. The biggest danger is probably traffic accidents, especially in winter. There are long stretches of unlit and potentially icy roads; large farming fields on either side of a road can mean blowing snow and slippery patches. Many of the smaller routes with one lane in either direction have a speed limit of 90km/h. Snow tires are required by law on vehicles during the winter months.
Some seedy bars in the Montérégie are labelled "danseuses". This is a euphamism for a strip club, many of which are actually brothels; steer clear if you want to avoid criminal elements.
Akwesasne Mohawk Reserve, in the southwest corner of the Montérégie, shares a border with reserves in Ontario and New York. There are rare occurrences of confrontations with police in this area; police try to patrol for cross-border cigarette and alcohol smuggling and locals insist Quebec police have no authority on the reserve. This should not usually affect tourists, but is something to be alert to.
[edit] Get Out
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Anshan
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Anshan is a city in Liaoning Province, China. Nicknamed "Capital of Chinese Steel Industry", Anshan in central Liaoning is a major iron and steel industrial site.
Get in
Anshan has an exit on the main Shen-Da Expressway between Shenyang and Dalian. The nearest airport is Shenyang to the north. Train service is frequent on the mainline through Anshan with service to Dalian and Shenyang. Overnight train service is available to Beijing. Long-distance bus service is available at the bus station across from the train station with frequent buses to Shenyang (leave as soon as filled, sometimes as quickly as 15 min after previous bus has left).
If you are in desperate hurry to leave the town, night drivers can be contacted through the taxi drivers located outside the main train station. The main night driver route is from Dalian to Shenyang and in reverse (cost averages Y500-800 depending on distance). Negotiate a rate and then expect to cough up a little additional during your trip since your fare might be sold to another driver along the way (like a relay race and you are the baton).
Get around
Buses to just about everty part of town from the area near the train station. Purchase a town map and it should have the bus routes on it. Buses to Qian Shan depart from the street behind the long-distance bus station which is located across from the train station on south side of square.
See
• World's Largest Jade Buddha - located in temple setting
Do
Buy
• Jade Carvings of Xiuyan County - Xiuyan County in Anshan is full of a kind of jade the people call the "national stone" of China, and in the higher end department stores (like Parkson), you can find decent pricing.
Eat
Drink
Sleep
• Anshan International Hotel, 219 Yuanlin Rd., Anshan, (0412)5555888 (fax: (0412)5555988).
Get out
• Qian Shan National Park, Located 10-15 km se of Anshan. The park is open from sunrise to sundown and costs 元50.
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Australian Bureau of Statistics
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Australian Bureau of Statistics
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Research article
Diversity, phylogenetic distribution, and origins of venomous catfishes
Jeremy J Wright
Author Affiliations
Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, MI 48109, USA
BMC Evolutionary Biology 2009, 9:282 doi:10.1186/1471-2148-9-282
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2148/9/282
Received:28 April 2009
Accepted:4 December 2009
Published:4 December 2009
© 2009 Wright; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background
The study of venomous fishes is in a state of relative infancy when compared to that of other groups of venomous organisms. Catfishes (Order Siluriformes) are a diverse group of bony fishes that have long been known to include venomous taxa, but the extent and phylogenetic distribution of this venomous species diversity has never been documented, while the nature of the venoms themselves also remains poorly understood. In this study, I used histological preparations from over 100 catfish genera, basic biochemical and toxicological analyses of fin spine extracts from several species, and previous systematic studies of catfishes to examine the distribution of venom glands in this group. These results also offer preliminary insights into the evolutionary history of venom glands in the Siluriformes.
Results
Histological examinations of 158 catfish species indicate that approximately 1250-1625+ catfish species should be presumed to be venomous, when viewed in conjunction with several hypotheses of siluriform phylogeny. Maximum parsimony character optimization analyses indicate two to three independent derivations of venom glands within the Siluriformes. A number of putative toxic peptides were identified in the venoms of catfish species from many of the families determined to contain venomous representatives. These peptides elicit a wide array of physiological effects in other fishes, though any one species examined produced no more than three distinct putative toxins in its venom. The molecular weights and effects produced by these putative toxic peptides show strong similarities to previously characterized toxins found in catfish epidermal secretions.
Conclusion
Venom glands have evolved multiple times in catfishes (Order Siluriformes), and venomous catfishes may outnumber the combined diversity of all other venomous vertebrates. The toxic peptides found in catfish venoms may be derived from epidermal secretions that have been demonstrated to accelerate the healing of wounds, rather than defensive crinotoxins.
Background
The venoms produced by cnidarians, mollusks, snakes, arachnids, insects, and some mammals have been the subject of multiple studies of chemical structure [1-3], pharmacology [2-5], and toxicology [5-7], in addition to several evolutionary studies [8-12], but information regarding these aspects of fish venoms is relatively sparse [13-18]. Until recently, even reliable estimates of the number of venomous fish species have been unavailable. Morphological examinations, combined with phylogenetic analyses have suggested that 585-650 species of spiny-rayed fishes are venomous, a number which rivals the known diversity of venomous snakes and is significantly higher than previous estimates of about 200 venomous spiny-rayed fish species [18]. We still lack estimates, however, for catfishes (Order Siluriformes), a diverse, monophyletic group with 34 recognized extant families and over 400 genera containing more than 3,000 known species [19]. The historical lack of such basic information may be largely responsible for the paucity of research on venomous fishes in general, and venomous catfishes in particular.
The venom glands of catfishes are found in association with sharp, bony spines along the leading edge of the dorsal and pectoral fins, which can be locked into place when the catfish is threatened (Fig. 1). When a spine enters a potential predator, the integument surrounding the venom gland cells is torn, releasing venom into the wound. Catfish venoms have been shown to display neurotoxic and hemolytic properties and can produce a variety of additional effects such as severe pain, ischemia, muscle spasm, and respiratory distress; though any single species' venom may not display all of these properties [20]. These effects are produced in a wide range of taxonomic classes of vertebrates, including mammals, reptiles, birds, and amphibians [21]. In humans, the primary symptoms are severe pain and swelling at the site of envenomation, though fatalities have been reported in cases involving Plotosus lineatus (Plotosidae) and Heteropneustes fossilis (Clariidae) [20]. Complications arising from secondary infection of the wound are also frequently encountered.
Figure 1. The Venom Delivery System of Catfishes. (A) Northern madtom (Noturus stigmosus) with dorsal and pectoral fin spines indicated by red arrows. (B) Pectoral girdle of Noturus stigmosus with articulated pectoral fin spines. Abbreviations: ps = pectoral fin spine, cle = cleithrum, cor = coracoid, cor-pp = posterior process of coracoid. (C) Cross section of the pectoral-fin spine of Noturus stigmosus showing the association of venom gland cells with the fin spine. Abbreviations: ps = pectoral spine, vgc = venom gland cells.
The chemical nature of piscine venoms is poorly known, though the loss of toxicity seen when these venoms are subjected to common denaturing agents suggests that proteins constitute the major toxic component of these secretions [16]. Thus far, detailed examinations of these proteins in catfishes have been limited to the venoms of Plotosus canius, a particularly toxic marine species found in Southeast Asia, and Ameiurus catus, a freshwater species found in the eastern United States. The neurotoxic and hemolytic properties of P. canius venom have been attributed solely to a 15 kDa protein, termed toxin-PC [22]. The venom of A. catus was thought to contain anywhere from two to eight toxic proteins with approximate molecular weights of 10 kDa [23]. Both the mechanism by which these toxins act and their physiological targets are very poorly understood. It is thought that cytolytic activity due to pore formation in cell membranes is a likely explanation, as this activity is present in other 'pain-producing' venoms, such as those produced by bees [24] and platypus [25], and reactions consistent with this mechanism have been observed in response to piscine venoms [16].
As a globally distributed and thus, biogeographically interesting group, catfishes have recently been a topic of interest in several phylogenetic studies [26-29]. When combined with these data, information regarding the distribution of venom glands within the Siluriformes can be examined in an evolutionary context, and we can begin to build a foundation to advance the studies of venom evolution in this group to the level seen in other venomous organisms. In this work, I use histological and toxicological techniques to elucidate the diversity and taxonomic distribution of venomous catfishes and examine these findings within the phylogenetic framework established by previous authors to provide a broad-scale hypothesis for the evolutionary origins of venom glands in catfishes. These examinations are further integrated with preliminary biochemical characterizations of venoms from several catfish species to highlight an intriguing, novel hypothesis for the evolutionary development of venom glands in catfishes.
Results
To establish a preliminary estimate of the number and phylogenetic distribution of venomous catfish species, 159 species from over 100 genera, representing 32 of the 34 siluriform families were examined for the presence of venom glands (Additional file 1). Material for representatives of the families Austroglanididae and Lacantuniidae was unavailable for study, but their omission from this study has little effect on estimates of the number of venomous catfish species, due to the low species diversity of these families (three species and one species, respectively). Structures identified as venom glands were observed in 20 families. Venom gland size, orientation, and cellular morphology were found to vary considerably between, and sometimes within, families (Additional file 1; Figs. 2, 3). Based upon the generic identity of the venomous species identified, the number of species contained within those genera, and the number of remaining unexamined species in those families shown to contain venomous representatives (See Methods for detailed explanation), an estimate of 1234-1625 venomous catfish species was developed (Table 1).
Additional file 1. List of catfish specimens from which histological preparations were made and examined. Presence or absence of a bony spine capable of effectively delivering venomous secretions is noted, as is a brief description of the condition of venom glands, in each specimen found to possess them. Taxonomic assignments follow [19].
Format: DOC Size: 265KB Download file
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Figure 2. Histological preparations of fin spines from several venomous catfish species. (A) Acrochordonichthys rugosus (Akysidae), (B) Liobagrus reini (Amblycipitidae), (C) Dianema longibarbis (Callichthyidae), (D) Chaca chaca (Chacidae), (E) Lophiobagrus cyclurus (Claroteidae), (F) Lithodoras dorsalis (Doradidae). Abbreviations: ps = pectoral fin spine, vgc = venom gland cells. Scale bars, 0.5 mm.
Figure 3. Additional histological preparations of fin spines from venomous catfish species. (A) Pimelodella mucosa (Heptapteridae), (B) Chiloglanis productus (Mochokidae), (C) Pseudolais pleurotaenia (Pangasiidae), (D) Plotosus canius (Plotosidae), (E) Schilbe mystus (Schilbidae), (F) Horabagrus brachysoma (incertae sedis). Abbreviations: ps = pectoral fin spine, vgc = venom gland cells. Scale bars, 0.5 mm.
Table 1. Taxonomic distributions and estimates of venomous catfish diversity.
The production of toxic compounds by representatives from several siluriform families was confirmed through analysis of effects of crude fin-spine extracts on a predatory fish species. The injection of fin-spine extracts caused symptoms of envenomation in all cases; in all cases but one (Plotosus lineatus), injection with control extracts prepared from fin tissue yielded no appreciable effect. Symptoms produced by the venoms tested included chromatophore expansion at the injection site, loss of coloration elsewhere on the body, hemorrhage, loss of equilibrium, muscle spasm, and in one instance (Plotosus lineatus), rapid mortality (Table 2). Symptoms of envenomation occurred immediately and were resolved within an hour in most trials. Though representatives from several families were not examined, species in those families possess cells associated with their fin spines that have similar, if not identical, morphologies to the venomous species tested, suggesting that these cells produce toxic substances in the untested families as well.
Table 2. The effects of several catfish species' venoms on Largemouth Bass.
The evolution of venom glands within the order Siluriformes was examined by performing maximum parsimony character optimization analyses on several previously published siluriform phylogenies that were reconstructed from both morphological [26,30] and molecular [28] data. Multiple phylogenies were analyzed due to the fact that the relationships of some siluriform families are either poorly resolved or vary between reported phylogenies. Given the widespread presence of venom glands in catfishes, it was expected that these previous systematic studies, in conjunction with the results presented above, would offer some insight into broader phylogenetic patterns of siluriform venom gland evolution in spite of the poor resolution of familial relationships found in these phylogenies.
Character optimization anlyses of these phylogenies indicate that this trait has arisen at least twice (Figs. 4, 5) and potentially three or more times (Fig. 6). Venom glands evolved once within the Loricarioidei, a diverse and exclusively Neotropical suborder of armored catfishes, in the family Callichthyidae. They also appear independently at least once basally within the Siluroidei, a clade containing all other non-loricarioid catfishes with the exception of the Diplomystidae. A recent molecular phylogeny based on nuclear gene sequences (RAG1 and RAG2) implies an additional evolution of venom glands within the Doradidae, owing to their placement within a clade of South American catfishes including the Aspredinidae and Auchenipteridae (members of which appear to lack venom glands) [[28]; Fig. 6].
Figure 4. Venom glands have evolved multiple times in catfishes. The results of a character optimization analysis of a siluriform phylogeny generated from 440 morphological characters indicate the independent evolution of venom glands within the Loricarioidei as well as within the Siluroidei, leading to the majority of venomous catfish diversity. Phylogeny redrawn from Diogo [26]. Red branches indicate venomous lineages, black branches indicate non venomous lineages, yellow branches indicate lineages not examined in this study.
Figure 5. Results of character optimization analysis using an alternative morphology-based phylogeny. Phylogeny redrawn from Mo [30], based on 126 morphological characters. Red branches indicate venomous lineages, black branches indicate non venomous lineages, and yellow branches indicate groups not examined in this study. As in Figs. 4 and 6, the independent evolution of venom glands is indicated in the Loricarioidei (sensu [26] and [28]), in the family Callichthyidae. Patterns of venom gland evolution in the Siluroidei are obscured, due to the poor resolution of basal relationships. Given the broad range of siluroid families in which venom glands are found and similarities in venom composition between these families, a single, relatively basal development of venom glands seems the most parsimonious and likely scenario.
Figure 6. Results of character optimization analysis using a recent molecular siluriform phylogeny. Phylogeny redrawn from Sullivan et al. [28], based on RAG 1 and RAG 2 nuclear data. Red branches indicate venomous lineages, black branches indicate non venomous lineages. Again, the independent evolution of venom glands is found in the Loricarioidei, in the family Callichthyidae. Independent evolution of venom glands must also be ascribed to the family Doradidae, due to its nesting within a clade containing the non-venomous Aspredinidae and Auchenipteridae. Similarly to Fig. 5, the evolution of venom glands at the base of the Siluroidei are obscured, due to poor resolution of basal relationships.
Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) was used to identify venom proteins with similar molecular weights that are shared between species (and families), potentially reflecting homology of these proteins. Comparisons with extracts prepared from caudal-fin tissue were used to identify putative toxin peptides. The composition of different species' venoms was found to vary considerably, but some strong similarities were also evident. A putative toxin peptide of approximately 110 kDa was found in very high concentrations in the venom extracts of eight of the nine species examined (Fig. 7). Although a protein with a similar molecular weight was also found in the caudal-fin extracts of several species, it was generally found in much lower concentrations, and previous authors have stated that at least some toxin producing cells may be present in the fin tissue of catfishes [13]. In addition to the siluroid species tested, a 110 kDa peptide also appears to be present in the venom extracts of several species of Corydoras. Corydoras is distantly related to the remaining species analyzed, and the possession of venom glands by members of the family Callichthyidae appears to represent an independent evolution of these structures. A protein having this molecular weight was not found in the fin-spine extracts of Pimelodus pictus, a species shown by the current study to be venomous, reflecting a secondary loss of this putative toxic peptide. Additionally, nearly every siluroid species examined displayed at least one (and often more) putative toxic peptide(s) of approximately 10-20 kDa in weight. These peptides appear to vary significantly within this range however, and no molecular weight was represented with the same frequency as the 110 kDa peptide described above.
Figure 7. SDS-PAGE analyses of venom extracts from several catfish species. Left lanes represent venom extracts, right lanes represent extracts prepared from fin tissue. Arrows indicate positions of unique venom protein bands or proteins found in greater concentrations in venom extracts than in fin tissue extracts. (?) represents ambiguity between smearing and an additional, unique venom peptide band. Large quantities of a 110 kDa peptide are found in the venom extracts of nearly all species shown, with the exception of Pimelodus. The presence and variation of venom peptides in the size range of 10-20 kDa is also clearly visible. Samples from non-venomous Ameiurus melas are shown for comparison.
Discussion
Venomous Catfish Diversity
Examinations of histological sections of pectoral-fin spines, in conjunction with character optimization analyses of previously published siluriform phylogenies and toxicological assays, imply that approximately 1250-1625 species of catfishes from at least 20 families are venomous. These numbers are much higher than previous estimates, based largely on anecdotal evidence, which suggested a maximum of 1000+ venomous catfish species [18]. Of these families, 14 (Akysidae, Anchariidae, Callichthyidae, Chacidae, Claroteidae, Cranoglanididae, Doradidae, Heptapteridae, Mochokidae, Pangasiidae, Pimelodidae, Pseudopimelodidae, Schilbidae, Siluridae) are shown to contain venomous taxa for the first time; six (Amblycipitidae, Ariidae, Bagridae, Clariidae, Ictaluridae, Plotosidae) have previously been demonstrated to contain venomous representatives [20]. The approximation of 1250 species of venomous catfishes is undoubtedly an underestimate, as many genera in siluriform families containing venomous taxa remain to be examined. New species of catfishes are also continuously being discovered and described (958 species described in the last 10 years according to the Catalog of Fishes [31]), with some venomous genera such as Chiloglanis (Mochokidae) containing an estimated 25 or more undescribed species [J.P. Friel, pers. comm.].
The apparently low incidence of independent venom gland evolution in catfishes stands in stark contrast to the results obtained for venomous spiny-rayed fishes, in which venom glands appear to have evolved independently no fewer than nine times [18]. The exact number of times that venom glands arose within the Siluroidei remains ambiguous, though the majority of possible resolved topologies would require only a single derivation. However, the hypothesis of an additional derivation of venom glands in the family Doradidae that would be necessitated by the results of recent molecular phylogenetic analyses [28,29] does warrant further investigation. The venom glands found in doradid species differ morphologically from those seen in other siluroid families, by virtue of their structure (discrete clusters of glandular tissue internally subdivided into pockets of glandular cells by integumentary septa vs. continuous single sheaths of glandular cells) (Figs. 2 and 3), orientation (limited to spaces between posterior serrae of dorsal and pectoral-fin spines vs. being found along the entire length of the spines) (Fig. 8), and visibility without magnification (Fig. 8). Future studies of doradid venom composition should help to clarify this issue.
Figure 8. The distinctive venom delivery apparatus of a doradid catfish. Rather than forming longitudinal bundles along the spine, as in other siluroid catfishes, the glandular tissue in doradids is found in macroscopically visible aggregations between the posterior serrae of the fin spine. Abbreviations: s = pectoral spine, ps = posterior serrae, gt = glandular tissue.
The loss of venom glands appears to be a common phenomenon within catfishes, which is not surprising given that bony fin spines have been lost in some families (Malapteruridae, most amphiliids). Genera in several families that contain venomous representatives (Heptapteridae, Pimelodidae, Siluridae) have also lost bony dorsal and/or pectoral-fin spines. Without an effective delivery system, there would seem to be no selection pressure for the maintenance of venom producing structures, leading to their reduction and eventual loss. The apparent loss of venom glands in groups that have maintained bony fin spines [Aspredinidae, Auchenipteridae, Sisoridae, some ictalurids (see Additional file 1)] is more unexpected, and explanations for these losses are not immediately apparent.
Inter- and intrageneric loss of venom glands was also found within the family Ictaluridae (Additional file 1). Both Ameiurus melas and Pylodictus olivaris lack any structures that could be identified as venom glands based on histological examination. Additionally, SDS-PAGE analysis detected no putative venom peptides in either species (Fig. 7). This finding was particularly surprising for A. melas, which had previously been considered venomous and quite virulent, based upon toxicological and histological work [13,20]. This discrepancy may be attributable to geographic variation in venom production; A. melas is a widely distributed species and the specimens examined in the current study were collected in Michigan, while those used in the previous toxicological study came from Texas. A potentially important factor in the case of Pylodictus is that this species can reach adult sizes that would presumably prohibit predation by even the largest North American predatory fishes (all of which are gape-limited predators), possibly weakening or eliminating selection for the maintenance of venom glands through adulthood.
The number of venomous catfishes estimated by this study (when combined with estimates of venomous spiny-rayed and cartilaginous fishes) supports previous claims that venomous fishes far outnumber all other venomous vertebrates [18], and also demonstrates that venomous catfish diversity likely equals or exceeds that of all other venomous vertebrates (including other fishes) combined (Table 3). Recently, some lizards and snakes traditionally considered to be non-venomous have been shown to produce several of the same toxic compounds as their venomous relatives [32]. Many of these species appear to lack a specialized mechanism for transmitting these compounds, possibly preventing them from being classified as venomous in the traditional sense [33], due to a potential inability to effectively utilize these compounds in feeding. However, recent work has shown that venom is likely to play a previously unsuspected, but major role in the feeding ecology of Varanus komodoensis (Komodo Dragon) [34]. This finding strongly indicates that such a role will be found for venom in other groups of lizards as well, potentially vastly increasing the estimate of venomous reptile diversity.
Table 3. Taxonomic distributions and estimates of venomous vertebrate diversity.
Evolution of Catfish Venoms
Cameron and Endean [35] hypothesized that the venom glands of fishes are derived from glandular epidermal cells that secrete toxic proteinaceous compounds (termed "ichthyocrinotoxins") when fishes are threatened or injured. While it is true that these compounds are secreted in these situations, the hypothesis that they serve in an antipredatory capacity in catfishes appears flawed. With the exception of ichthyocrinotoxins associated with the epidermis of the dorsal and pectoral fin, there is no effective delivery device for these compounds, which are produced all over the body. This is of particular importance, as all assays demonstrating toxicity of epidermal secretions of catfishes have relied on intravenous injection of these compounds as a toxicological assay [36-40]. Furthermore, the presence of epidermal secretions does not appear to be a significant deterrent to potential predators, as they will attack and feed on distressed catfishes, as well as other baits coated with catfish epidermal secretions [[41]; pers. obs.].
That venom glands in catfishes produce similar compounds to epidermal glandular cells has been indicated by immunocytochemical assays [39]. The results of SDS-PAGE analyses presented here offer additional support for the similarity of these secretions. The major toxic factor of the skin secretion of Arius bilineatus has been isolated and shown to have a molecular weight of approximately 39 kDa [40]. The venom of Arius jordani clearly shows a strong band at approximately 39 kDa which is found in low concentration in the control lane (Fig. 7). The presence of this protein in the control sample is likely due to the presence of epidermal secretory cells in the tissue sample used, while the low concentration is due to the removal of most of the epidermal secretions before sample preparation. While these cells were also probably present in spine samples, the large difference in concentration indicates that venom gland cells are likely responsible for production of most of this protein band. A similar case is seen in the electrophoretic profile of Plotosus lineatus, which shows major toxin bands at 15-16 kDa and 13-14 kDa (Fig. 7). While the larger band is similar in weight to toxin-PC, as characterized by Auddy and Gomes [22], the lower band is very similar in weight to a toxic fraction isolated from the skin secretions of this species [37,38], with the slight discrepancy in estimated size possibly being due to differences in sample preparation and analysis.
While the venom gland cells in catfishes (and other fishes as well) are likely to be derived from epidermal secretory cells, an alternative scenario to Cameron and Endean's antipredatory hypothesis is also able to explain their origin. Studies of the epidermal secretions of several Arius species have indicated that these compounds are able to accelerate healing of wounds and may also have some antimicrobial properties [41-43]. The spines of catfishes act to effectively increase their cross-sectional circumference when locked into place, and would likely be the first structures to contact a gape-limited predator's tissues during an attack. As such, the spines would often be damaged, and individuals with larger numbers of epidermal secretory cells surrounding the spine could gain a selective advantage due to decreased healing time and a corresponding decreased chance of infection of exposed tissues. This selection may have led to increased aggregations of these cells around the fin spines, with the toxic effects of their secretions being an epiphenomenon to their primary healing benefits. Once the toxic secretions had become associated with an effective delivery device, selection for increased toxicity, as seen in some plotosid and clariid species, could begin to operate. Explicit tests of this scenario will require more detailed structural and genetic characterizations of these compounds.
The symptoms of envenomation produced by a diverse array of catfish species' venoms are very similar and a large number of putative toxins appear to fall within a well-defined molecular weight range. The conserved molecular weight patterns and toxic effects of catfish venom peptides suggest two possible scenarios for the evolution of venoms in catfishes: widespread convergent evolution of catfish venom toxins with similar targets and thus similar molecular characteristics and effects, or common origins of toxic peptides with subsequent species-specific alterations. The widespread presence of venom glands shown by the character optimization evidence discussed above strongly suggests that the latter case is the more parsimonious and likely scenario, even in cases where phylogenetic resolution of basal siluriform divergences is lacking.
Conclusion
This study utilizes several lines of investigation to increase our knowledge of several poorly understood areas of the biology of venomous catfishes. These investigations have demonstrated that at least 1250, and possibly over 1600 species of catfishes may be venomous, a number far greater than any previous estimate of venomous catfish diversity. In conjunction with previous systematic studies, these findings also offer insight into the evolutionary history of venom glands in the order Siluriformes, indicating at least two independent evolutionary origins of these structures. Finally, the symptoms of catfish envenomation, along with preliminary biochemical characterizations of toxic catfish venom peptides, may suggest a novel selective explanation for the evolution of catfish venom glands and their secretions.
Finer-scale studies of venom gland evolution in fishes will require continued systematic studies of venomous fish families to elucidate the relationships of the species contained therein. Additionally, examinations of the chemical composition of fish venoms and the identities and structures of their constituents will provide valuable insight into the mechanisms and potential selective factors driving venom evolution in fishes, as well as their potential for biomedical research and pharmaceutical bioprospecting.
Methods
Venom Gland Survey and Histological Techniques
The right pectoral-fin spine was removed from 158 catfish specimens (see Additional file 1), housed in the fish collection of the University of Michigan Museum of Zoology. Spines were decalcified in CalEx® according to the manufacturer's instructions, after which segments from the distal third of the spine of an appropriate size for histological preparation were removed. These segments were subjected to automated dehydration and paraffin infiltration and embedding at the Tissue Core Facility of the University of Michigan Comprehensive Cancer Center. Serial sections of 0.7 microns were then obtained from each spine sample. Sections were stained with hematoxylin and eosin and mounted on glass slides.
Spines were examined for the presence of venom glands using a Nikon YS2-T compound microscope. Morphological confirmation of the presence of venom gland cells was achieved by comparisons with previously published photomicrographs of venom glands in catfishes and spiny rayed fishes [20,35,44,45], descriptions of piscine venom gland cellular anatomy [20], and sections obtained from the spines of catfish species that have been shown to secrete venomous substances by previous studies [13,20]. When a representative of a particular genus was found to possess venom glands, all members of that genus were presumed to be venomous, except in the case of the ictalurid genus Ameiurus, where the examination of multiple species within the genus indicated otherwise. These generic counts of venomous species formed the basis for the minimum estimate of venomous catfish species (Table 1). The number of species contained in unexamined genera from families containing venomous representatives was added to the minimum estimate to give a maximum estimate of venomous catfish species (Table 1).
Venom gland extract preparation and assay
Representatives of the catfish families Ariidae, Bagridae, Callichthyidae, Ictaluridae, Mochokidae, Pangasiidae, Pimelodidae, Pseudopimelodidae, and Plotosidae were obtained either from field collections (Ictaluridae) or the aquarium trade (other families). Specimens were euthanized using MS-222 at a concentration of 300 mg/L in fresh water. All further preparations were carried out either on ice or under refrigeration at 4°C. Spines and caudal fin tissue were removed from each specimen, rinsed in physiological saline and gently scraped with a microspatula in order to remove any excess epidermal secretions, and weighed to the nearest 0.001 g using a GeneMate digital balance. Spines were minced and then further homogenized in a 2 mL Dounce homogenizer along with either marine (Plotosidae) or freshwater (other families) euteleost physiological saline at a volume of 2 mL/g of tissue [46]. The homogenate was then centrifuged at 6,000 rpm at 4°C for 20 minutes and the supernatant collected. The supernatant served as the crude venom extract. Control extracts prepared from caudal fin tissue were prepared in the same manner.
Largemouth Bass were collected from Boyden Creek, Washtenaw Co., MI in October of 2008. Bass were anesthetized in MS-222 at a concentration of 75 mg/L of fresh water and weighed to the nearest 0.1 g. They were then placed in 10 G experimental aquaria in a room with natural light and allowed to acclimate for a period of 72 hours. After the 72 hour acclimation period, bass were injected in the caudal peduncle at a depth of 2 mm with 2 μL/g body weight of either crude venom extract or control extract. Individuals were then observed at one minute, one hour, and 24 hours after injection for symptoms consistent with envenomation (Table 2). For each species of catfish tested, two bass were injected with venom extract and two were injected with caudal fin control extract.
Character Optimization Analyses
Several previously published phylogenetic hypotheses for the order Siluriformes [26,28,30] were examined using MacClade 4.0 PPC [47]. Presence and absence of venom glands was traced onto the trees using the criterion of maximum parsimony. Specific taxa that were present in the phylogenetic reconstruction but which were not examined in the current study were coded as ambiguous (?) within the data matrix.
SDS-PAGE Analyses
Crude extracts were prepared for SDS-PAGE analysis by reduction with NuPAGE® reducing agent and loading buffer, according to manufacturer's instructions. Reduced samples were subjected to electophoresis in NuPAGE® precast 4-12% Bis-Tris polyacrylamide gels in 1× MES running buffer for 35 minutes, at 200 V in an x-Cell SureLock™ Mini Cell. Reduced peptides were visualized using SimplyBlue™ SafeStain according to manufacturer's instructions. Molecular weights of venom and caudal fin extracts were estimated by comparison with Novex® Sharp Protein Standard. Proteins unique to venom extracts (relative to caudal-fin extracts) were treated as putative toxins, pending further characterization.
Acknowledgements
I thank the staff at the Tissue Core Facility of the University of Michigan Comprehensive Cancer Center for consultation regarding and performance of steps involved in histological preparation of samples. Thomas Duda kindly provided lab space for performance of SDS-PAGE analyses. I also wish to thank W. Fink, G. Smith, T. Duda, D. Nelson, J.M. Wright, H. Ng, P. Chakrabarty, R. Oldfield, and K. Birkett for helpful discussions and suggestions for the improvement of this manuscript. All animal care was performed in accordance with University of Michigan Committee on the Use and Care of Animals (UCUCA) regulations and guidelines. Experimental procedures involving live animals were approved under UCUCA protocol # 09713. Financial support was provided by the University of Michigan Museum of Zoology and the University of Michigan Rackham Graduate School.
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In my work with entrepreneurs, especially small business owners in my country Nigeria, one re-occurring theme is their approach towards marketing. Each time I’m in a consulting or strategy session with a client and I ask the question; “how do you get clients?”
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Friday, September 03, 2010
Gotcha of the Day: Linksys WRT54G2 causes ssh sessions to freeze
A few weeks ago, I finally got fed up with having my laptops randomly lose connectivity with the wireless router. I figured the best fix would be to replace my old, cheap, router with something more robust.
So I did - I purchased the well reviewed Linksys WRT54G2 Wireless-G Broadband Router. I figured 600 4+ star reviewers couldn't be wrong.
And for the most part, I'm happy with the router. Everything was working great until I started noticing some very annoying behavior: ssh sessions that were left unused froze up.
Luckily, I make heavy use of screen, so no real work was lost. But it sure was a hassle.
I poked around in the admin interface on the router, and didn't see anything I could configure to fix this (though, admittedly, I wasn't really sure what I was looking for - a stop ssh from freezing checkbox, perhaps?). So, off to Google I went.
Turns out, ssh freezing up is actually a pretty common issue. And luckily, the fix is painless. I just added:
ServerAliveInterval=4
to ~/.ssh/config and it appears like all is well again.
I've got a new router and working ssh connections - can one ask for anything more?
LinkWithin
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< Previous
Crankiness Antidote >
(4) : Is short fiction devalued by being available for free? Hey, here's the elephant in the room that keeps being pointed out and yet remains elephant-shaped: there's way more short fiction than there is market for it. In my writing group we critique 2-3 stories a month. Half of 'em are a rewrite away from publication quality. They're also likely years away from publication, because the market is so small and response times so long.
Why do the markets pay so poorly? That's the natural result of massive oversupply. Why is there so much bad free stuff online? My portfolio shows the problem in miniature. My old crappy stories are online because I didn't know any better. My dynamite new stuff circulates endlessly through snail and electronic mail. Sure, I'm bitter, but it seems pointless to complain about this because the solution is obvious.
Seriously, what am I doing? I don't care about money--there's not enough to care about. If I wanted an audience I'd split my stories into RSS-feed cliffhangers and put them in syndication once they passed writing group muster. All that's left is the feeling that there are dues I ought to be paying. I've got a bad case of professionalism.
Who needs it? Life is too short. I know what position I'm sliding towards and I keep resisting it. Maybe I'll start writing novels instead; those take a lot longer to crank out, at least.
Filed under:
Comments:
Posted by Evan at Mon Aug 25 2008 20:42
"The truth is, reading is always more important than writing"
- Roberto Bolano
"writing is better than waiting"
- Roberto Bolano
Posted by kirkjerk at Mon Aug 25 2008 23:26
I'm starting to wonder some of the same things about indy games...
Posted by Brendan at Tue Aug 26 2008 12:14
I'm writing a blog response, but I'm curious as to whether you dealt with the same awkward intragroup tension and politics at VP as Nora seems to have done. You weren't at the same session, were you?
Posted by Leonard at Tue Aug 26 2008 13:42
I am famously oblivious to intragroup tension, but I didn't notice any. I think my class (which was a couple years after Nora's) got along pretty well. I was happy with my preselected 1:1 choices, so I didn't need to try and wheedle my way into additional ones, but I can see how someone might resort to tricks to grab instructor time.
[Main] [Edit]
Unless otherwise noted, all content licensed by Leonard Richardson
under a Creative Commons License.
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Patterson Wing
From Cvillepedia
Revision as of 15:57, 16 August 2010 by 629579396 (Talk | contribs)
(diff) ← Older revision | Latest revision (diff) | Newer revision → (diff)
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This article is a stub. You can help cvillepedia by expanding it.
The Patterson Wing of the Martha Jefferson Hospital is one of Charlottesville's individually protected properties, meaning any exterior changes or potential demolition would have to be approved by the Board of Architectural Review. The wing is located at 459 Locust Avenue[1].
Notes
1. "Charlottesville : Architectural Design Control District and Individually Protected Property Information." Charlottesville : Home. Web. 16 Aug. 2010. <http://www.charlottesville.org/Index.aspx?page=812>.
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Board and Chip Vendors
From eLinux.org
Revision as of 17:49, 17 July 2012 by Wmat (Talk | contribs)
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This page has a list of the companies or organizations that make processors or boards for embedded products. If you are looking for companies who sell Linux software or Linux-related services, see the Vendors page. If you are looking for companies who sell end-user products based on Linux, see Companies. If you are looking for information about specific development boards, see Category:Development Boards
Contents
A
B
• Bluetechnix makes tiny Blackfin modules to simplify custom board development
• Broadcom - makes ARM chips for mobile phone market
C
D
E
• EFlag Tech does custom Blackfin platform designs (software and hardware)
• eInfochips - The Solution People Open-RD based platform
• Elphel, Inc provide high performance Network Cameras based on Free Software and Hardware designs. Axis EtraxFS & Spartan 3e 1200k gates FPGA.
• Embest provides standard single board computers and custom modules based on different ARM processors from Atmel, Cirrus, NXP, Samsung and Texas Instruments for ARM embedded applications.
F
• Freescale Semiconductor - Wikipedia entry
• Freescale makes the MX31 ARM11-based processor (and associated development boards), among others.
• Freescale makes several PPC-based processors (and associated development boards) as well.
G
• Gumstix sells various very small processor and add-on boards. Especially interesting for robotics related projects.
H
• HITEG LTD does custom embedded board ,it focused on IT outsourcing and embedded technology(software and hardware)
• Hua Heng Tech does custom Blackfin platform designs (software and hardware)
• HV Sistemas S.L. makes tiny Blackfin modules to simplify custom board development
I
K
M
N
• NEC - makes ARM chips, used to make lots of MIPS chips
Q
• Qualcomm - makes multicore ARM MSM products that support Linux
• Their Snapdragon platform provides a 1GHz ARM core and advanced DSP.
R
S
T
• [Tianyeit]
• Sell the tiny Package -- Computer In Package base on TI OMAP35x/AM3517/omap4430/omap4460/dm3730/am3359
• Timll
• Reference Design and customized HW/SW Design Based on TI OMAP35x/AM3517
• TechNexion
• Expandable and fully customizable ARM system modules and interface boards
• Embedded x86 boards with coreboot and linux core extensions
• Texas Instruments - Wikipedia entry
• Texas Instruments makes the MSP430 MCUs, TMS320 C2000/C5000/C6000 DSPs, DaVinci/OMAP ARM+DSP-based processors, and others.
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Error
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2 revisions of this difference (11530 and 13338) were not found.
This is usually caused by following an outdated diff link to a page that has been deleted. Details can be found in the deletion log.
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Coco d'Or 3
From generasia
Jump to: navigation, search
CD+DVD Cover
CD Only Cover
Artist
Coco d'Or
Album
Coco d'Or 3
Released
2011.03.09
Catalog Number
AVCD-16228 (CD+DVD)
AVCD-16227/B (CD Only)
Price
¥3,800 (CD+DVD)
¥3,000 (CD Only)
Tracklist
1. Unforgettable (Original: Nat King Cole)
2. Don't Know Why (Original: Norah Jones)
3. Candy (Original: Big Maybelle)
4. Satin Doll (Original: Ella Fitzgerald)
5. Alfie (Original: Cilla Black)
6. CARNIVAL (Original: The Cardigans)
7. How crazy are you? (Original: Meja)
8. Tea for two feat. blanc. (Original: Nanette and Tom)
9. Come on-a My House (Original: Rosemary Clooney)
10. All of me (Original: Belle Baker)
11. Over the rainbow (Original: Judy Garland)
12. The Christmas Song (Original: Mel Tormé)
Information
Coco d'Or 3 is the fourth Jazz cover album released by Hiro under the name Coco d'Or and is entirely arranged by Dave Matthews.
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C++ Challenge- try this
Newbie Member
5Apr2012,01:07 #1
Background
Due to a decrease in advertising profit, your favorite (and previously free) social networking site has decided to charge a monthly fee to each member. Frustrated, you set out to make your own social networking site, VisageTome.
For now, you will need to make a class to store each person's name, favorite food, and list of friends. This class should include methods to access and modify these variables. You will also need to allow the user to modify this information.
Requirements
Part 1 - Make People
Create a class to store the following information for each person:
First name
Favorite food
List of friends
Allow the user to add new people to the system
Allow the user to display all data about all people in the system
Part 2 - Make Connections
Allow the user to add and remove friendships between any two people
Part 3 - Make Dinner
Allow the user to modify any person's favorite food
Allow the user to select a person and display all of that person's friends who share the same favorite food
part 4 -optional- Make Bacon (only for the especially skilled)
Report the Bacon Number of any person; this requires your program to begin with actor Kevin Bacon already in the system
Kevin Bacon's favorite food is bacon; do not allow the user to change this
Here, the Bacon Number should be computed via friendships:
Kevin Bacon himself has a Bacon Number of 0
Any friend of Kevin Bacon has a Bacon Number of 1
In general, a person's Bacon Number is k+1, where k is the lowest non-negative Bacon Number of any of that person's friends
If there is no possible connection between a person and Kevin Bacon, that person's Bacon Number is -1
Requirement Notes
General
The list of friends for each person must be a vector.
Do not allow the user to enter duplicate names into the system.
Any user input that causes your program to break or to behave incorrectly will prevent pass-off of the assignment.
Friendships
A new person begins with a name and a favorite food, but no friends.
All friendships are bi-directional; do not create one-way friendships.
Newbie Member
5Apr2012,01:41 #2
FYI this is my hw sooo feel free to help me if you choose, or to not. (also admin can ban me if they want :-) its worth a shot since I am behind 3 assignments and an exam and last day of class is the 11th!!... thats what happens when you get a job...)
Mentor
17Apr2012,15:17 #3
Thank you for fessing up that this was your homework (that would have been my first question anyway, because you aren't the first to post a homework question as a "challenge").
How far have you got and where are you stuck? I won't do this project for you (although others might) but I will help you get unstuck.
(I see the last day of class was the 11th so presumably it's no longer an issue but if you've got an extension you might still want help.)
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About this Journal Submit a Manuscript Table of Contents
Case Reports in Rheumatology
Volume 2012 (2012), Article ID 724013, 4 pages
doi:10.1155/2012/724013
Case Report
Pulmonary Sarcoidosis following Etanercept Treatment
Department of Rheumatology, Wycombe General Hospital, Queen Alexander Road, Wycome, Buckinghamshire HP11 2TT, UK
Received 31 October 2012; Accepted 26 November 2012
Academic Editors: S. S. Koca and S. C. Plastiras
Copyright © 2012 Kuljeet Bhamra and Richard Stevens. 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
Tumour necrosis factor (TNF) is an important cytokine involved in the pathology of a number of inflammatory conditions, and thus blockade with anti-TNF therapies is becoming the cornerstone in managing such diseases. With increasing use, evidence is collected for the association of sarcoid-like granulomatous disease developing after the initiation of anti-TNF-α therapy, with disease reversal after discontinuation.
1. Introduction
We report a case of a 37-year-old married Pakistani-born woman, resident in the UK since the age of 19, who developed pulmonary sarcoidosis on treatment with etanercept for psoriatic arthritis. She first presented in 2009 with dactylitis affecting her left foot during the post partum period. She later went onto develop psoriatic plaques over her limbs, scalp, and trunk with worsening small and large joint arthritis. Her psoriatic arthritis was treated first with sulphasalazine. Due to side effects, her treatment was changed to methotrexate, with the later addition of leflunomide. Despite full-dose combination DMARD therapy and maintenance low-dose oral prednisone (5–10 mg/day), her disease remained active, requiring intramuscular and on occasion intravenous pulsed methyl-prednisolone to achieve even indifferent control and allow her to cope with looking after her 3 young children (PsARC score tender joints (TJ) 5, swollen joints (SJ) 6, physician global (PhG) 4/5, patient global (PtG) 4/5, DAS28 = 6.12, CRP 40 mg/L). Following screening, including a full history of potential exposure to tuberculosis (TB) and a normal baseline chest X-ray, she was commenced on etanercept 50 mg weekly sub.cut. in April 2010 and leflunomide was discontinued. She made a prompt response, achieving near joint and skin remission. (PsARC at three months TJ 0, SJ 2, PhG 1, PtG 2, CRP 1 mg/L, DAS28 = 2.03) and her maintenance prednisolone was phased out over the subsequent 3 months. She discontinued methotrexate on her own initiative 4 months after starting etanercept. She remained well until seven months into her etanercept treatment when she presented to clinic with a 3-week history of persistent dry cough and mild exertional breathlessness, having just returned from a 5-week stay in Pakistan.
Chest X-ray showed widespread reticulonodular shadowing with prominence of the of right hilum suggestive of lymphadenopathy (Figure 1(a)); staining for acid fast bacilli and TB elispot both negative, serum ACE 49.9 U/L (20–70), corrected calcium 2.4 mmol/L (2.10–2.55).
Figure 1: Chest X-ray pre-and postdiscontinuation of anti TNF-α therapy and commencement of oral prednisolone. (a) Chest X-ray with widespread reticulonodular shadowing with prominence of the of right hilum suggestive of lymphadenopathy pre-anti-TNF-α therapy. (b) Chest X-ray showing improvement in the extent of reticulonodular shadowing post-discontinuation of anti-TNF-α therapy and the commencement of oral prednisolone.
High resolution computed tomography showed multiple small nodules throughout the lung, few peribronchovascular nodules, with multiple enlarged mediastinal and hilar lymph nodes (Figures 2(a)-2(b)). Bronchoscopy performed revealed the presence of endobronchial nodes bilaterally; two transbronchial biopsies were taken from the right lower lobe with aid of screening.
Figure 2: High resolution computed tomography showed multiple small nodules throughout the lung, few peribronchovascular nodules, with multiple enlarged mediastinal and hilar lymph nodes.
Histological analysis showed the presence of noncaseating granulomata with small number of surrounding lymphocytes. Special stains performed showed that there were no identifiable acid fast bacilli on Ziehl-Nielson stain or fungal element on PAS or Grocott stains (Figures 3(a)3(c)).
Figure 3: Histological analysis of transbronchial biopsies. (a) H&E stain showing presence of noncaseating granuloma with surrounding lymphocytes. (b) Ziehl-Nielson—no acid fast bacilli seen. (c) Grocott Stain—no fungal elements seen.
The investigations therefore make a diagnosis for miliary TB highly unlikely and thus suggestive of sarcoidosis given her clinical picture. Etanercept was discontinued and prednisolone commenced.
2. Discussion
Tumour necrosis factor-α (TNF-α) is produced by a number of inflammatory cells such as macrophages and its role is implicated in the pathogenesis of granulomatous inflammation; blockade of TNF-α offers a potential role for targeted therapy. However, a series of nation-wide case reports have reported the association of sarcoid-like granulomatous disease after initiation of anti-TNF-α therapy, with disease reversal after discontinuation. A possible mechanism for this association is that anti-TNF-α therapies modulate a CD4+ Th1 cytokine response, key to the immunopathogenesis of sarcoidosis. CD4+ T cells interact with antigen presenting cells which initiate the formation and maintenance of granulomas, resulting in differentiation of selective Th1 cells secreting IFN-γ and IL-2 [1, 2]. In the chronic state, TNF-α, IL-12, IL-18 are the main cytokines produced. These cytokines are key in driving the Th1 commitment in the granulomatous process. Therefore blockade of TNF-α should have a therapeutic effect on sarcoidosis [1]. The immunopathogenesis remains poorly understood; a possible explanation is that there is overproduction of other cytokines that play a crucial role in granuloma formation with TNF-α blockade. Etanercept, a soluble TNF-α receptor fusion protein, is thought to enhance T-cell production of IFN-γ which is a key cytokine in the formation of granulomas in the acute stages of sarcoidosis [1, 3].
A number of studies have been carried out assessing the role of anti TNF-α in treatment of sarcoidosis, but their role remains questionable. A study using etanercept for stage II or III pulmonary sarcoidosis in seventeen patients was terminated early due to treatment failure when compared to conventional corticosteroid therapy [4]. Likewise, a double-blind randomised controlled study in eighteen patients with methotrexate resistant, corticosteroid dependent ongoing ocular sarcoidosis, showed a lack of steroid sparing effect and failure of ophthalmology global improvement [5]. These two studies using etanercept have failed to show treatment benefit in patients with progressive or methotrexate resistant sarcoidosis.
Our patient continues to improve on a reducing regimen of oral corticosteroid therapy, with disappearance of symptoms and resolution of pulmonary nodulosis. However, the question remains on what to do next when inflammatory arthritis becomes active. There is limited data available regarding treatment options in such patients; with what we know is rechallenging with another anti TNF-α, the right thing to do?
In contrast, two retrospective series reported symptomatic improvement in patients receiving infliximab when used in patients with chronic extrapulmonary disease (lupus pernio, uveitis, neurosarcoidosis), refractory to oral corticosteroid therapy or in patients who had not responded to etanercept [6]. However, a smaller study showed no difference in primary endpoints when used in patients with biopsy proven stage II-IV pulmonary sarcoidosis that had a suboptimal response or intolerance to oral corticosteroid therapy (minimum of 3 months treatment) [4]. In spite of this, a number of case reports to date are available highlighting the unexpected development of sarcoidosis following treatment with anti TNF-α, thus their role is controversial in granulomatous conditions. Consequently the use of corticosteroids is still the cornerstone of treatment in patients requiring systemic therapy.
Again, although the evidence is limited, leflunomide has been reported as an efficacious alternative therapy in treatment of sarcoidosis, thus offering the possibility of use for patients where sarcoidosis has developed following anti TNF-α therapy. Unfortunately our patient’s psoriatic arthropathy failed treatment with leflunomide.
3. Conclusion
The evidence available remains limited in order to draw firm conclusions. Further studies are required to clarify the role of a second anti TNF-α, and until then corticosteroids remain the preferred option.
References
1. R. P. Baughman, S. A. Strohofer, J. Buchsbaum, and E. E. Lower, “Release of tumor necrosis factor by alveolar macrophages of patients with sarcoidosis,” Journal of Laboratory and Clinical Medicine, vol. 115, no. 1, pp. 36–42, 1990. View at Scopus
2. D. Tong, N. Manolios, G. Howe, and D. Spencer, “New onset sarcoid-like granulomatosis developing during anti-TNF therapy: an under-recognised complication,” Internal Medicine Journal, vol. 42, no. 1, pp. 89–94, 2012.
3. H. Nunes, P. Soler, and D. Valeyre, “Pulmonary sarcoidosis,” Allergy, vol. 60, no. 5, pp. 565–582, 2005. View at Publisher · View at Google Scholar · View at Scopus
4. J. P. Utz, A. H. Limper, S. Kalra et al., “Etanercept for the treatment of stage II and III progressive pulmonary sarcoidosis,” Chest, vol. 124, no. 1, pp. 177–185, 2003. View at Publisher · View at Google Scholar · View at Scopus
5. R. P. Baughman, E. E. Lower, D. A. Bradley, L. A. Raymond, and A. Kaufman, “Etanercept for refractory ocular sarcoidosis: results of a double-blind randomized trial,” Chest, vol. 128, no. 2, pp. 1062–1067, 2005. View at Publisher · View at Google Scholar · View at Scopus
6. R. P. Baughman and E. E. Lower, “Infliximab for refractory sarcoidosis,” Sarcoidosis Vasculitis and Diffuse Lung Diseases, vol. 18, no. 1, pp. 70–74, 2001. View at Scopus
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Bibliography: Cover: Dark Gods
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Title: Cover: Dark Gods
Author: David O'Connor
Year: 1987
Type: COVERART
ISFDB Record Number: 320371
User Rating: This title has fewer than 5 votes. VOTE
Current Tags: None Add Tags
Publications:
Copyright (c) 1995-2011 Al von Ruff.
ISFDB Engine - Version 4.00 (04/24/06)
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Molecules 2007, 12(8), 1910-1939; doi:10.3390/12081910
Review
Biological Activities of Hydrazone Derivatives
Marmara University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 34668, Turkey
* Author to whom correspondence should be addressed.
Received: 13 March 2007; in revised form: 11 August 2007 / Accepted: 16 August 2007 / Published: 17 August 2007
Download PDF Full-Text [194 KB, uploaded 2 October 2008 11:53 CEST]
Abstract: There has been considerable interest in the development of novel compounds with anticonvulsant, antidepressant, analgesic, antiinflammatory, antiplatelet, antimalarial, antimicrobial, antimycobacterial, antitumoral, vasodilator, antiviral and antischistosomiasis activities. Hydrazones possessing an azometine -NHN=CH- proton constitute an important class of compounds for new drug development. Therefore, many researchers have synthesized these compounds as target structures and evaluated their biological activities. These observations have been guiding for the development of new hydrazones that possess varied biological activities.
Keywords: Hydrazones; hydrazide-hydrazones; biological activity; isoniazid.
Article Statistics
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Cite This Article
MDPI and ACS Style
Rollas, S.; Küçükgüzel, S.G. Biological Activities of Hydrazone Derivatives. Molecules 2007, 12, 1910-1939.
AMA Style
Rollas S, Küçükgüzel SG. Biological Activities of Hydrazone Derivatives. Molecules. 2007; 12(8):1910-1939.
Chicago/Turabian Style
Rollas, Sevim; Küçükgüzel, S. G. 2007. "Biological Activities of Hydrazone Derivatives." Molecules 12, no. 8: 1910-1939.
Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
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Activity Not Available
Estimated Cost
Analyzed almost 3 years ago based on code collected almost 3 years ago.
Project Cost Calculator
$ .00
478,651 lines
129 person-years
$ 7,082,977 *
*Using the Basic COCOMO Model
Estimate seems way too high?
Ohloh scans all files at any given code location to calculate the cost estimate.
Ohloh lets you exclude files and direc-tories from this calculation on the Code Locations page. You can get a more realistic estimate by excluding:
• External dependencies or libraries
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About Cost Estimates
• Software cost estimation is tricky business even when all the variables are known -- knowlegdge which we certainly don't have.
• We calculate the estimated cost of the project using the Basic COCOMO model.
• For those familiar with the details, we are using coeffcients a=2.4 and b=1.05.
• Please note that COCOMO was created to model large institutional projects, which often don't compare well with distributed open-source projects.
• COCOMO is meant to include the design, specification drafting, reviewing and management overhead that goes along with producing quality software.
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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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User:Marie-Eve Val
From OpenWetWare
Revision as of 11:31, 13 December 2011 by Marie-Eve Val (Talk | contribs)
Jump to: navigation, search
Vibrio cholerae
Vibrio cholerae with big segregation problems
Marie-Eve VAL
INSTITUT PASTEUR
Unité "Plasticité du Génome Bactérien"
Département Génomes et Génétique
CNRS URA2171
25 rue du Dr. Roux
75724 PARIS cedex 15
FRANCE
Email me through OpenWetWare
Contents
Research interests
I am a post-doctoral research fellow in Didier Mazel's lab at the Institut Pasteur of Paris. I have a great interest in bacterial genome structuration, organization and maintenance ... and a special interest in multipartite genomes. Owing to its bi-chromosomal genome architecture and its importance in public health, Vibrio cholerae, the causative agent of cholera, has become a preferred model to study bacteria with multipartite genomes. My approach is to drastically alter V. cholerae’s genome structure to gain more insight into multipartite genomes. To do so, I developed a site-specific recombination-based engineering tool, which provides us with a powerful means to massively reorganize in principle any prokaryotic genome. This genetic tool consists in harnessing the λ and HK022 recombination systems to perform a large panel of genome reorganizations. By controlling the location and the orientation of each partner recombination site, we can obtain a large variety of genome rearrangements. The laboratory of Didier Mazel was an ideal place to initiate such a project since they have developed a large set of genetic tools to work in the vibrios and Didier Mazel has substantial knowledge and experience in site-specific recombination, bacterial genetics and genome analysis.
Education
Professional Training
Publications
1. Das B, Bischerour J, Val ME, and Barre FX. . pmid:20133778. PubMed HubMed [Paper1]
Molecular keys of the tropism of integration of the cholera toxin phage.
2. Génolevures Consortium, Souciet JL, Dujon B, Gaillardin C, Johnston M, Baret PV, Cliften P, Sherman DJ, Weissenbach J, Westhof E, Wincker P, Jubin C, Poulain J, Barbe V, Ségurens B, Artiguenave F, Anthouard V, Vacherie B, Val ME, Fulton RS, Minx P, Wilson R, Durrens P, Jean G, Marck C, Martin T, Nikolski M, Rolland T, Seret ML, Casarégola S, Despons L, Fairhead C, Fischer G, Lafontaine I, Leh V, Lemaire M, de Montigny J, Neuvéglise C, Thierry A, Blanc-Lenfle I, Bleykasten C, Diffels J, Fritsch E, Frangeul L, Goëffon A, Jauniaux N, Kachouri-Lafond R, Payen C, Potier S, Pribylova L, Ozanne C, Richard GF, Sacerdot C, Straub ML, and Talla E. . pmid:19525356. PubMed HubMed [Paper2]
Comparative genomics of protoploid Saccharomycetaceae.
3. Val ME, Kennedy SP, El Karoui M, Bonné L, Chevalier F, and Barre FX. . pmid:18818731. PubMed HubMed [Paper3]
FtsK-dependent dimer resolution on multiple chromosomes in the pathogen Vibrio cholerae.
4. Val ME, Bouvier M, Campos J, Sherratt D, Cornet F, Mazel D, and Barre FX. . pmid:16109379. PubMed HubMed [Paper4]
The single-stranded genome of phage CTX is the form used for integration into the genome of Vibrio cholerae.
All Medline abstracts: PubMed HubMed
Useful links
Personal tools
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[4]
But all this is not so surprising after all, so very different was he from all other kings, both those who have inherited their thrones from their fathers and those who have gained their crowns by their own efforts; the Scythian king, for instance, would never be able to extend his rule over any other nation besides his own, although the Scythians are very numerous, but he would be well content if he could maintain himself in power over his own people; so the Thracian king with his Thracians, the Illyrian with his Illyrians, and so also all other nations, we are told. Those in Europe, at any rate, are said to be free and independent of one another even to this day. But Cyrus, finding the nations in Asia also independent in exactly the same way, started out with a little band of Persians and became the leader of the Medes by their full consent and of the Hyrcanians1 by theirs; he then conquered Syria, Assyria, Arabia, Cappadocia, both Phrygias, Lydia, Caria, Phoenicia, and Babylonia; he ruled also over Bactria, India, and Cilicia; and he was likewise king of the Sacians, Paphlagonians, Magadidae, and very many other nations, of which one could not even tell the names; he brought under his sway the Asiatic Greeks also; and, descending to the sea, he added both Cyprus and Egypt to his empire.
1 The extent of his kingdom
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hide References (7 total)
• Commentary references to this page (1):
• W. W. How, J. Wells, A Commentary on Herodotus, 3.19
• Cross-references to this page (3):
• Raphael Kühner, Bernhard Gerth, Ausführliche Grammatik der griechischen Sprache, KG 1.3.2
• Raphael Kühner, Bernhard Gerth, Ausführliche Grammatik der griechischen Sprache, KG 3.6.1
• Basil L. Gildersleeve, Syntax of Classical Greek, Forms of the subject.
• Cross-references in general dictionaries to this page (3):
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[13] Thereupon they all went their way and proceeded so to do. At daybreak on the following day the staff-officers presented themselves at the gates of the king. So Cyrus went in with them to Cyaxares and began to speak as follows:
“I am sure, Cyaxares,” said he, “that you have1 this long time been thinking no less than we of the proposition that I am going to lay before you; but perhaps you hesitate to broach the subject for fear it should be thought that you speak of an expedition from here because you are embarrassed at having to maintain us.
1 He lays his plan before Cyaxares
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Server Hacked? How To Notify Google to Restore Google Search Rankings
Nov 8, 2007 • 9:26 am | (2) by | Filed Under Google Search Engine Optimization
What happens if you discover a folder on your server that has a bunch of spammy content that has no relevance to your site whatsoever? Typically, Google will deindex your site when it discovers this content. Therefore, you need to be on top of the game and ensure that it doesn't happen.
Unfortunately for someone on Google Groups, it did.
Bergy of the Google Webmaster Central Team, therefore, offered advice on what you should do when you are afraid that your rankings will drop, or worse, if you'll be deindexed. He suggests the following:
Delete the spammy content: If it's not relevant, you don't need it.
Get Google to reconsider your site for reinclusion: Simple and self-explanatory. You don't want to be deindexed because of being an innocent victim. Google has more information about submitting a reinclusion request.
Check with your web host: Make sure that everything is current on your host, including control panels, bulletin board software, blog software (Wordpress users have been hit really hard lately!), and any other applications that may require updating.
Good advice.
Forum discussion continues at Google Groups.
Previous story: 51% of Google AdSense Publishers are Older Than 30 Years Old
blog comments powered by Disqus
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CMD sent two reporters to track ALEC in Oklahoma
Click here to help support our future investigations.
Clean and Safe Energy Coalition
From SourceWatch
Jump to: navigation, search
This article is part of the Center for Media & Democracy's focus on the fallout of nuclear "spin."
This article is part of the Center for Media & Democracy's spotlight on front groups and corporate spin.
The Clean and Safe Energy Coaltion (CASEnergy) is a public relations campaign for new reactors launched in 2006, funded by the Nuclear Energy Institute (NEI) industry group, and headed by former Bush Environmental Protection Agency administrator Christine Todd Whitman and former Greenpeace activist Patrick Moore (who left that group in 1986). [1] CASEnergy was launched on April 24, 2006.[1] On its website, the PR firm Hill & Knowlton boasted that the group is "a national grassroots organization that advocates the benefits of nuclear energy. The CASEnergy Coalition is a Hill & Knowlton campaign run out of the Washington, DC office."[2]
Contents
Mission statement
According to the group's website, "The Clean and Safe Energy Coalition (CASEnergy Coalition) supports the increased use of nuclear energy to ensure an environmentally clean, safe, affordable and reliable supply of electricity. Nuclear power enhances America's energy security and economic growth, helps attain cleaner air and improves the quality of life, health and economic well-being for all Americans." It also claims that nuclear energy good for US security.[2]
Front group
The Columbia Journalism Review (CJR) described CASEnergy as a front group for the nuclear power industry, created by the PR giant Hill & Knowlton. [3]
The CJR criticised the Washington Post for simply referring to Moore as an "environmentalist" and a co-founder of Greenpeace — without mentioning that he is funded by the nuclear industry. A string of other newspapers followed suit, failing to mention that Moore is also a paid spokesman for the nuclear industry. CJR said it is "maddening that Hill & Knowlton, which has an $8 million account with the nuclear industry, should have such an easy time working the press".
The words "clean" and "safe" were deliberately used as part of the nuclear industry's multi-million pound campaign to repackage itself. It is interesting that the industry carries on using these words even after similar campaigns were found to be misleading.
Personnel
• Christine Todd Whitman - co-chair
• Patrick Moore - co-chair
• Nina Cann-Woode - field representative [4]
• Deborah L. Nelson - media contact (listed on a June 2008 CASEnergy release [5]) and vice-president at Hill & Knowton [6]
• Don Meyer - media contact (listed on May and Oct 2006 press releases) - "CASEnergy spokesman Don Meyer [is] a senior vice president with Washington public relations firm Hill & Knowlton," reported Nucleonics Week ("Two New Groups Formed to Press for Greater Use of Nuclear Power," by Daniel Horner and Tom Harrison, April 27, 2006)
• Nathan Drevna - media contact (listed on Nov 2006 press release) - also a Hill & Knowlton employee, according to multiple press releases [3][4][5]
Members
Organizations
The Coalition boasts a long list of members and individual supporters – but the website also states that there is no fee or joining process for membership, so joining takes little more than the click of a mouse. [7]
As of November 2006, the website listed the following organizations as members[8]:
• ABB [6]
• AFL-CIO, Building & Construction Trades Department
• Alliance for Sound Nuclear Policy
• AmerenUE
• American Boiler Manufacturers Association
• American Council on Science and Health
• American Energy Independence
• American Homeowners Grassroots Alliance
• American Iron and Steel Institute
• American Nuclear Insurers
• American Nuclear Society, Columbia, SC Chapter
• American Public Power Association
• Analytical Nuclear Services Company
• Applied Research Center
• AREVA, Inc.
• Arizona Public Service
• Arkansas Environmental Federation
• Arkansas State Chamber of Commerce
• Asbestos Workers Union Local 67- Florida
• Associated Equipment Distributors
• Associated Industries of Arkansas
• Associated Industries of Florida
• Baton Rouge Area Chamber of Commerce
• Baton Rouge Workforce Investment Board
• B&D Consulting
• Bechtel Power Corporation
• Blackledge Furniture
• Boilermakers Local 433
• Bricklayers Local Union 1 - Florida
• Brookhaven-Lincoln Chamber of Commerce
• Brown McMahon & Weinraub, LLC
• Capital Area Agency on Aging Louisiana
• Cedar Rapids City Building Trades Council, IA
• Center for Advanced Power Systems - Florida State University
• ChemCorr, LLC
• Chicago and Cook County Building and Construction Trades Council
• Chicago Federation of Labor
• Chicago Plumbers Local Union 130
• Chicago Urban League
• City of St. Francisville, Louisiana
• Citizens for Nuclear Technology Awareness
• CMS Energy
• Conference of Minority Transportation Officials
• Constellation Energy
• Consumers First, Inc.
• ConverDyn
• Copeland & Johns, Inc.
• Copiah-Lincon Community College
• Cornell University
• Creative Video
• Detroit Regional Chamber of Commerce
• Distilled Spirits Council of the U.S.
• Dominion
• DTE Energy
• Duke Power Company
• Edison Electric Institute
• Edlow International Company
• E-J Electric Installation Company
• Electric Consumers' Alliance
• Electricians Local Union 108 - Florida
• Elevator Construction Local Union 74 - Florida
• The Energy Association of New York State
• Energy Northwest
• Entergy Corporation
• Exelon Corporation
• Florida Carpenters Regional Council
• Florida Petroleum Council
• FirstEnergy Corp.
• Florida Power & Light
• Florida State University Center for Advanced Power Systems
• GE Energy
• General Atomics
• The Gladlands
• Greenspirit Strategies Ltd.
• Hawkeye Labor Council, AFL-CIO
• Highlines Construction Company Louisiana
• H.O.P.I. Consulting
• HTS Consulting
• Idaho National Laboratory
• Illinois Chamber of Commerce
• Illinois Energy Association
• Illinois Manufacturers Association
• International Access Corporation
• International Brotherhood of Boilermakers
• International Brotherhood of Electrical Workers
• International Brotherhood of Teamsters
• International Paper
• iNuclear
• Iron Workers Local Union 397 - Florida
• Iron Workers Local Union 474- New Hampshire
• Jackson Economic Development Alliance
• Johnson, Baily, Henderson, McNeel Architects
• Kirk Consulting Group, Inc.
• L-3 Communications MAPPS
• Laborers Locals 43, IA
• Lansing Regional Chamber of Commerce
• Lawrence County Community Development Association
• Louisiana Association of Building and Industry
• Louisiana Chemical Association
• Louisiana Municipal Association
• Manchester Latino Caucus
• Maracor Software & Engineering, Inc.
• Marked Tree Economic Development, AK
• MEAG Power
• Michigan Chamber of Commerce
• Michigan Electric Cooperative Association
• Michigan Grocers Association
• Michigan Institute of Laundering and Drycleaning
• Michigan Movers Association
• Michigan Retailers Association
• Midwest Carwash Association
• Mississippi Development Corporation
• Mississippi Manufacturers Association
• Mississippi Municipal League
• Mississippi State Board for Community and Jr. Colleges
• Mississippi Technology Alliance
• Mitsubishi Power Systems, Inc.
• Morgan, Lewis & Bockius, LLP
• Morris, Demag, McCarty, Inc.
• MPR Associates, Inc.
• NAACP, Tampa Branch
• NAC International
• National Association of Manufacturers
• National Electrical Contractors Association
• National Enrichment Facility
• National Ready Mixed Concrete Association
• National Rural Electric Cooperative Association
• Nazchez-Adams County Development Authority
• Nebraska Public Power District
• New England Energy Alliance
• North American Young Generation in Nuclear
• North Carolina State University, Department of Nuclear Engineering
• Nuclear Energy Institute
• Nuclear is Our Future
• NuStart Energy Development, LLC
• Oglethorpe Power Corporation
• Omaha Public Power District
• 100 Black Men Baton Rouge
• Operating Engineers Local 925 - Florida
• The Outlaw Group
• Painters Local Union 88 - Florida
• PDF Conference
• Pebble Bed Modular Reactor Limited
• PG&E Corporation
• Pinnacle West
• Pioneer Service And Engineering Co., Inc
• Plumbers and Pipefitters Local 123
• Plumbers and Pipefitters Local 597 - Illinois
• PNM Resources
• Port of Greater Baton Rouge
• Power Resources, Inc
• PPL Susquehanna
• Prince Igor Productions
• Professional Radiation Consulting, Inc.
• Progress Energy
• Promet Energy Partners, LLC
• PVS Chemicals, Inc.
• Public Service Enterprise Group (PSEG)
• Quad City Federation of Labor
• R. Brooks Associates, Inc.
• The Riverside Advocacy Center
• Rock-Tenn Company
• RWE Nukem, Inc.
• Sandia National Laboratories
• Santee Cooper
• SCANA Corporation
• Scientech, LLC
• 60 Plus Association
• Sheet Metal Workers' International Association
• SMWIA Local Union 105 - California
• Southeast Iowa Building and Construction Trades
• Southern Company
• Southwest Mississippi Partnership
• SPX Building Corporation
• Sterling Heights Area Chamber of Commerce
• STP Nuclear Operating Company
• Sunbelt Energy Resources, Inc.
• Talisman International, LLC
• Tampa Bay Partnership
• Teamsters Local 299, MI
• Texas Independence Energy, LP
• Thorenco, LLC
• TXU Power
• University of Cincinnati
• University of Massachusetts, Lowell - Nuclear Engineering Department
• University of Florida, Department of Nuclear and Radiological Engineering
• University of Missouri-Columbia, Nuclear Science and Engineering Institute
• University of South Carolina - Nuclear Engineering Department
• University of Tennessee, Nuclear Engineering Department
• University of Wisconsin - Nuclear Engineering and Engineering Physics Program
• U.S. Chamber of Commerce
• Urban League of Greater Jackson
• USEC, Inc.
• Vermont Chamber of Commerce
• Vicksburn and Warren County Economic Development Foundation
• The Vidal Group
• Voyager Alernative Energy Solutions
• Walthall County Economic Development Authority
• Washington Group International
• West Feliciana Parish Police Jury
• Westinghouse Electric Company
• WOLFCO, Inc.
Former members
Individuals
The group listed the following "sampling of individuals" as of May 5, 2006[7]:
• Iowa State Representative Philip Wise
• New Hampshire State Representatives Caitlin A. Daniuk and Michael Rollo
• Michigan State Senator Buzz Thomas
• Reverend Willie Toone - North End Church of God and Christ, Michigan
• Reverend Charles Williams - Michigan
• Greg Fedon - Warren Jaycees - Michigan
• Barney Bishop, President, Associated Industries of Florida
• Brownstone, Michigan Town Supervisor Arthur Wright
• Denis Beller, Professor, University of Las Vegas
• Mike Hamby - Former Executive Director of the Florida Democratic Party
• Keith Bullen - Volt Technical Services
• Jim Scaratino - Coalition for New Mexico Wilderness
• Berol Robinson - Environmentalists for Nuclear Energy
• Christopher Yeaw - United States Naval War College
Funding
In April 2006 a spokesman for the NEI told New York Times reporter, Matthew L. Ward, that it was providing all the funding for the group but refused to state what the budget was. [8]
Contact information
CASEnergy Coalition
607 Fourteenth Street, NW
Suite 300
Washington, DC 20005
Phone: 202-338-CASE (2273)
Fax: 202-337-4230
Website: http://cleansafeenergy.org/
Articles and resources
Related SourceWatch articles
References
1. ‘Former EPA Administrator Christine Todd Whitman and Greenpeace Co-Founder Dr. Patrick Moore to Chair CASEnergy Coalition’, CASEnergy press release, dated April 24, 2006, accessed November 2006.
2. Hill & Knowlton, "USA: The Hypothesis: Nuclear Power Offers Clean Energy, Clean Air", Hill & Knowlton website, accessed October 2008.
3. "False Fronts: Why to Look Behind the Label", Editorial, Columbia Journalism Review July-August 2006.
4. John Murawski, "Progress' nuclear plans attract friends, foes," The News & Observer (Raleigh, North Carolina), June 11, 2008.
5. Press release, "Nuclear Energy's Resurgence Promises to Spur Job Growth," CASEnergy via PR Newswire, June 17, 2008.
6. "2007 ABR: Hill & Knowlton," PR Week, April 23, 2007.
7. Clean and Safe Energy Coalition website – FAQs, undated, accessed November 2006.
8. - Clean and Safe Energy Coalition website – Members, undated, accessed November 2006.
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Family:David Dugger and Tempy Milton (1)
Watchers
Facts and Events
Marriage? 4 Mar 1813 Bulloch, Georgia, United States
Children
BirthDeath
1.
2.
3.
4.
5.
6.
Children
Several children are proven by the 1850 census, though it isn't clear if they are all Tempy's or if some belong to David's second wife Clarissa.
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Person:Willard Cole (6)
Watchers
Willard Leonard Cole
m. 29 JUN 1903
Facts and Events
Name Willard Leonard Cole
Gender Male
Birth? 6 JAN 1868 Colestin, Jackson County, Oregon
Census? lived in Keswick, CA and was the superintendant of the Iron Mountain railroad.
Marriage 29 JUN 1903 Shasta, Californiato Alice Fairbanks
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Place:Cobalt, Timiskaming, Ontario, Canada
Watchers
NameCobalt
TypeTown
Coordinates47.4°N 79.683°W
Located inTimiskaming, Ontario, Canada
source: Getty Thesaurus of Geographic Names
source: Family History Library Catalog
the text in this section is copied from an article in Wikipedia
Cobalt is a town in the district of Timiskaming, province of Ontario, Canada, with a population of 1,133 (as per the Canada 2011 Census.)
In 2001 Cobalt was named "Ontario's Most Historic Town" by a panel of judges on the TV Ontario program Studio 2, and in 2002 the area was designated a National Historic Site.
Research Tips
This page uses content from the English Wikipedia. The original content was at Cobalt, Ontario. 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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Place:Juniata Terrace, Mifflin, Pennsylvania, United States
Watchers
NameJuniata Terrace
TypeBorough
Coordinates40.585°N 77.58°W
Located inMifflin, Pennsylvania, United States
source: Getty Thesaurus of Geographic Names
source: Family History Library Catalog
the text in this section is copied from an article in Wikipedia
Juniata Terrace is a borough in Mifflin County, Pennsylvania, United States. The population was 502 at the 2000 census.
Research Tips
This page uses content from the English Wikipedia. The original content was at Juniata Terrace, Pennsylvania. 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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Template:Obstetrical procedures
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New Zealand (NZ) My Account
Talley's Frozen Foods Ltd
Port Motueka, Motueka, Nelson
New Zealand
Phone: 03 528 2800
http://www.talleys.co.nz
Opening Hours: 24 Hours, 7 Days
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Zenbu is a collaboratively edited directory of businesses, places or things. You can help build Zenbu, edit this entry, report an error or email it to a friend.
Login required: Edit, Export, Add branch / neighbour / new
Zenbu ID 1114250, 611 views since 06/07/2007
Last updated 15/08/2007 by burgla
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Australian Bureau of Statistics
Celebrating the International Year of Statistics 2013
ABS Home > Statistics > By Catalogue Number
9309.0 - Motor Vehicle Census, Australia, 31 Jan 2012 Quality Declaration
Latest ISSUE Released at 11:30 AM (CANBERRA TIME) 22/08/2012
Page tools: Print Page Print All RSS Search this Product
MEDIA RELEASE
22 August 2012
Embargoed: 11.30 am (AEST)
125/2012
Diesel vehicles increase by 60%
The number of registered diesel vehicles has increased by 60.6% from 2007 to 2012, according to the Australian Bureau of Statistics.
Queensland had the largest percentage of diesel powered vehicles with 26.3%, followed by New South Wales (25.50%) and Victoria (21.4%). The Australian Capital Territory had the smallest percentage of diesel powered vehicles with 1%.
At 31 January 2012, diesel powered vehicles made up 15.9% of registered cars in Australia, compared to 14.7% at the same time last year.
Over the same period, petrol powered vehicles decreased from 82.1% to 81.1%.
The number of vehicles registered in Australia at 31 January 2012 was 16.7 million (up 2.5% from 2011).
Motorcycles continued to grow in popularity at a faster rate than any other vehicle type in the twelve months to January 2012. From 2007 to 2012, motorcycle (including scooter) registrations had an average annual growth rate of 7.7%.
For further information see Motor Vehicle Census (cat. no 9309.0).
Media notes:
When reporting ABS data you must attribute the Australian Bureau of Statistics (or the ABS) as the source.
© 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
4513.0 - Criminal Courts, Australia, 2011-12 Quality Declaration
Latest ISSUE Released at 11:30 AM (CANBERRA TIME) 14/02/2013
© 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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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.
One often sees business plans or pitches along the lines of "yeah we're going after a well-entrenched market, but it's a very big one and we need to get only x% of it to be profitable" where x is often ridiculously low.
Is this a valid business model? I'm pretty sure reading or hearing somewhere how bad of an idea that was, does anyone has any pointers?
share|improve this question
2 Answers
Yes, it's bad, investors will rate you right away as clueless.
One way to think about it: why is your x% any more reasonable than say, 10 times less, or 10 times more? You do realize that when you say "housing is a trillion dollar market", and we only need to capture 1% to be billionaires, it doesn't make any sense. 1% seems low, which is why you assume: "anyone could get 1% of anything". It's top-down thinking. Now think bottom-up. 1% of the housing market is 10 million households. How am I going to get 10 million people to use my product? If you can answer that, then you are in good shape.
One more way to think about this: redefine your market so you become the leader in that sub-market. That's pretty much the only way that makes sense. We want to be the best at "housing for 2-income families in New York". Ok, now I can believe you know what you are trying to do.
share|improve this answer
Lindelof,
There is little value to this type of a "plan". I use quotes because it is NOT a plan at all - it is only a hope. As a wise mentor once told me Hope is not a plan. This is a TOP-DOWN view of the potential of your business.
The little value is just to give you and the investor a hypothetical view of the potential. So you can give a very large Y ($B) and a small X (<5%) say that there is a huge potential. Remember that if you show something like 20+% in 3 years, then your investor will ask you to hand over whatever you have been smoking :) and you will lose credibility. So... this X% of Y$ market is not useful and if this is all you have put in front of your investor - you will be shown the door.
To make your plan credible you need a BOTTOMS-UP PLAN - a real plan. A real plan is not just numbers starting from zero customers/revenue growing to some realistic number over 5 years, but one that is supported by ACTIONS that your team will undertake to achieve those. These actions can be in the Development, Marketing and most importantly Sales areas.
Example: If I have an Enterprise business, and I show say 5 customers in year 1, then I need to show actions that may be something like:
1. Attend 3 conferences, collect 200 leads
2. Target and qualify 50 of them
3. Pursue and close 5 of them with 2 sales personnel
These actions will be supported by a hiring (Sales/marketing) and investment plan (for marketing, lead-gen, promotions etc). Now the 5 customers (and their revenue) becomes a believable number.
Repeat this for Years 2-5 and you have a real plan supported by actions that shows the investor that you have thought through the details. By Year 5 you may have 100 customers at ~$500K a piece which will put you at $50M revenue. If your addressable market was $1B then you have reached 5% of the addressable market.
Hope this helps.
Siva
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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 am not sure how I should be paying taxes for freelance/consulting work. With some of my clients I just signed a consulting agreement, and an NDA and then I invoice them. They pay me via credit card or check and I cash it directly into my bank account.
How do I account for taxes in situations like this?
share|improve this question
3 Answers
up vote 0 down vote accepted
You'll normally need to file a schedule C with your taxes and declare all the income/expenses, and then this will be used to adjust your gross income from which you compute taxes.
Depending on your corporate structure (if any) this could be more involved, overall you'll want to spend some time looking it up, or likely talking to an accountant.
share|improve this answer
It will depend on what country you are in. I would recommend speak to an accountant or at least visit your government tax website.
share|improve this answer
If you haven't incorporated, then you're a sole proprietor. Centurion is right on the schedule C. But you also need to pay estimated taxes quarterly if you are above a threshold. Part of it depends on whether you are also paying taxes as an employee. You also need to register with your state and county and pay any local taxes they have.
None of it is overly complicated after you do it the first time, but it can be confusing the first time, so if you're confused, go for the accountant. There can be fees and penalties for not filing or filing late, so don't ignore this or put it off until the end of the year.
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Tell me more ×
Answers OnStartups is a question and answer site for entrepreneurs looking to start or run a new business. It's 100% free, no registration required.
I have a web service targeted at web designers that currently earns about $2,000 per month in revenue. It is a SaaS business and my customers have been with me for years and we are growing (albeit slowly) and adding new customers with little to no marketing efforts.
My expenses are about $120/month for hosting fees and the support is minimal, 1-2 hours per week if that. It's a mature, rock-solid product that needs somebody to take it to the next level and market it. I have built this software up over the last 4 years and am ready to pursue other things. It is a good business for somebody to purchase and grow it.
My question is: How do I price my product for sale and how much is this worth? I have heard taking your monthly revenue and multiply by 36 months (3 years) which puts me in the ball park of 72k.
share|improve this question
7 Answers
up vote 10 down vote accepted
You say that it's a good business for someone to purchase and grow, yet, you have not substantially grown it yourself. This will be a huge alarm bell to any potential purchaser. After all, if it's "that easy" to grow it, you would have done so already.
If you really want to sell it and get a good price for it, I would recommend that you start marketing it (either via your own, or someone else's efforts) and when you can show month on month growth, you'll be in a far better place to negotiate a good sale.
share|improve this answer
I suggest you do not sell it. Instead, find a partner and/or employ freelancers and be in a passive role if timd is your constraint.
share|improve this answer
Your number sounds about right. I guess all depends if you can convince potential buyers that by putting some effort on it they can considerably grow the business
share|improve this answer
Three times revenue is very high for the current climate. Maybe one times would be more realistic. It depends on the precise nature of the business, competition, scope for expansion, etc.
share|improve this answer
A very popular site to sell existing websites is https://flippa.com/ if you look at their Just Sold section and sort by price you'll see websites which sold for over a million dollars. Your best bet is to find similar websites see what they sold for. If non exist find websites generating similar revenue, see what proof was given such as verified Analytics logs, Financials etc for past few months. It's your web site you can list it for what you want 2x, 3x, whatever. But if you're site is making $1,880 after expenses you should consider spending another hundred bucks for someone to manage the support. I'm sure your server fees are on auto pay so why sell when you can pay someone to manage the site and you sit and collect another grand + each month?
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A more realistic multiplier for yearly revenue is x1, but that is IF you find a buyer who is interested in buying your business. While profit margins matter, revenue matters more at least on the big scale, see this article http://www.princetoncapitalllc.com/Selling-a-Business-for-Sale-Articles/Revenue-vs-ebitda.php
It's possible to get a multiplier of x2 or x3 from VCs based on future revenue potential of a quickly growing business (in good size market), but your business is too small for any VCs to be interested. I agree with Nick Stevens that showing a steady growth over time will be your best argument for pricing your business as that's the only proof of potential.
Some additional considerations: 1. Is your product/idea easy to replicate? If it is, it's possible to relax too much and start loosing all future customers to competition and fight against flat or declining revenue. This is especially true for web sites with high sensitivity to search engine rankings (neglect on SEO that results in a rank drop will take months to repair). 2. Are you in a niche market? If yes, how far can you grow your customer base before you max out and/or have to expand your product to interest more customers? 3. Is your product easy to own/maintain for someone without your skills and experience?
Others have suggested to just hire someone for the minimal work there is and collect cash, but if you want to sell because you need capital for some other venture closer to your heart consider selling part of a business. Since prospective partner will be taking on less risk with you around you might get better price per share than if you would selling 100% of it and if things go well the partner might consider buying you out eventually.
Good Luck!
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Not sure I agree with @nick 100%... maybe, but not entirely. Oftentimes programmers or folks with amazing technical skills create a product and don't really know how to market it. In fact, it's impressive that you have any profit at all. Many startup struggle to get their first dollar, but it would help to know more before making a judgement.
In any case, these answers should not be distracted so much by your revenue having this little knowledge about your business. That strikes me as misdirected. In your case, based on your post, it's far more important:
1) how many customers you have. You imply that you easily acquire customers, in the plural, and so I can only assume that you have more than 1.
2) What is your rate of acquiring new customers vs. churn? So how often do you gain vs. lose customers over a given period of time. People want to know that it's not just friends and family using your product out of goodwill. They also want to see that the number has increased over time and not peaked. As long as you acquire customers faster than losing them, your good.
3) It might take "little to no marketing efforts", but it always costs something to acquire and maintain a customer. What is the avg. cost of acquisition? and what does a customer cost to maintain on a monthly basis?
4) What is your revenue model? Do you have free users as well? What is the cost of maintaining them? Does the cost differ from that of paying users? If you have 5 paying customers that drive $2k a month in profit
5) How do you typically acquire the customers you mention? Word of mouth? Referrals? A phone call? Virally? Search marketing? This is important because a potential acquirer may have the means, knowledge, and people to do any one of these things better than you. For example, I might look at your model and see that you have no idea how to work a progression funnel or run multivariate tests to increase conversion rates. Much of which can be automated inexpensively.
6) what is the niche/market/vertical/target customers? This will tell us something about total potential opportunity, and it might also hit to ways of attracting potential acquirers who know that market (or prospects in that market) much better than you.
It's impossible to say without knowing more, but acquirers often look for upside in deals like this where the founder had the skills to get an idea off the ground, but have no idea how to scale it. So humility is important here. The $2k/mo. alone is inconsequential and does not make an opportunity like this attractive.
What looks good is when a business is scalable and has any traction at all in the marketplace. Besides, not every "acquirer" is a big company or a VC firm, sometimes other entrepreneurs look for ideas like this as side projects for the same reasons that people flip houses.
So my recommendation is that you find a business partner who can scale up the business as another commenter suggested, or start working on a business plan that addresses the questions above as a starting point. No one will seek you out with that kind of revenue, so you need to have a compelling story to tell, and you need to have something that looks like a diamond in the rough.
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Multiple Time Scales Analysis of Precipitation in Hotan, China
Jiqing Lv, Bing Shen, Shuhong Mo
Abstract
The wavelet transform and detrended fluctuation analysis (DFA) were introduced briefly. Then DFA and discrete wavelet were used to analyze the fluctuation characteristics of precipitation in Hotan from 1954 to 2003. It was shown by analysis with the methods of de-trend fluctuation and wavelet transform that the precipitation in Hotan will decreased in near future for several years, and will last 21 months at least.
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roxygen (0.1-3)
4 users
Literate Programming in R.
http://roxygen.org
http://cran.r-project.org/web/packages/roxygen
A Doxygen-like in-source documentation system for Rd, collation, namespace and callgraphs.
Maintainer: Peter Danenberg
Author(s): Peter Danenberg <pcd@roxygen.org>, Manuel Eugster <Manuel.Eugster@stat.uni-muenchen.de> with contributions from Hadley Wickham <hadley@rice.edu>
License: GPL (>= 2)
Uses: digest, gsubfn, testthat
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Medieval Studies
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WCF vs ASP.NET Web services
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WCF vs ASP.NET Web services (Unpublished)
In this post I will explain the Difference between ASP.NET web service and programming WCF services like ASP.NET web services. It also discusses how we use the both technologies for developing the web services.
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What an Architect Should Know About Smooth Streaming (Unpublished)
Ever wondered what it takes to deliver a really good streaming video experience over the web? Think it’s only possible if you have the infrastructure, resources, and bandwidth of a major CDN (Content delivery network) provider? Microsoft has created a new technology called Smooth Streaming (or Smooth HD) which allows adaptive streaming of Silverlight content over HTTP. What this means is that the video file can leverage edge servers and cache services plus the Smooth streaming client will automatically detect the clients bandwidth and hardware capabilities and adjust the video quality to give them the best experience. So, if the bandwidth is low the client will request the lower bit-rate version of the subsequent files.
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Wikia
SRD:Ammunition
Talk0
9,503pages on
this wiki
AmmunitionEdit
Projectile weapons use ammunition: arrows (for bows), bolts (for crossbows), or sling bullets (for slings). When using a bow, a character can draw ammunition as a free action; crossbows and slings require an action for reloading. Generally speaking, ammunition that hits its target is destroyed or rendered useless, while normal ammunition that misses has a 50% chance of being destroyed or lost.
Although they are thrown weapons, shuriken are treated as ammunition for the purposes of drawing them, crafting masterwork or otherwise special versions of them (see Masterwork Weapons), and what happens to them after they are thrown.
S
S cont.
S cont.
Back to Main PageSystem Reference DocumentWeapons
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Carroll County, IllinoisEdit This Page
From FamilySearch Wiki
United States Illinois Carroll County
Guide to Carroll County Illinois genealogy. Birth records, marriage records, death records, census records, family history, and military records.
Illinois
Online Records
Coordinates: 42.06°0′N 89.92°0′W / 42.06°N 89.92°W / 42.06; -89.92
Carroll County, Illinois
Map
Location in the state of Illinois
Location of Illinois in the U.S.
Facts
Founded: February 22, 1839
County Seat Mount Carroll
Courthouse
Photo courtesy Illinois Regional Archives Depository, Illinois State Archives
Address Carroll County Courthouse
301 North Main St.
Mt. Carroll, Illinois 61053
(815) 244-0221
Carroll County Website
Contents
Carroll County Organization
Carroll County's civil records start the following years:
Beginning Dates for Carroll County Records
Birth Marriage Death Census Land Probate
1877 1839 1877 1840 1837 1839
County records are most often kept at the County Courthouse or another local repository. For further information about where the records for Carroll County are kept, see the Carroll County Courthouse page.
Historical Facts
Charles Carroll.JPG
The county is named after Charles Carroll of Carrollton (1737-1832), a signer of the Declaration of Independence.
Boundary Changes
Prior to County Formation
County Formation and After
For more information see Origin and Evolution of Illinois Counties or Carroll County Fact Sheet (Illinois State Archives). For interactive county boundary maps see Illinois County Boundaries, 1790-Present, Illinois Historical Counties, or Illinois County Maps and Atlases.
Record Loss
Records and Resources
Biography
Cemeteries
Illinois cemetery records often identify birth, death, relationship, and military information, as well as religious affiliation.
Find A Grave, list of cemeteries. Additional information can be found at local level (city, township, etc.)
Census
For information and tips on accessing census records online, see Illinois Census.
Federal
Historical populations
Census Pop.
190018,963
191018,035−4.9%
192019,3457.3%
193018,433−4.7%
194017,987−2.4%
195018,9765.5%
196019,5072.8%
197019,276−1.2%
198018,779−2.6%
199016,805−10.5%
200016,674−0.8%
201015,387−7.7%
IL Counties 1900-1990
State
1840 Pensioners
• A Census of Pensioners for Revolutionary or Military Services: With their Names, Ages, and Places of Residence, as Returned by the Marshalls of the Several Judicial Districts, Under the Act for Taking the Sixth Census. Washington, D.C., 1841. FHL 973 X2pc 1840; FHL 2321; digital version at Google Books. [See Illinois, Carroll County on page 186.]
Church History and Records
Church records may give birth, death and marriage information. It is usually best to locate church records with a search at a local level such as the city, town, or village.
Court Records
Original court records are held in the office of the Circuit Court Clerk. See Illinois Court Records for more information about using court records.
The following abstracts and copies of original records may be accessed through the Illinois Regional Archives Depository (IRAD) located at Northern Illinois University - search for Franklin County records. For information on how to use IRAD see the NIU IRAD Wiki page.
• 1849-1861 County Court Miscellaneous Files IRAD-NIU
• 1867-1944 Insanity Dockets IRAD-NIU
Directories
Ethnic Research
African American
The following have information concerning African American research.
Funeral Homes
Genealogy
Mailing Lists
Message Boards
History
Land and Property
Original land records are held in the office of the County Clerk . See Illinois Land and Property for more information about using land records.
Online Resources
Maps
Military History and Records
Civil War
Civil War service men from Carroll County served in various regiments. Men often joined a company (within a regiment) that originated in their county. Listed below are companies or regiments that were formed from men of Carroll County.
- 7th Regiment, Illinois Cavalry, Company B (Also known as Rosecran's Escort).
- 15th Regiment, Illinois Infantry, Company K.
- 34th Regiment, Illinois Infantry, Company I.
- 45th Regiment, Illinois Infantry, Companies A and E.
- 55th Regiment, Illinois Infantry, Company H.
- 61st Regiment, Illinois Infantry, Companies A and B.
- 71st Regiment, Illinois Infantry, Company B.
- 91st Regiment, Illinois Infantry, Company I.
- 92nd Regiment, Illinois Infantry, Companies C and I.
- 142nd Regiment, Illinois Infantry (100 days, 1864), Company G.
- 146th Regiment, Illinois Infantry, Company A.
World War I
World War II
Naturalizations
The Carroll County Genealogical Society's website includes several naturalization collections:
Newspapers and Obituaries
Probate Records
Original estates and wills are held in the office of the Circuit Court Clerk. See Illinois Probate Records for more information about using probate records.
The following abstracts and copies of original records may be accessed online, through the Family History Library or the Illinois Regional Archives Depository (IRAD) located at Northern Illinois University - search for Carroll County records. For information on how to use IRAD see the NIU IRAD Wiki page.
Copies of Original Records
• 1839-1962 Probate Record IRAD-NIU
• 1860-1955 Probate Appraisement Record IRAD-NIU
• 1865-1957 Probate Inventory Record IRAD-NIU
• 1865-1967 Probate Will Record IRAD-NIU
Online Resources
The Clerk of the Circuit Court has responsibility for the probate records of Carroll County. Carroll County is building a free, searchable database of all Closed Probate Records. (id: probate; password: cccc)
Repositories
County Courthouse
County records are most often kept at the County Courthouse or another local repository. For further information about where the records for Carroll County are kept, see the Carroll County Courthouse page.
Family History Centers
Family History Centers (FHCs) are branches of the Family History Library in Salt Lake City, Utah (United States) and are located all over the world. Their goal is to provide resources to assist you in the research and study of your genealogy.
You may search your address for a center near you on the FamilySearch site.
Currently there are no Family History Centers located directly in Carroll County. The following centers are located in surrounding counties. Their wiki pages may supply hours and other information.
Freeport Illinois Family History Center
1716 S Forest Rd.
Freeport, Illinois 61032
Telephone: (815) 232-3310
Sterling Illinois Family History Center
2709 N 16th Avenue
Sterling, Illinois 61081
Telephone: (815) 625-1229
Illinois Regional Archives Depository (IRAD)
The Illinois Regional Archives Depositories (IRAD), managed by the Illinois State Archives, houses the archival records of local Illinois counties, townships, municipalities and school districts. The seven Regional Depositories are housed on state university campuses scattered throughout Illinois.
The Northern Illinois University (IRAD-NIU) holds the records for Carroll County. Learn more about finding and using their records.
Illinois Regional Archives Depository
c/o Regional History Center
Founders Memorial Library, Room 400
Northern Illinois University
DeKalb, IL 60115
Telephone: (815) 753-1807
Public Libraries
The following Carroll County libraries have collections of specific interest to genealogists.
Lanark Public Library
110 W. Carroll St.
Lanark, Illinois 61046
Telephone: (815) 493-8045
Note that their Genealogy and Local History collection does not circulate.
Social Groups Online
Societies
Taxation
Vital Records
See Illinois Vital Records for more information about Vital records in Illinois.
Vital records consist of birth, death, marriage and divorce records. Original birth and death certificates recorded until the year 1916 are kept by the Carroll County Clerk while those recorded after 1916 are kept by the Illinois Department of Public Health with a copy to the County Clerk. Original marriage records are usually kept by the County Clerk from the establishment of the county to the present. Original divorce records are generally in the office of the Circuit Court Clerk.
The following abstracts and copies of original records may be accessed through online databases, the Family History Library and the Illinois Regional Archives Depository (IRAD) located at the Northern Illinois University (NIU) - search for Carroll County records. For information on how to use IRAD see the IRAD Wiki page.
Births
Copies of Original Records
Online Resources
Marriages
Copies of Original Records
• 1839-1964Marriage Record
Online Resources
Deaths
Copies of Original Records
• 1872-1906 Coroner's Inquest Record
• 1877-1913 Death Certificates
• 1877-1963 Death Record Index
• 1920-1928 Death Certificate Record, Stillbirths
Online Resources
Websites
References
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• This page was last modified on 12 April 2013, at 18:59.
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Category:Saint Vincent and the GrenadinesEdit This Page
From FamilySearch Wiki
This category is for articles about genealogical research in Saint Vincent and the Grenadines. Do not put compiled family histories or genealogies here.
Authority used to create this category: CIA World Factbook.
Pages in category "Saint Vincent and the Grenadines"
The following 4 pages are in this category, out of 4 total.
L
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Media in category "Saint Vincent and the Grenadines"
This category contains only the following file.
• This page was last modified on 28 March 2008, at 04:50.
• This page has been accessed 777 times.
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Maryland Naturalization and Citizenship
From FamilySearch Wiki
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[[Portal:United States Naturalization|Portal:United States Naturalization ]]>[[Maryland|Maryland]]
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''[[United States of America|United States]] [[Image:Gotoarrow.png]] [[United States Naturalization Records|U.S. Naturalizations]] [[Image:Gotoarrow.png]] [[Maryland]] [[Image:Gotoarrow.png]] [[Maryland_Naturalization_and_Citizenship|Naturalizations]]''
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== Introduction ==
== Introduction ==
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*Naturalization Petitions 1906-1930. National Archives Publication M1640. Digitized at [http://www.footnote.com/search.php?query=maryland+naturalization Footnote].
*Naturalization Petitions 1906-1930. National Archives Publication M1640. Digitized at [http://www.footnote.com/search.php?query=maryland+naturalization Footnote].
Additional naturalization records are at the National Archives, Washington D.C.
+
Additional naturalization records are at the National Archives, Washington D.C.
=== Post 1906 Records ===
=== Post 1906 Records ===
Revision as of 20:22, 20 April 2010
United States U.S. Naturalizations Maryland Naturalizations
Contents
Introduction
This section contains information unique to naturalization in Maryland.
For a general treatment of naturalization in the United States click here. That material will not be repeated here, but it is information you need to know to use naturalization records effectively. It will explain:
• The naturalization process
• The information the records might contain
• How to locate records
• How to use records
• Limitations of the records
• Naturalization law
• Changes that have occurred in the records
• Useful websites
• Definitions of terms unique to naturalization.
Naturalization Recolds
Colonial Naturalization
Few naturalizations were required in the colonial period since most immigrants came from the British Isles. The provincial legislature and the Governor and Council naturalized some foreigners. The earliest naturalizations were granted by the legislature in the form of laws. They contain little information beyond the name of the person being naturalized and their country of origin.
Early naturalizations were also granted by the New Jersey Supreme Court and the Chancery Court. Naturalization done in the courts became a multi-step process and the records created there began to take on more of the the form we expect from naturalization records.
The majority of those naturalized before 1776 came from European countries such as France, Switzerland, and Germany. These early naturalizations contain little information. They may, however, contain the religious affiliation of the applicant since only Protestants were allowed to be naturalized.
Most persons were naturalized in the later colonial period under a 1740 Act of Parliment. Some of the Supreme Court naturalizations fom 1741 to 1873 have survived, with the majority of the records being created before the American Revolution. These records are available at the New Jersey Archives in Trenton.
Nnaturalizations granted by the legislature can be found transcribed in the following five-volume set:
• Laws of the Royal Colony of New Jersey 1703-1775. Trenton, New Jersey: New Jersey State Library, Archives and History Bureau, 1977. The volumes are at the New Jersey State Archives and other libraries. The Family History Library has some of the volumes. The call number is FHL book 974.9 B49a.
The Maryland State Archives has several indexes to colonial naturalizations found in Provincial and General Court, General Assembly, and Governor and Council records of 1634 to 1776. Naturalizations of colonial German immigrants, including lists previously published in the Archives of Maryland are in:
• Wyand, Jeffrey A., and Florence L. Wyand, Colonial Maryland Naturalizations. Baltimore, Maryland: Genealogical Publishing Company, 1975. (Family History Library book 975.2 W5w.) This source may include religion, birth date and place, death date and place, or residence.
Post-1790 Records
After 1790 under federal naturalization law, aliens could declare intention to become citizens and later be naturalized in any federal, county, or city court. At this time the county courts, especially the Court of Common Pleas became a major place for naturalizations to take place. The Family History Library has copies of many of these county court records on microfilm.
Researchers need to realize that not all immigrants naturalized, nor have all naturalization records survived. People could own land, do business, settle estates, and live unhindered without it. The only unique privilege that came from being naturalized was the right to vote and buy land from the Federal Government.
The Maryland State Archives has most county naturalization records, indexes to many state and county records from 1777-1917, and indexes to Baltimore city and county naturalizations from 1796 to 1933. They also have a card index to naturalizations in the U.S. circuit court, 1852-1918, and U.S. district courts from 1797-1951 and another card index to records for the colonial period, 1637-1776.
You can find abstracts of naturalization records in:
• Oszakiewski, Robert Andrew, comp. Maryland Naturalization Abstracts. Two Volumes. Westminster, Maryland: Family Line Publications, 1995, 1996. (Family History Library book 975.2 P48o.) Volume one is County and Baltimore City, Maryland 1784-1851; the U.S. Circuit Court for Maryland, 1790-1851. Volume two is The County Court of Maryland, 1779-1851; the U.S. Circuit Court for Maryland, 1790-1851. These two volumes list name, place of origin, sources, naturalization date, and age.
Maryland Naturalization Records at National Archives -- Mid-Atlantic Region of Philadelphia
• Indexes to naturalization petitions to the U.S. Circuit and District Courts for the District of Maryland, 1797 to 1951. National Archives Publication M1168. Digitized at Ancestry.com. Also on film at the Family History Library (Family History Library films beginning with 1380472).
• Declarations of intention, 1911 to 1957, and petitions for naturalization, 1903 to 1955, from the U.S. District Court for the District of Maryland.
• Circuit court declarations of aliens and registry of aliens, 1816 to 1828.
• Declarations of intention, 1906 to 1911, for the U.S. Circuit Court for the District of Maryland (Family History Library film 1738366).
• U.S. District Court intentions and petitions, 1792 to 1931 (on 67 Family History Library films beginning with 1738367).
• U.S. Circuit Court intentions, 1906 to 1911 (Family History Library film 1738366).
• U.S. Circuit Court petitions, 1790 to 1911 (Family History Library films 940136-142).
• Naturalization Petitions 1906-1930. National Archives Publication M1640. Digitized at Footnote.
Additional naturalization records are at the National Archives, Washington D.C.
Post 1906 Records
For naturalization records after September 1906, use the Genealogy Program at www.uscis.gov. At that time the federal government standardized the naturalization process courts and required to the courts to send a copy of papers they created to the Immigration and Naturalization Service (INS) now the USCIS. Duplicate copies were often kept in the New Jersey court.
Web Sites
National Archives: http://www.archives.gov/
National Archives-Midatlantic Region: http://www.archives.gov/midatlantic/
Maryland State Archives: http://www.msa.md.gov/
Many counties are beginning to digitize their records or place indexes online. Other naturalization records, especially those that were granted in federal courts are being added to paid sited such as Ancestry or Footnote.
References
Maryland Research Outline. Salt Lake City, Utah: Intellectual Reserve, Inc., Family History Department, 1998, 2001.
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Skip to main content Help Control Panel
Lost? Search this Naples Florida website...|Add our search|Login A+ A- 54.235.20.17
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HAPPY DAY CAFE ( LJ + JS INC )
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LJ + JS INC
935 N COLLIER BLVD
HAPPY DAY CAFE ( LJ + JS INC )
935 N COLLIER BLVD
Owner: MINAHAN, JENNIFER
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Modify
Opened 4 years ago
Closed 3 years ago
#3816 closed defect (worksforme)
wrong key-value pair
Reported by: CSchultz Owned by: team
Priority: normal Component: Core validator
Version: tested Keywords: aerodromes
Cc:
Description
Hello,
My Validator-Plugin (v17722) tells me, that there is a wrong key-value combination in a tag...
<node id="...">
<tag k="aeroway", v= "aerodrome">
<tag k=name v="Lüneburg" >
but in the OSM Wiki is written that this tagging is right.
what is the matter
Thanks
Christoph Schultz
Attachments (1)
lüneburg-flugh.osm (2.0 KB) - added by CSchultz 4 years ago.
the area with the node which create the warning in validator plugin
Download all attachments as: .zip
Change History (2)
Changed 4 years ago by CSchultz
comment:1 Changed 3 years ago by mjulius
• Resolution set to worksforme
• Status changed from new to closed
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as The resolution will be set. Next status will be 'closed'.
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VELOCITY AND PRESSURE BOUNDARY CONDITIONS FOR FLOW OVER THE PERMEABLE BOUNDARY OF A POROUS MEDIUM
Ismail Aydin
Abstract
Effect of permeability on pressure distribution over the permeable surface of a porous medium is investigated. Measured pressure distributions comparing impervious and permeable cases are presented. Flow of the free fluid over the permeable boundary and flow of the fluid in the porous medium are computed numerically, maintaining the interaction of the two flow fields through the boundary conditions at the permeable surface. Turbulence is modeled by a low Reynolds number k-e model including a novel technique to model surface roughness effect eliminating the need for wall functions.
Keywords
porous media; boundary condition; velocity; pressur
Full Text: PDF
This work is licensed under a Creative Commons Attribution 3.0 License.
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20.109(S13):Module 1
From OpenWetWare
Jump to: navigation, search
20.109(S13): Laboratory Fundamentals of Biological Engineering
Home Schedule Spring 2013 Assignments
DNA Engineering Protein Engineering Cell Engineering
Module 1
Instructors: Shannon Hughes, Jonathan Runstadler, and Agi Stachowiak
TA: Ian Tay
In this module, you'll complete two mini-investigations while gaining foundational skills -- in laboratory techniques, data analysis, and both written and oral communication -- that will serve you well in the remaining two modules. Throughout, host–pathogen interactions and their implications for human health will be a unifying theme. You'll study two pathogen types that can infect birds: bacteria and fungus. As a class, you will perform a phylogenetic analysis of the bacteria found in two distinct bird populations and look for differences. This study has parallels to recent investigations of human microbiome diversity that shed light on variations in metabolism, susceptibility to infection, etc. We will also learn what bacteria you might be exposed to the next time you accidentally encounter bird feces! As individuals, you will design and test primers for diagnosing infection with the fungus microsporidia. It has previously been found that microsporidia infections are common in several bird populations that have contact with humans -- aquatic birds that may visit reservoirs or beaches, pets such as parrots and lovebirds, and pests such as pigeons -- and it is speculated that zoonotic transfer may occur. Although most people can rapidly clear such an infection, immunocompromised people such as children, the elderly, and HIV-infected individuals are at risk for serious complications. Improving the sensitivity and/or specificity of microsporidia diagnosis could thus be useful in environmental testing and subsequent health care recommendations. Your class-wide study of animal/environmental bacteria populations has similar implications for managing disease risk.
We thank the Runstadler lab for access to bird samples (pre-screened for flu and everything!), and especially Wendy Puryear for helpful technical discussions as this module was developed. We also thank Professor Karen Snowden at Texas A & M University for access to microsporidia spores and for invaluable advice about imaging methods for identifying microsporidia.
Module 1 Conceptual Overview. Experimental goals are shown in yellow, related concepts in blue, and related application areas in green. Stars span both experiments, while triangles are associated with a single experiment.
Module 1 Day 1: Context-setting and primer design
Module 1 Day 2: DNA extraction
Module 1 Day 3: PCR and paper discussion
Note: 1 week between day 3 and day 4.
Module 1 Day 4: DNA cloning
Module 1 Day 5: DNA sequencing and primer analysis
Module 1 Day 6: Journal club I
Module 1 Day 7: Phylogenetic analysis
Module 1 Day 8: Journal club II
Laboratory Report
Primer design summary
TA notes, mod 1
Personal tools
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rimamilena's bookmarks
"Individuality is founded in feeling; and the recesses of feeling, the darker, blinder strata of character, are the only places in the world in which we catch real fact in the making, and directly perceive how events happen, and how work is actually done."
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Angelis, Barbara De on love
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"Love's greatest gift is its ability to make everything it touches sacred."
Angelis, Barbara De on love
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"Forgive me my nonsense as I also forgive the nonsense of those who think they can talk sense."
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I'm female and made my book on 10th September 2009.
My book as a pdf
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Quotation added by staff
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Avoiding a problem doesn't solve it. Thornley, Bonnie Jean
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Children are curious and are risk takers. They have lots of courage. They venture out into a world that is immense and dangerous. A child initially trusts life and the processes of life. Bradshaw, John
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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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212 - The Extra Degree
The one extra degree makes the difference. This simple analogy reflects the ultimate definition of excellence. Because it's the one extra degree of effort, in business and life, that can separate the good from the great. This powerful book by S.L. Parker and Mac Anderson gives great examples, great quotes and great stories to illustrate the 212° concept. A warning - once you read it, it will be hard to forget. Your company will have a target for everything you do ... 212°
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14 Jan 2005 spirit » (Journeyer)
i miss you too Pete. Recentlog without Zaitcev T= "my linux server at work with RH ES 3 connected to EMC DMX1000 won't reboot without manual divine intervention. honestly, an open case before this congregation" & in short T=!hosed!
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Posts: 184 | Thanked: 427 times | Joined on Oct 2009 @ Colombia
#71
Just got the PayPal address Donate link
Thanks for any donation!
__________________
My apps for Harmattan [Scrobbler] - [QStarDict] - [Lights Off] - [Resistor Color Code] - [Transmission Remote] - [Pomodoro] - [Pockeego] - [8]
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Posts: 14 | Thanked: 5 times | Joined on Jan 2008 @ Finland
#72
Originally Posted by Elleo
I've managed to implement enough of the QML UI for QtRapids to make the most basic functionality usable:
Still a fair amount to do before it's really complete though.
Hey, nice work man! I know I estimated the QML port to be ready somtime in April, but due to unforeseen circumstances I have not had the time and motivation to work on this. And I was a bit disappointed that the project got left to such a point that I had some of the basic functionality "almost working".
But for what it's worth, you could apply for the project rights at the Qtrapids
Garage site
and push your stuff to another git branch. I would be more than happy to take a look at the progress!
Cheers
Posts: 309 | Thanked: 244 times | Joined on Jan 2011 @ Touring
#73
Great work so far, hope you have the time to port it for the Maemo5/N900 as well.
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Vicenza
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Vicenza is a city located in North Eastern Italy. The city and the surrounding countryside and hills are particularly famous for the many works, and particularly the Villas, by Palladio. Because of the architectonic contributions of Andrea Palladio, it was included in UNESCO's list of world heritage places in 1994.
[edit] Understand
Vicenza is an ancient city. In 157 b.D. it entered into the roman empire with the name Vicetia or Vincentia. In 889 it was destroyed by Ungari, and in 1001 it became an episcopal stronghold. In 1404 it became part of the Republic of Venice.
The XVI century was very important for Vicenza because Andrea Palladio built several villas and palaces. During the XIX century, after the fall of Napoleone, the city was taken by Austria, but in 1848 the citizens rebelled against the austrian government and in 1866 it finally became part of the Kingdom of Italy.
[edit] Get in
[edit] By train
The train station is located on the southern part of the town, at the end of Viale Roma. Piazza Castello and the old town is a mere 5-minute walk from the station.
The railstation of Vicenza is on the line connecting Milan to Venice. There are also a number of trains to other major cities and destinations such as Bologna to the south, Bolzano to the north, and Trieste to the east via connections Verona, Padova, Venice, and Trento.
Trains to the towns and cities around Vicenza depart daily (times provided are for the regionale trains). The most common are to Verona (1 hour), Padova (25 minutes), Venice (1 hour 15 minutes). Trains also depart for Bassano del Grappa, Treviso, Castelfranco, Rovigo, Sirmione, and Ferrara.
Taking international trains from Vicenza is possible, but it could be slower and/or more expensive since the city is not a major station for train transit. Instead, it is highly recommended to book a train to France, Spain or Switzerland from Milan; Austria and Germany from Verona; and Eastern Europe from Venice. Book a separate (cheap) ticket to these cities and make your connection from there.
More info on Trenitalia [1]. When booking overseas train tickets, make sure to ask for the "Smart" special deal, which provides up to a 50% discount. The deal is especially good for destinations in Eastern Europe such as Budapest or Belgrade, where tickets could be as low as 15 euros one-way (instead of 50 euros and above). Trenitalia requires you to buy the ticket 7-15 days in advance, so make sure you plan your trip ahead of time. The website only accepts Italian credit cards, so your best bet is to buy your ticket at the train station.
[edit] By car
Vicenza could be reached via the following highways: A4 - from Torino, Milan, Venice or Trieste; A31 - from Schio, Asiago, and Bassano del Grappa; A22 - From Bolzano, Trento, Garda Lake, Mantova and Modena via Verona; A13 - from Bologna and Florence via Padova
A number of strade statale (SS), strade regionale (SR) and strade provinciale (SP) criss-cross Vicenza, and they are a great way to reach many of the great small towns that surround Vicenza. The roads going south to Colli Euganei through Colli Berici, to the northeast to Recoaro Terme, and to the northwest to Treviso via Bassano del Grappa and Asolo are particularly beautiful and highly recommended for those looking for drives through groves of olive trees, vineyards, hills, hidden valleys, and remote hill towns. However, it is not recommended for going to major towns such as Verona, Padova, or Venice. These roads are almost always backlogged with traffic and marred by seriously ugly industrial areas.
[edit] By bus
Vicenza is connected to other cities with a bus servirce offered by Ferrovie Tramvie Vicentine [2] . It is a less comfortable service than train, but it can reach several places that don't have a train station. Some long distance destinations (such as Milan and Venice) are possible, but by and large the buses only serve the province of Vicenza and the immediate towns outside of it. The bus station is located about 100 meters to the left of the train station.
[edit] By bicycle
If you are up for it, it is easy to reach Vicenza via the smaller roads listed above via bicycle. Cycling is a very popular activity in Italy, and many are even brave enough to attempt the alpine crossing from countries in the north to Italy. Stay on the secondary roads however, as it is not only illegal but incredibly dangerous to ride your bicycle in the autostrada. Also, do the trip from mid-Spring to late Summer as Northern Italy suffers very heavy fog during Autumn and Winter, and snow and ice conditions could be very dangerous and unpredictable especially in the mountains.
[edit] Get around
[edit] By foot
Vicenza's city center is small enough to be comfortably explored on foot. The main road through the old town is Corso Palladio, which contains the best of the city center's shopping as well as most of Palladio's urban palaces. The hike from the city center to Monte Berico is uphill but still not so strenuous, and the road circles around to Villa Valmarana ai Nani down to the entrance to the Rotonda. Although most recommendations are to take the bus to the Rotonda and back, this walk will get you to some of the best and uncrowded parts of Vicenza.
[edit] By bicycle
There are a number of bicycle rental companies in Vicenza as well as surrounding towns and cities that service Vicenza. For a listing of these companies as well as to book a bicycle rental, inquire at the Tourism Offices in Piazza Matteoti next to the Teatro Olimpico or at the Piazza dei Signori right in front of the Basilica Palladiana.
[edit] By bus
The city is well-serviced by bus. Times and schedules are posted on their website at [3] (in Italian only). The most important lines are #1 to the shopping malls and #8 to the Rotonda.
[edit] By car
Vicenza's city center is small enough that there is no need for a car if you only want to explore the city center, Monte Berico and the Rotonda. In fact, it is also not recommended if you are only staying within these areas as the ZTL (zona trafico limitato--no drive zones) is very strictly enforced, encompasses most if not all of the city center, and changes frequently and without notice.
However, if you are planning on driving around the surrounding country side to see the villas and go wine-tasting, there are really no other realistic option other than to drive a car. Car rental companies Avis and Hertz are both located within a two-minute walk from the train station.
[edit][add listing] See
[edit] Landmarks
• Basilica Palladiana or "Palazzo della Ragione" (1549-1617) is a massive structure on the city's main square (Piazza dei Signori), designed by the architect Palladio. Built early in Palladio's career, the building sports a look closer to the Venetian Gothic style than the neoclassical style he would later revolutionize. It still has the old and leaning clock tower from a previous building on that site. Unfortunately, the building is closed for restoration until further notice.
• Loggia del Capitanio right in front of Basilica Palladiana on Piazza dei Signori. Also made by Palladio around 1571, but in red brick without any stucco. Built later in Palladio's career, this building's Neoclassical style stands in great juxtaposition to the Basilica across it and is a testament to Palladio's artistic development. Closed to the public except during exhibitions.
• Teatro Olimpico anchors one end of Corso Palladio and is arguably one of Palladio's two great masterpieces. Teatro Olimpico is the oldest enclosed theater in the world, and is most noteworthy for its use of Renaissance perspective in a three-dimensional space. The facade is decorated with stone carvings, wooden statues, and painted tromp l'oeil to make it look like a busy street scene. The theater is open Tuesdays-Sundays 0900-1700. There are two possible combined tickets that include entrance to the theater: the Palladio Card [4] which includes entrance to many other Palladio buildings around town, or the Vicenza Card [5] which includes entrances to civic museums in the city center. It is also possible to attend performances in the theater, especially during the months of July (during the city's Jazz Festival) and October (during the Classical Theater cycle).
• Chiesa di Santa Corona was built in 1261 to house relics from Christ's crown of thorns. Nowadays, it's most important possession are a chapel designed by Palladio, Veronese's Adoration of the Magi and Bellini's Baptism of Christ.
• Palazzo Leoni Montanari [6] is located further down the street from Chiesa di Santa Corona. A beautifully decorated palace, the building houses a decent collection of Russian icons as well as a collection of capricci and paintings by Pietro Longhi.
• Palazzo Valmarana Braga [7] is a monumental palace built by Palladio, and the first in Palladio's career to include columns running along the entire length of the building's facade. Open Wednesdays 1000-1800.
• Palazzo Barbaran is the only palace started and completed by Palladio in the city center. The interior of the palace is decorated with frescoes, most noteworthy of which are the ones done by Zelotti. Open Wednesdays 1000-1800.
• Palazzo Thiene [8] is a beautiful palace designed by Palladio. Sadly, it is the headquarters of a bank, so much of the interior has been changed to accomodate its present purpose. The owners, however, own a great number of works of art. These are typically put on display from time to time. Open Tuesdays, Wednesday and Fridays 0900-1700. Closed July and August.
• Criptoportico Romano One of the few remaining traces of roman Vicenza, these tunnels were formerly used as walkways between villas to protect the walker from the elements. Located in an obscure corner of Piazza Duomo. Open Saturdays 1000-1130 and every second Sunday of the month from 1000-1200 and 1430-1600. Entrance is free.
• Basilica dei SS. Felice and Fortunato is one of the oldest structures in Vicenza. Built in AD 300, the church is one of the most important examples of paleo-Christian architecture in Northern Italy. Inside, mosaic floors and frescoes are lit by a singular rose window.
• Il Santuario di Monte Berico [9] located on top of Monte Berico and visible from every part of the city center, this church was built in the 19th century to replace a Gothic structure built to honor a promise the city made to the Virgin Mary to build a church after a devastating plague ended. An apparition was purported to have occurred here, and every 8th of September flocks of devotees walk from the base of the hill up to the church. The walk from the town to the church is lined with beautiful porticoes. The interior of the church is the mostly richly decorated in the city, with an overabundant use of gold, marble and fresco work. In the old convent is a huge painting by Veronese the "Supper of St. Gregory the Great." Torn apart into 32 pieces during the Austrian invasion, the painting was miraculously pieced together and later restored to its original location.
• Villa Valmarana ai Nani [10] is located just a kilometer or so west of Monte Berico. The Villa compound consists of three buildings - the owner's residence, a guest house, and stables constructed between 1669 and 1720. As pretty and serene the villa's setting is, the reason to visit this villa is its interiors. All three buildings are extensively covered with frescoes by Giamattista and Giandomenico Tiepolo, who were hired by the Valamrana family in 1757. Light, airy, and decidedly Rococo, the villa is the Tiepolos' masterpiece and one of the pinnacles of Rococo art in Europe. Open Tuesdays to Sundays 1000-1200 and 1500-1800. Closed from November to March.
• Villa Capra or the Rotonda [11] is the highlight--and sometimes, main and only reason--of anyone's trip to Vicenza. Designed by Palladio in 1591, it is the architect's thesis project, containing all of his revolutionary ideas into one perfect and harmonious building. It is hard sometimes to see the building for what it is, especially for american and British tourists, because it has been copied so many times and inspired other great buildings all over the world. As harmonious as the exterior is, the interior is also breathtaking, being completely frescoed with tromp l'oeil scenes from the villa's ideal everyday life. The grounds are open on Tuesdays to Sundays, 1000-1200 and 1500-1800. the interior is only open on Wednesdays and Saturdays. The entire villa is closed from November to February. The best time to visit is in late Spring, when the surrounding hills are covered with fiery-red poppies. Even if the villa is closed, it is often enough just to admire the villa from the gate and from the road, the way it is intended to be seen by non-residents.
[edit] Museums
• Palazzo Chiericati is possibly the most magnificent urban palazzo in Vicenza. Located right across the street from Teatro Olimpico, the palazzo's facade is strikingly decorated with a columnade and a series of statues lining its cornice. The interiors are not as magnificent, but it houses the city's picture gallery with works from the Tiepolos, Veronese, Bellini, Titian, and local Vicentine artists. In the palazzo's main foyer, there is an amusingly unusual ceiling fresco - people and animals are painted from the 'natural' perspective. The museum is open Tuesdays to Sundays, 0900-1700.
• Natural History and Archeological Museum [12] holds a small natural exhibit and archaeological finds tracing Vicenza's history from the prehistoric period up to the Lombard invasion. Open Tuesdays to Sundays 0900-1700.
• Risorgimento and Resistance Museum Located about a kilometer from the Monte Berico church, this museum traces Vicenza's involvement in Italy's unification in the 19th century. Open Tuesdays to Sundays 0900-1300 and 1415-1700.
• Museo Diocesano contains artifacts and treasures from the nearby Duomo, archaeological finds chronicling the long history of Catholicism in Vicenza and oddly enough, a very big display of marble balls. Open Tuesdays to Fridays 1530-1900.
[edit] Piazze (Squares)
• Piazza dei Signori The city's main square and its love letter to Palladio.
• Piazza Castello The main entrance to the city and the main terminal for bus within the city walls. Also contains Palladio's incomplete Palazzo Porto.
• Piazzale della Vittoria Right outside il Santuario di Monte Berico, affording the best panoramic view of the city. Especially pretty on a clear day with views of the surrounding prealpine and alpine mountains protecting the city from the north. The best place in town to grab a spritz and watch the sunset.
• Piazza delle Erbe & Piazza delle Poste The area right behind the Basilica Palladiana and the center of the city's meager nightlife.
• Piazza del Duomo
• Piazza Lorenzo
• Piazza Matteoti Location for Teatro Olimpico and the Palazzo Chiericati and a popular meeting point for locals.
[edit] Parks
• Campo Marzo Contains a popular dog park and the town's luna park open during the first and second weeks of September.
• Giardini Salvi Sculptures and the closest green space to the old town.
• Parco Querin a pleasant park on the northern part of town and a good place to see tree blossoms in the Spring.
[edit][add listing] Do
• Hike, bike or drive and explore the Colli Berici, discovering small towns, excellent wineries, and hidden restaurants along the way.
• Put on your Sunday best and walk down Corso Palladio to join the locals in their daily passeggiata.
• Grab lunch to go from il Ceppo or Pam and have a picnic on the base of Palazzo Chiericati's columns.
• Print a list of Palladio's more obscure villas, hire a car, and go on a treasure hunt in search of Palladio's creations littering the edge of town.
• Grab a pint in the Drunken Duck in Quinto Vicentino and know what Italian beer is all about.
• Go for a spritz before dinner either at the base of Palladio's statue in Piazza dei Signori to people watch or in Bar Pellegrino at the Piazzale della Vittoria to watch the sun set.
• Prowl around the flea market for good deals on unique finds (every second Sunday of the month).
• Join the faithful on the 8th of September for a procession up to Monte Berico.
[edit] Learn
Unlike the nearby towns of Padova and Verona, Vicenza does not have university and thus, no significant student population. However, you can always do what the locals do and commute weekly and sometimes daily to nearby universities if you want to attend.
There are numerous language schools in Vicenza, such as Interlingua [13].
[edit] Work
Although Vicenza was one of the top performers during the Italian economic miracle [14] of the 50s and 60s, and still one of the richest towns in Italy, jobs for foreigners are few and far between. Although leather and gold are top exports and computer manufacturing is big business, foreigners especially from outside of the EU Economic Zone have much difficulty finding a job in the private sector. The most viable form of employment is teaching English, which brings in foreigners from the UK, USA, and Canada. Nevertheless, opportunities are more likely in the bigger towns of Padova and Verona.
For Americans, one option would be to be employed through the Department of Defense either as a government employee or contractor working for the Army base located in the outskirts of Vicenza.
[edit][add listing] Buy
[edit] Brands & Malls
• Corso Palladio is the main shopping district in Vicenza, with the street lined with name brands such as Zara and H&M as well as local tailors and designers.
• For the usual mall experience, Palladio Mall and the Piramidi Mall are both with a 30-minute ride from the city center via line #1.
[edit] Local Specialties
• Grappa from Bassano del Grappa
• Ceramics from Nove
• Tocai wine from Colli Berici
[edit] Flea Markets
• Vicenza, 2nd Sunday of the month
• Marostica, 1st Sunday of the month (0800-1900)
• Lonigo, 2nd Sunday of the month (0700-1900)
• Malo, 3rd Sunday of the month
• Noventa Vicentina, 1st Sunday of the month
• Recoaro Terme, last Sunday of the month (0900-1800)
• Thiene, 1st Saturday of the month
• Although outside of Vicenza, the flea market in Piazzola sul Brenta is worth the trip. Held on the last Sunday of the month, it is one of the biggest in Northern Italy.
[edit] Food Markets
• Camisano, every Sunday, the biggest in Vicenza province with specialties from all over Veneto as well as sellers of clothes, kitchen supplies, and everyday goods.
• Vicenza, every Tuesday and Thursday
• Bassano del Grappa, every Thursday
• Thiene, every Monday
• Montecchio Maggiore, every Friday
• Arzignano, every Tuesday
• Lonigo, every Monday
[edit][add listing] Eat
Although "cucina povera" seems to be more associated with Tuscany and the south than the Veneto, Vicenza's cuisine is deeply defined by the foods people prepared generations ago when Vicenza, along with the Veneto, experienced crippling poverty as a result of droughts, plagues, famines and wars caused by political machinations. For example, the local nickname "magnagatti" (literally cat-eaters) originated from a time when rumors started to circulate that the people of Vicenza, out of poverty and desperation, started eating cats. Although the truth behind the rumor is debatable, the locals' full acceptance of the nickname and pride in being called cat-eaters attest to the resilience of Vicenza's people as well as its culinary traditions. Although Vicenza now enjoys one of the highest standard of living in Italy, its cuisine is still rooted in basic preparations of what is typically considered lowly ingredients to make excellent dishes.
Some local dishes and specialties include:
• Baccala alla vicentina - rehydrated stockfish cooked in milk and served with polenta. This dish is so legendary in Vicenza and Italy in general that there is even an official organization dedicated to its preservation. [15]
• Trippa vicentina - stewed tripe, similar to trippa alla parmigiana
• Bigoli co 'larna - thick pasta cooked in a duck meat sauce
• Risi e bisi - risotto made with peas from Lumignano
• Risotto con asparagi bianchi - risotto made with the famous white asparagus from Bassano del Grappa
• Torresano allo spiedo - doves cooked in spitfire and served with polenta
Other specialties include: sopressa (a type of salami) from Val di Pasubio, Asiago cheese from Altopiano di Asiago, truffles from Nanto, cherries from Marostica, and chestnuts and wine from Colli Berici. Although there are a number of good restaurants in the city center, the best way to enjoy local specialties is by finding locally-renowned but little-known restaurants in the Colli Berici area. The best way to start your search is through the group "Le Buone Tavole dei Colli Berici" [16].
[edit] Budget
• Righetti [17] A good and inexpensive self-service restaurant located in Piazza del Duomo. Mondays to Fridays, 1200-1500 and 2100-2200.
• Spaghetteria al Fiore Via Borgo Berga, 15. Small, unfussy restaurant serving big plates of pasta for 5-7 euros. The atmosphere is not sophisticated, but comfy. Closed Wednesdays.
• Pizzeria da Vittorio Via Borgo Berga, 52. Purportedly the best pizza in town. Very limited seating and erratic hours. Located about 100 meters from Palladio's Arco delle Scalette.
• Tutto Gelato Contra del Gambero, 26. Normally open until midnight on Summers, closed on Mondays. The best gelato in Vicenza with a very friendly price tag to boot.
• Ristorante Jin Gu Viale Riviera Berica, 447. Frankly, there are no good Chinese restaurants in Vicenza. Except for this one place, which is fairly decent. An almost 10-minute drive from Vicenza, don't expect much if you're from Asia, New York, or the UK, but expect a whole lot more if you've been searching for good Chinese around town and about to give up.
• Bar Pizzeria Vesuvio Corso Palladio, 204. Cheap, decent, and open when other restaurants are not. Try the fruit pizzas with apple or pear. Also features cheap Vicenza cuisine. Closed Mondays.
[edit] Mid-range
• Pizzeria al Vecio Portego [18] The best pizzeria within the city center and very popular with the locals.
• Venchi Corso Andrea Palladio, 54. Cioccolatiero in the city center also serving ice cream. A chain gelateria, so if you missed it in another city in Italy you can always expect the same high quality from this one.
• La Conchiglia d'Oro Via Bassano, 7. Close to the soccer stadium, this local landmark serves up good pasta and seafood for a good price. Try the penne pasta with shrimp and a big plate of fish, shellfish and squid and die happy of seafood overload.
• Antico Guelfo [19] Contra' Pedemuro San Biagio, 90. A small intimate dining room with constantly rotating seasonal menus.
[edit] Splurge
• Pretto Gelato Arte Italiana [20] Piazza delle erbe, 7. A newly-opened store with gelato flavors designed by Michelin-starred chefs. Their "classic" flavors are good, but for the price does not compare to Tutto Gelato. Instead, go for their more adventurous flavors featuring ingredients such as ginger, licorice and peanuts.
• Ristorante agli Schioppi [21] Contra' Piazza Castello, 24. This is the restaurant many locals take out-of-towners to show them classic vicentino cuisine. Good food, hefty price tag.
• Ristorante Ponte delle Bele [22] Contra' Ponte delle Bele, 5.
[edit][add listing] Drink
[edit] Local Products
Like other places in the Veneto--and increasingly, the rest of Italy--Vicenza's drinks of choice are the spritz and the prosecco. Spritz is originally an Austrian invention, owing to the region's former status as a part of the Austrio-Hungarian Empire. Although there are as many versions of the drink as there are bars in the Veneto, the most common versions in Vicenza are made with prosecco, a splash of soda, Aperol or Campari, and a slice of orange. Spritz Aperol tends to be sweeter, while Spritz Campari tends to be more bitter. Prosecco, Italy's version of sparkling white wine, is cheap and common in the city due to its close proximity to the prosecco-producing areas in the northeast namely Asolo, Conegliano and Valdobiaddene. Much like champagne (just don't call it "Italian champagne"!) the best prosecco tend to be smooth, producing smaller and more refined bubbles. Unlike champagne, prosecco tends to be cheap regardless of quality. Both drinks are usually consumed as aperitivi, but it isn't uncommon to drink only spritz or prosecco on a night out.
Grappa is also a local product, with production concentrated in the northern hills close to Bassano del Grappa or in the Colli Berici. It is usually consumed as a digestif or as a coffee-fortifier ("caffe corretto"). It is a strong liquor, but there tends to be little binge-drinking associated with it amongst the Italians. Every fall, the city hosts Distillerie Aperte [23], conducting tours and tastings of the best distilleries in the area.
Although not as big as say production in Piemonte or Toscana, wine is still a major produce in the region. The two most important variants are the Recioto from Gambellara and the Tai Rosso from the Colli Berici. Both are labelled DOC, the Recioto receiving the highest and prestigious appelation DOCG. For those who want to know more about these wines, the Strada del Vino Colli Berici [24] and the Strada del Recioto [25] link many of the province's best producers and provides opportunities to taste local wines alongside local produce and local countrysides.
[edit] Night Life
There isn't much in terms of night life in Vicenza per se, but the city is hardly dead on Friday nights and weekends. Although the city can get downright depressing on winter nights, spring and summer signal an explosion of merriment, when young people come out again and fill the city's bars and clubs.
In the historic center, the Piazza dei Signori, Piazza delle Erbe and Contra Pescheria Vecchia are the liveliest, with big groups of young people hanging around until late hours on weekends. Clubbing is an unknown activity in the center, instead concentrated in the SR 11/SS 46 intersection (about ten minutes from the historic center). Although a great place for a night out, featuring lively and sometimes packed clubs and live music, caution in this part of town should be exercised due to a moderate rate of crime associated with drugs, prostitution, illegal cabs, as well as general disturbance caused by public intoxication. Nevertheless, it is a relatively safe place for a night out.
For English-speaking guests looking to make friends with local Italians, there is an English Speaking Hour every Thursday from 9PM until closing. The location changes frequently, so check out the group's Facebook page [26] for current information. It is not unusual to make friends on a Thursday and find yourself on a hike or excursion with your new-found friends two days later.
[edit][add listing] Sleep
[edit] Budget
• Ostello di Vicenza, V. Giuriolo, 9, 0444/540222 (fax: 0444/547762), [27]. 17.00€ (with common bath), 20.00€ (with private bath). edit
• Camping Vicenza, Strada Pelosa, 239, 36100 - Vicenza (VI) (2 km south east, located at the exit of the Vicenza-East tollgate), +39 0444 582311, [28]. edit
[edit] Mid-range
• Hotel Campo Marzio Viale Roma, 21, Vicenza. Tel +39 0444 545700 Fax.+39 0444 320495 Email info@hotelcampomarzio.it. Special Offers and direct Booking. The Hotel Campo Marzio, located just 20 meters from the pedestrian zone and 200 meters from the railway station, easy to reach, is the most central 4-star hotel in Vicenza with free parking. The Campo Marzio's position will allow you to discover the main attractions of the city. Monuments, museums, shops and restaurants are all within easy reach, including Piazza dei Signori with the Basilica Palladiana (500 metres). Hotel Campo Marzio offers an Internet Point in the hall, and ADSL high-speed WiFi in all rooms. The reception, open 24 hours, is serviced by a multilingual staff, always available to make your stay as pleasant as possible.
• NH Jolly Tiepolo, Viale S. Lazzaro, 110, +39 0444 954011 [29]. The NH Jolly Tiepolo is a modern and elegant structure, built in 2000. The location between the exhibition centre, shopping district and the historical district, makes the hotel the perfect place whether you are travelling for business or leisure purposes.
• Hotel Castagna, Via Archimede,2 - 36041 Alte di Montecchio Maggiore - Vicenza, ++39 0444 490 540 (, fax: ++39 0444 499 677), [30]. edit
• G Boutique Hotel [32] Via Antonio Giuriolo 10, Piazza Matteotti, Vicenza. +39 0444 326458. A relatively cheap yet seriously cool hotel located just a few steps from Palazzo Chericati.
[edit] Splurge
[edit] Agriturismo
The agriturismo (or operating farms with a functioning B&B) movement is as popular in Vicenza as it is in the rest of Italy. The idea is that instead of a holiday rental in an urban area, vacationers stay and enjoy the Italian countryside as guests in these farms, which provide rooms as well as meals and tours to the surrounding countrysides. Accomodations range from simple rooms in converted farmhouses to grand rooms in ancient villas that dot the surrounding landscape. In addition to enjoying accommodations with friendly locals in a relatively bucolic setting, guests also get an opportunity to try local specialties with ingredients grown by the farm or by farmers in the surrounding area. For more information on agriturismo and to book a stay, click on this [33] link.
[edit] Contact
[edit] Stay safe
[edit] Get Out
• Bassano del Grappa A beautiful small town 45 minutes north known for Palladio's wooden bridge, grappa, white asparagus, and Jacopo Bassano.
• Marostica A walled town 30 minutes north known for its biannual human chess game.
• Recoaro Terme A spa town an hour northwest situated in the middle of dreamy, mist-covered mountains.
• Asiago A mountain city an hour and a half north known for cheese and miles of cross-country skiing lanes.
• Pasubio The highest mountains in the Prealpi Vicentini, come here for remarkable WWI ruins such as the 52 Gallerie, fresh cheese from mountain-top malghe and sorpressa, the local Vicentine salami.
• Folgaria The closest major alpine skiing resort, about 90 minutes northwest.
• Montagnana A walled town about 40 minutes south that hosts a big prosciutto festival as well as a palio every August.
• Colli Euganeii Padova's version of the Colli Berici, containing ancient volcanoes and ancient towns such as Arcua Petraraca (Petrarch's resting place) and the walled towns of Monselice and Este.
• Cittadella and Castelfranco Small walled towns on the way to Treviso, with Castelfranco playing host to Giorgione's Pala di Madonna
• Padova Giotto's Renaissance masterpiece, St. Anthony's cathedral, the first botanical garden in the world, and the second oldest university in the world. A great nightlife to boot.
• Verona
• Lake Garda, although Lake Ledro is as stunning with much less tourists, albeit much, much smaller.
• Venice
• Ferrara
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Australian Bureau of Statistics
Celebrating the International Year of Statistics 2013
ABS Home > Statistics > By Release Date
3302.0 - Deaths, Australia, 2001
Previous ISSUE Released at 11:30 AM (CANBERRA TIME) 02/12/2003
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MORTALITY CONTIUES TO DECLINE
The Australian death rate continued to decline in 2001. The age-standardised death rate is down by 5% since 2000 and 36% since 1981. There were 128,540 deaths registered in Australia in 2001, approximately 250 more than the number registered in 2000 (128,290).
Over the past 20 years there has been a sustained decline in death rate for all states and territories. The highest age-standardised death rate in 2001 was in the Northern Territory and the lowest was in the Australian Capital Territory.
LIFE EXPECTANCY CONTINUES TO INCREASE
Life expectancy at birth continued to increase, reflecting the general decrease in death rates. A boy born in 1999-2001 could expect to live 77.0 years, while a girl could expect to live 82.4 years. Since 1981 life expectancy at birth has increased by 6 years for males and 4 years for females.
Internationally, Australia's life expectancy at birth for males ranks behind Japan (78 years), beside Switzerland, Hong Kong, and Sweden (each 77 years), and is above that of New Zealand (76 years), the United Kingdom (75 years) and the United States of America (74 years).
Australia's life expectancy at birth for females is similar to Hong Kong and Sweden (each 82 years). It falls behind Japan (85 years), France, Spain and Switzerland (each 83 years), and is above Canada, Greece and New Zealand (each 81 years), the United Kingdom and the United States of America (each 80 years).
Male life expectancy at birth was highest in the Australian Capital Territory (78 years), while female life expectancy at birth was highest in the Australian Capital Territory and Western Australia (both 83 years). The lowest life expectancy was in the Northern Territory where a boy born in 2001 could expect to live an average of 71 years, and a girl, 76 years.
In 1999-2001 life expectancy at birth for males and females varied across the regions of Australia by up to 11 years. Male life expectancy at birth was highest in Canberra (79 years) followed by Outer Adelaide, Melbourne and Perth (each 78 years), while female life expectancy at birth was highest at 83 years in Moreton (Queensland), Perth, Canberra, Melbourne and South-West (Western Australia).
Male life expectancy at birth was lowest in the balance of the Northern Territory (68 years) followed by the Kimberley (70 years), and North-West Queensland (71 years). Female life expectancy was lowest in the balance of the Northern Territory (73 years), the Kimberley (78 years), and North-West Queensland (78 years).
VARIATIONS IN MORTALITY
The 2001 infant mortality rate was 5.3 deaths per 1,000 live births, an increase of 2% from 2000, but a decrease of 47% since 1981. In 2001, over one-third (39%) of all infant deaths occurred within one day of birth.
Overall, the age-standardised death rate for males was 58% higher than the female rate. The greatest difference in age-specific death rates occurred in the 15-19 years age group where the male death rate was over three times higher than the female death rate.
Males and females who had never married had age-standardised death rates of almost twice those of their married counterparts.
INDIGENOUS MORTALITY
There were 2,100 deaths registered in 2001 where the deceased person was identified as being of Aboriginal, Torres Strait Islander or both origins (Indigenous). Overall the Indigenous population had age-standardised death rates at least twice as high as the total population.
The 2001 infant mortality rate for Indigenous Australians (10.6 deaths per 1,000 live births) was over twice the infant mortality rate for all Australians (5.3).
The median age at death for Indigenous people in 2001 was 54 years, around 24 years less than the median age for all deaths (79 years).
Indigenous life expectancy at birth was about 20 years less than for the total population, 56 years for Indigenous males compared to 77 years for all Australian males and 63 years for Indigenous females compared to 82 years for all Australian females. Experimental life tables of Indigenous people is presented in Appendix 1.
The life expectancy of Indigenous people in both New Zealand and the United States of America is higher than for Indigenous Australians, and the difference to the total population is not as great as in Australia. In 1995-1997 the New Zealand Maori population had a life expectancy at birth of 67 years for males and 72 years for females, 7 years lower than for the total male population and 8 years lower than the total female population. In 1996-1998 the American Indian and Alaska Native population of the United States of America had a life expectancy at birth of 67 years for males and 74 years for females, 6 years lower than for the total male population and 5 years lower than the total female population.
CAUSES OF DEATH
During the last decade, IHD and cancer remained the two leading causes of death. In recent years cancer has overtaken IHD as the leading cause of death for both men and women. This has been the result of the long-term downward trend in the standardised death rate for IHD, declining by 59% for males and 53% for females from 1981 to 2001. Over the same period the standardised death rate for malignant neoplasms declined by just 13% for males and 6% for females.
In 2001, malignant neoplasms was the leading cause of death, accounting for 36,800 deaths or 29% of all deaths. IHD was the second leading cause of death, contributing 26,200 deaths or 20% of all deaths. Cerebrovascular diseases (stroke) contributed 9% of all deaths while chronic lower respiratory diseases contributed 5% of all deaths.
© 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
6403.0.55.001 - Average Retail Prices of Selected Items, Eight Capital Cities, Dec 2008
Previous ISSUE Released at 11:30 AM (CANBERRA TIME) 04/02/2009
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Contains average retail prices of selected items included in the Consumer Price Index for each of the six state capitals, Canberra and Darwin. The CPI covers a wide range of goods and services arranged in eleven groups which are in turn divided into subgroups. The items for which average prices are shown in this publication comprise a selection of items from the CPI food group and the following non-food subgroups: household supplies; sport and other recreation; private motoring; and alcoholic drinks.
© 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
5625.0 - Private New Capital Expenditure and Expected Expenditure, Australia, Sep 1999
Previous ISSUE Released at 11:30 AM (CANBERRA TIME) 25/11/1999
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• About this Release
ABOUT THIS RELEASE
Previously: Private New Capital Expenditure, Australia, Actual and Expected Expenditure, Preliminary (ISSN: 1033-5048)
Absorbs: 5626.0
Preliminary estimates derived from a sample survey of private businesses. Contains estimates of actual and expected new capital expenditure by type of asset (new buildings and other structures/equipment, plant and machinery) and by selected Australian and New Zealand Standard Industrial Classification industries. These statistics are expressed in current prices and chain volume measures, in original, seasonally adjusted and trend terms and are available for Australia and by state/territory.
See also 5626.0 and 5646.0.
© 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
Celebrating the International Year of Statistics 2013
ABS Home > Statistics > By Release Date
8731.0 - Building Approvals, Australia, Sep 1995
Previous ISSUE Released at 11:30 AM (CANBERRA TIME) 01/11/1995
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• About this Release
Number of dwelling units and value of residential buildings approved (houses and other residential by type) for private and public sector; value of alterations and additions to residential buildings and value of non-residential building by class of building (eg. hotels, offices, etc.) approved. Seasonally adjusted and trend estimates for the number of dwelling units and value of buildings approved; quarterly values of building approved at average 1989-90 prices.
This publication has been converted from older electronic formats and does not necessarily have the same appearance and functionality as later releases.
© 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
Sparse PLS discriminant analysis: biologically relevant feature selection and graphical displays for multiclass problems
Kim-Anh Lê Cao1*, Simon Boitard2 and Philippe Besse3
Author Affiliations
1 Queensland Facility for Advanced Bioinformatics, University of Queensland, 4072 St Lucia, QLD, Australia
2 UMR444 Laboratoire de Génétique Cellulaire, INRA, BP 52627, F-31326 Castanet Tolosan, France
3 Institut de Mathématiques de Toulouse, Université de Toulouse et CNRS (UMR 5219), F-31062 Toulouse, France
For all author emails, please log on.
BMC Bioinformatics 2011, 12:253 doi:10.1186/1471-2105-12-253
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2105/12/253
Received:3 November 2010
Accepted:22 June 2011
Published:22 June 2011
© 2011 Lê Cao 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
Variable selection on high throughput biological data, such as gene expression or single nucleotide polymorphisms (SNPs), becomes inevitable to select relevant information and, therefore, to better characterize diseases or assess genetic structure. There are different ways to perform variable selection in large data sets. Statistical tests are commonly used to identify differentially expressed features for explanatory purposes, whereas Machine Learning wrapper approaches can be used for predictive purposes. In the case of multiple highly correlated variables, another option is to use multivariate exploratory approaches to give more insight into cell biology, biological pathways or complex traits.
Results
A simple extension of a sparse PLS exploratory approach is proposed to perform variable selection in a multiclass classification framework.
Conclusions
sPLS-DA has a classification performance similar to other wrapper or sparse discriminant analysis approaches on public microarray and SNP data sets. More importantly, sPLS-DA is clearly competitive in terms of computational efficiency and superior in terms of interpretability of the results via valuable graphical outputs. sPLS-DA is available in the R package mixOmics, which is dedicated to the analysis of large biological data sets.
Background
High throughput technologies, such as microarrays or single nucleotide polymorphisms (SNPs) are seen as a great potential to gain new insights into cell biology, biological pathways or to assess population genetic structure. Microarray technique has been mostly used to further delineate cancers subgroups or to identify candidate genes for cancer prognosis and therapeutic targeting. To this aim, various classification techniques have been applied to analyze and understand gene expression data resulting from DNA microarrays ([1-3], to cite only a few). Genome wide association studies using SNPs aim to identify genetic variants related to complex traits. Thousands of SNPs are genotyped for a small number of phenotypes with genomic information, and clustering methods such as Bayesian cluster analysis and multidimensional scaling were previously applied to infer about population structure [4].
Variable selection
As these high throughput data are characterized by thousands of variables (genes, SNPs) and a small number of samples (the microarrays or the patients), they often imply a high degree of multicollinearity, and, as a result, lead to severely ill-conditioned problems. In a supervised classification framework, one solution is to reduce the dimensionality of the data either by performing feature selection, or by introducing artificial variables that summarize most of the information. For this purpose, many approaches have been proposed in the microarray literature. Commonly used statistical tests such as t- or F-tests are often sensitive to highly correlated variables, which might be neglected in the variable selection. These tests may also discard variables that would be useful to distinguish classes that are difficult to classify [5]. Machine Learning approaches, such as Classification and Regression Trees (CART, [6]), Support Vector Machines (SVM, [7]) do not necessarily require variable selection for predictives purposes. However, in the case of highly dimensional data sets, the results are often difficult to interpret given the large number of variables. To circumvent this problem, several authors developed wrapper and embedded approaches for microarray data: Random Forests (RF, [8]), Recursive Feature Elimination (RFE, [3]), Nearest Shrunken Centroids (NSC, [9]), and more recently Optimal Feature Weighting (OFW, [5,10]). Other approaches were also used for exploratory purposes and to give more insight into biological studies. This is the case of Linear Discriminant Analysis (LDA), Principal Component Analysis (PCA, see [11,12] for a supervised version), Partial Least Squares Regression (PLS, [13], see also [14-16] for discrimination purposes), to explain most of the variance/covariance structure of the data using linear combinations of the original variables. LDA has often been shown to produce the best classification results. However, it has numerical limitations. In particular, for large data sets with too many correlated predictors, LDA uses too many parameters that are estimated with a high variance. There is therefore a need to either regularize LDA or introduce sparsity in LDA to obtain a parsimonious model. Another limitation of the approaches cited above is the lack of interpretability when dealing with a large number of variables.
Numerous sparse versions have therefore been proposed for feature selection purpose. They adapt well known ideas in the regression context by introducing penalties in the model. For example, a l2 norm penalty leads to Ridge regression [17] to regularize non invertible singular matrices. In particular, penalties of type l1 norm, also called Lasso [18], or l0 norm, were also proposed to perform feature selection, as well as a combination of l1 and l2 penalties [19]. These penalties (l1 and/or l2) were applied to the variable weight vectors in order to select the relevant variables in PCA [20,21] and more recently in Canonical Correlation Analysis [22-24] and in PLS [25-27]. [28,29] also proposed a penalized version of the PLS for binary classification problems. Recently, [30] extended the SPLS from [27] for multiclass classification problems and demonstrated that both SPLSDA and SPLS with an incorporated generalized framework (SGPLS) improved classification accuracy compared to classical PLS [31-33].
Multiclass problems
In this study, we specifically focus on multiclass classification problems. Multiclass problems are commonly encountered in microarray studies, and have recently given rise to several contributions in the literature [34] and more recently [35,36]. Extending binary classification approaches to multiclass problems is not a trivial task. Some approaches can naturally extend to multiclass problems, this is the case of CART or LDA. Other approaches require the decomposition of the multiclass problem into several binary problems, or the definition of multiclass objective functions. This is the case, for example, of SVM one-vs.-one, one-vs.-rest or multiclass SVM.
Sparse PLS-DA
We introduce a sparse version of the PLS for discrimination purposes (sPLS-Discriminant Analysis) which is a natural extension to the sPLS proposed by [25,26]. Although PLS is principally designed for regression problems, it performs well for classification problems [37,38]. Using this exploratory approach in a supervised classification context enables to check the generalization properties of the model and be assured that the selected variables can help predicting the outcome status of the patients. It is also important to check the stability of the selection, as proposed by [39,40]. We show that sPLS-DA has very satisfying predictive performances and is well able to select informative variables. In contrary to the two-stages approach recently proposed by [30], sPLS-DA performs variable selection and classification in a one step procedure. We also give a strong focus to graphical representations to aid the interpretation of the results. We show that the computational efficiency of sPLS-DA, combined with graphical outputs clearly give sPLS-DA a strong advantage to the other types of one step procedure variable selection approaches in the multiclass case.
Outline of the paper
We will first discuss the number of dimensions to choose in sPLS-DA, and compare its classification performance with multivariate projection-based approaches: variants of sLDA [41], variants of SPLSDA and with SGPLS from [30]; and with five multiclass wrapper approaches (RFE, NSC, RF, OFW-cart, OFW-svm) on four public multiclass microarray data sets and one public SNP data set. All approaches perform internal variable selection and are compared based on their generalization performance and their computational time. We discuss the stability of the variable selection performed with sPLS-DA and the biological relevancy of the selected genes. Unlike the other projection-based sparse approaches tested, we show that sPLS-DA proposes valuable graphical outputs, also available from our R package mixOmics, to guide the interpretation of the results [42,43].
Results and Discussion
In this section, we compare our proposed sPLS-DA approach with other sparse exploratory approaches such as two sparse Linear Discriminant Analyses (LDA) proposed by [41], and three other versions of sparse PLS from [30]. We also include in our comparisons several wrapper multiclass classification approaches. Comparisons are made on four public cancer microarray data sets and on one SNP data set. All these approaches perform variable selection in a supervised classification setting, i.e. we are looking for the genes/SNPs which can help classifying the different sample classes.
We first discuss the choice of the number of dimensions H to choose with sPLS-DA, the classification performance obtained with the tested approaches and the computational time required for the exploratory approaches. We then perform a stability analysis with sPLS-DA that can help tuning the number of variables to select and we illustrate some useful graphical outputs resulting from the by-products of sPLS-DA. We finally assess the biological relevancy of the list of genes obtained on one data set.
Data sets
Leukemia
The 3-class Leukemia version [1] with 7129 genes compares the lymphocytes B and T in ALL (Acute Lymphoblastic Leukemia, 38 and 9 cases) and the AML class (Acute Myeloid Leukemia, 25 cases). The classes AML-B and AML-T are known to be biologically very similar, which adds some complexity in the data set.
SRBCT
The Small Round Blue-Cell Tumor Data of childhood (SRBCT, [44]) includes 4 different types of tumors with 23, 20, 12 and 8 microarrays per class and 2308 genes.
Brain
The Brain data set compares 5 embryonal tumors [45] with 5597 gene expression. Classes 1, 2 and 3 count 10 microarrays each, the remaining classes 4 and 8.
GCM
The Multiple Tumor data set initially compared 14 tumors [46] and 7129 gene expressions. We used the normalized data set from [47] with 11 types of tumor. The data set contains 90 samples coming from different tumor types: breast (7), central nervous system (12), colon (10), leukemia (29), lung (6), lymphoma (19), melanoma (5), mesotheolima (11), pancreas (7), renal (8) and uterus (9).
SNP data
The SNP data set considered in our study is a subsample of the data set studied by [48] in the context of the Human Genome Diversity Project, which was initiated for the purpose of assessing worldwide genetic diversity in human. The original data set of [48] included the genotypes at 525,910 single-nucleotide polymorphisms (SNPs) of 485 individuals from a worldwide sample of 29 populations. In order to work on a smaller sample size data set with still a large number of classes or populations (K = 7) and with a high complexity classification, we chose to keep only the African populations: Bantu Kenya, Bantu South Africa, Biaka Pygmy, Mandenka, Mbuty Pygmy, San and Yoruba. We filtered the SNPs with a Minor Allele Frequency> 0.05. For computational reasons, in particular to run the evaluation procedures using the wrapper methods, we randomly sampled 20,000 SNPs amongst the ones of the original dataset. The aim of this preliminary analysis is to show that sPLS-DA is well able to give satisfying results on biallelic discrete ordinal data (coded 0, 1 or 2, i.e. the number of mutant alleles at one SNP for one individual) compared to the other approaches.
Choosing the number of sPLS-DA dimensions
In the case of LDA or sparse LDA (sLDA), it is of convention to choose the number of discriminant vectors H ≤ min(p, K - 1), where p is the total number of variables and K is the number of classes. The p-dimensional data will be projected onto a H-dimensional space spanned by the first H discriminant vectors, also called dimensions in the case of sPLS.
To check if the same applies to sPLS-DA, we have plotted the mean classification error rate (10 cross-validation averaged 10 times) for each sPLS-DA dimension (Figure 1 for the Brain and SNP data sets, see Additional file 1 for the other data sets). We can observe that the estimated error rate is stabilized after the first K - 1 dimensions for any number of selected variables for the microarray data sets. For the SNP data set, H should be set to K - 2. The latter result is surprising, but can be explained by the high similarity between two of the classes: the Bantu Kenya and Banty South Africa populations, as illustrated later in the text.
Figure 1. Choosing the number of dimensions in sPLS-DA. Estimated classification error rates for Brain and SNP (10 cross-validation averaged 10 times) with respect to each sPLS-DA dimension. The different lines represent the number of variables selected on each dimension (going from 5 to p).
Additional file 1. Tuning the number of dimensions in sPLS-DA. Estimated classification error rates for Leukemia, SRBCT and GCM (10 cross-validation averaged 10 times) with respect to each sPLS-DA dimension. The different lines represent the number of variables selected on each dimension (going from 5 to p).
Format: EPS Size: 33KB Download file
Therefore, according to these graphics, reducing the subspace to the first K - 1 (K - 2) dimensions is sufficient to explain the covariance structure of the microarray (SNP) data. In the following, we only record the classification error rate obtained after K - 1 (K - 2) deflation steps have been performed with sPLS-DA - this also applies to the tested variants of SPLS from [30].
Comparisons with other multiclass classification approaches
We compared the classification performance obtained with state-of-the-art classification approaches: RFE [49], NSC [9] and RF [8], as well as a recently proposed approach: OFW [10] that has been implemented with two types of classifiers, CART or SVM and has also been extended to the multiclass case [5]. These wrapper approaches include an internal variable selection procedure to perform variable selection.
We compared the classification performance of sPLS-DA to sLDA variants proposed by [41] based on a pooled centroids formulation of the LDA predictor function. The authors introduced feature selection by using correlation adjusted t-scores to deal with highly dimensional problems. Two shrinkage approaches were proposed, with the classical LDA (subsequently called sLDA) as well as with the diagonal discriminant analysis (sDDA). The reader can refer to [41] for more details and the associated R package sda.
Finally, we included the results obtained with 3 other versions of sparse PLS proposed by [30]. The SPLSDA formulation is very similar to what we propose in sPLS-DA, except that the variable selection and the classification is performed in two stages - whereas the prediction step in sPLS-DA is directly obtained from the by-products of the sPLS - see Section Methods. The authors in [30] therefore proposed to apply different classifiers once the variable selection is performed: Linear Discriminant Analysis (SPLSDA-LDA) or a logistic regression (SPLSDA-LOG). The authors also proposed a one-stage approach SGPLS by incorporating SPLS into a generalized linear model framework for a better sensitivity for multiclass classification. These approaches are implemented in the R package spls.
Figure 2 displays the classification error rates estimated on each of the five data sets for all the tested approaches and Table 1 records the computational time required by the exploratory approaches to train the data on a given number of selected variables. Table 2 indicates the minimum estimated classification error rate obtained on each data set and for most of the approaches. Note that this table should be interpreted in conjunction with the results displayed in Figure 2 to obtain a better comprehensive understanding of how all approaches perform in relation with each other.
Figure 2. Comparisons of the classification performance with other variable selection approaches. Estimated classification error rates for Leukemia, SRBCT, Brain, GCM and the SNP data set (10 cross-validation averaged 10 times) with respect to the number of selected genes (from 5 to p) for the wrapper approaches and the sparse exploratory approaches.
Table 1. Computational time
Table 2. Minimum classification error rate estimated for each data set for the first best approaches (percentage) and the associated number of genes/SNPs that were selected.
Details about the analysis
The aim of this section is to compare the classification performance of different types of variable selection approaches that may require some parameters to tune. We performed 10 fold cross-validation and averaged the obtained classification error rate accross 10 repetitions, and this for different variable selection sizes (Figure 2).
The wrapper approaches were run with the default parameters or the parameters proposed by the authors [8,50]. The sDDA and sLDA approaches are actually two-stages approaches as variables need to be ranked first before sLDA/DDA can be applied, but they do not require any other input parameter than the number of variables to select. sPLS-DA, SPLSDA-LOG/LDA and SGPLS require as input the number of PLS dimensions as discussed above. In addition, while sPLS-DA requires the number of variables to select on each dimension as an input parameter, SPLSDA-LOG/LDA and SGPLS require to tune the η parameter that varies between 0 and 1 - the closer to 1 the smaller variable selection size, so that it matched the variable selection sizes with the other approaches. SPLSDA-LOG/LDA are performed in two steps: one step for variable selection with SPLS and one step for classification.
Complexity of the data sets
All data sets differ in their complexity. For example, the 4-class SRBCT data set is known to be easy to classify [5] and most approaches - except NSC, have similar good performances. Analogously, the GCM data set that contains numerous classes (11) gives similar overall classification error rates for all approaches. The Brain and Leukemia data sets with 5 and 3 classes respectively seem to increase in complexity, and, therefore, lead to more accentuated discrepancies between the different approaches. The SNP data set is more complex due to the discrete ordinal nature of the data (3 possible values for each variable), a high number of populations (7) that have similar characteristics - some of them, for instance Bantu Kenya and Bantu South Africa, are closely related. Consequently, it can be expected that a large number of SNP may be needed to discriminate at best the different populations. This is what we observe, but, nonetheless, most approaches (except OFW) perform well, in particular NSC.
Computational efficiency
We only recorded the computational time of the exploratory approaches sDDA, sLDA, SPLSDA-LOG, SPLSDA-LDA, SGPLS and sPLS-DA as the wrapper approaches are computationally very greedy (the training could take from 15 min up to 1 h on these data). Some computation time could not be recorded as a R memory allocation problem was encountered (SNP data for sLDA and SGPLS).
The fastest approach is sDDA (except for Leukemia). This approach is not necessarily the one that performs the best, but is certainly the most efficient on large data sets. sPLS-DA is the second fastest one. The SPLSDA approaches were efficient on SRBCT but otherwise performed third, while SGPLS computation time was similar to sPLSDA except for large multiclass data set such as GCM.
Wrapper approaches
Amongst the wrapper approaches, RFE gave the best results for a very small selection of variables in most cases. The performance of RFE then dramatically decreased when the number of selected variables becomes large. This is due to the the backward elimination strategy adopted in the approach: the original variables are progressively discarded until only the 'dominant' mostly uncorrelated variables remain. RF seemed to give the second best performance for a larger number of variables. OFW-cart also performed well, as it aggregates CART classifiers, whereas OFW-svm performed rather poorly. This latter result might be due to the use of the one-vs-one multiclass SVM. NSC seemed affected by a too large number of variables, but performed surprisingly well on the SNP data.
sDDA/sLDA
Both variants gave similar results, but we could observe some differences in the GCM data set. In fact, [41] advised to apply sDDA for extremely high-dimensional data, but when a difference was observed between the two approaches (GCM, Leukemia), it seemed that sLDA performs the best. However, in terms of computational efficiency, sDDA was the most efficient.
SPLSDA-LOG/SPLSDA-LDA
SPLSDA-LDA gave better results than SPLSDA-LOG except for SRBCT where both variants performed similarly. On Leukemia, Brain and SNP, SPLSDA-LDA had a similar performance to sPLS-DA but only when the selection size became larger.
SGPLS
SGPLS performed similarly to sPLS-DA on SRBCT and gave similar performance to sPLS-DA on Leukemia when the selection size was large. However, it performed poorly in Brain where the number of classes becomes large and very unbalanced. SGPLS could not be run on GCM data as while tuning the η parameter, the smallest variable selection size we could obtain was 100, which did not make SGPLS comparable to the other approaches. On the SNP data SGPLS encountered R memory allocation issues.
sPLS-DA
sPLS-DA gave similar results to sDDA and sLDA in the less complex data sets SRBCT and GCM. The performance obtained on Brain was quite poor, but results were very competitive in Leukemia for a number of selected genes varying between 5 and 30. Note that the number of selected variables is the total number of variables selected accross the K - 1(K - 2) chosen dimensions (SNP data). In overall, sPLS-DA gave better results than the wrapper approaches, and remained very competitive to the other exploratory approaches. One winning advantage of sPLS-DA is the graphical outputs that it can provide (see next Section), as well as its computational efficiency.
Stability analysis of sPLS-DA
It is useful to assess how stable the variable selection is when the training set is perturbed, as recently proposed by [39,40]. For instance, the idea of bolasso [40] is to randomize the training set by drawing boostrap samples or drawing n/2 samples in the training set, where n is the total number of samples. The variable selection algorithm is then applied on each subsample with a fixed number of variables to select and the variables that are selected are then recorded [40]. proposed to keep in the selection only the variables that were selected in all subsamples, whereas [39] proposed to compute a relative selection frequency and keep the most stable variables in the selection.
We chose to illustrate the latter option as we believe that the stability frequency, or probability, gives a better understanding of the number of stable discriminative variables that are selected in sPLS-DA. The highly correlated variables will get a higher probability of being selected in each subsample, while the noisy variables will have a probability close to zero. This stability measure can also guide the user in the number of variables to choose on each sPLS-DA dimension. Once the number of variables to select has been chosen for the first dimension, the stability analysis should be run for the second dimension and so on. Note that [39] proposed an additional perturbation by introducing random weights in the Lasso coefficients, called random lasso. This latter approach could not, however, be directly applied in the sPLS-DA algorithm due to its iterative nature.
Figure 3 illustrates the stability frequencies for the first two dimensions of the sPLS-DA for the GCM and SNP data sets using bootstrap sampling (i.e. of size n). The frequencies obtained on the GCM data set clearly show that the first 3 variables are often selected accross numerous bootstrap samples on the first dimension. We can see that while most microarray data could achieve a reasonably high stability frequency (see Additional file 2), this was not the case, however, for the SNP data. Several SNPs may contain similar information, this may induce a lower stability across the bootstrap samples for a small variable selection. Once the variable selection size grows larger, then there is enough stable information to be retained.
Figure 3. Stability analysis. Stability frequency using bolasso for the first two dimensions of sPLS-DA for GCM (top) and SNP data (bottom). One has to sequentially choose the most stabler genes/SNPs in the first dimension in order to pursue the stability analysis for the next sPLS-DA dimension.
Additional file 2. Stability analysis. Stability frequency using bolasso for the first two dimensions of sPLS-DA for Brain (top) and SRBCT data (bottom). One has to sequentially choose the most stabler genes/SNP in the first dimension in order to go on to the next sPLS-DA dimension.
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We also noticed that once we reached too many dimensions (i.e. close K - 1), then the frequencies of all variables dropped, which clearly showed that sPLS-DA could not distinguish between discriminative variables and noisy variables any more (not shown).
Data visualization with sPLS-DA
Representing the samples and the variables
Data interpretation is crucial for a better understanding of highly dimensional biological data sets. Data visualization is one of the clear advantage of projection-based methods, such a Principal Component Analysis (PCA), the original PLS-DA or sPLS-DA, compared to the other tested approaches (wrapper methods, SPLSDA and SGPLS). The decomposition of the data matrix into loading vectors and latent variables provide valuable graphical outputs to easily visualize the results. For example, the latent variables can be used to represent the similarities and dissimilarities between the samples: Figure 4 illustrates the difference in the sample representation between classical PLS-DA (no variable selection) and sPLS-DA (26 genes selected on the first 2 dimensions) for the Brain data set. Variable selection for highly dimensional data sets can be beneficial to remove the noise and improve the samples clustering. A 3D graphical representation can be found in Additional file 3 with sPLS-DA. Figures 5, 6 and 7 compare the sample representation on the SNP data set using PCA (SNP data set only), classical PLS-DA and sPLS-DA on several principal components or PLS dimensions. On the full data set, PCA is able to discriminate the African hunter gatherers populations San, Mbuti and Biaka from the 4 other populations that are very similar (Mandeka, Yoruba, Bantu South Africa and Bantu Kenya). This is a fact that was previously observed [48] and it indicates a good quality of the data. With PCA however, the differentiation between the 4 populations Mandeka, Yoruba, Bantu South Africa and Bantu Kenya is not very clear, even for further dimensions (Figure 5). On the contrary to PCA, PLS-DA (Figure 6) and sPLS-DA (Figure 7) are able to discriminate further these 4 populations on dimensions 4 and 5. In particular, the Mandeka population is well differentiated on dimension 4, and so is the Yaruba population on dimension 5. In terms of sample representation and in contrary to what was obtained with the Brain data set (Figure 4), the difference between PLS-DA and sPLS-DA is not striking on this particular data set. This is probably because the SNP variables, although containing redundant information, are all informative and mostly not noisy. This also explains the good population clusters obtained with PCA (Figure 5). However, the variable selection performed in sPLS-DA has two advantages: firstly it reduces the size of the data set for further investigation and analyses; secondly, since each (s)PLS dimension focuses on the differentiation of some particular populations (Figures 5 and 6) and since sPLS selects an associated subset of variables on each on these dimensions, each of these subsets of variables is well able to differentiate these particular populations. This variable selection therefore gives more insight into the data (see [25] for more details). Figure 8 illustrates the weights in absolute value of the sparse loading vectors for each sPLS-DA dimension in the Brain data set. Only the genes with a non-zero weight are considered in the sPLS-DA analysis and were included in the gene selection (50 genes in total for this example). Generally, the sparse loading vectors are orthogonal to each other, which permits to uniquely select genes across all dimensions. The latent variables can also be used to compute pairwise correlations between the genes to visualize them on correlation circles and better understand the correlation between the genes on each dimension (Figure 9(a)). Note that this type of output is commonly used for Canonical Correlation Analysis.
Figure 4. Brain data: sample representation and comparison with classical PLS-DA. Comparisons of the sample representation using the first 2 latent variables from PLS-DA (no variable selection) and sPLS-DA (26 genes selected).
Additional file 3. Brain data: sample representation in 3D. Example of 3D samples plot using the first 3 latent variables from sPLS-DA with the R mixOmics package.
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Figure 5. SNP data: sample representation with PCA. Sample representations using the first 5 principal components from PCA.
Figure 6. SNP data: sample representation with classical PLS-DA. Sample representation using the first 5 latent variables from PLS-DA (no SNPs selected).
Figure 7. SNP data: sample representation with sPLS-DA. Sample representation using the first 5 latent variables from sPLS-DA (1000 SNPs selected on each dimension).
Figure 8. Brain data: representation of the loading vectors. Absolute value of the weights in the loading vectors for each sPLS-DA dimension. Only the genes with non zero weights are considered in the sPLS-DA analysis and are included in the gene selection.
Figure 9. Brain data: variable representation. (a) projection of the sPLS-DA selected variables on correlation circles with the R mixOmics package; (b) biological network generated with GeneGo using the same list of genes. Genes that are present in the network (b) are labelled in green, red and magenta in (a).
On the contrary, the pooled centroid formulation used in sDDA and sLDA do not provide such latent variables, and, therefore, lack of such useful outputs. The same can be said about the wrapper approaches, which often have a much higher computational cost than the sparse exploratory approaches applied in this study.
Brain data set: biological interpretation
Comparisons between the gene lists
The ultimate aim when performing variable selection is to investigate whether the selected genes (or SNPS) have a biological meaning. We saw for example that some of the tested approaches gave similar performances, even though they select different variables.
We therefore compared the lists of 50 genes selected with the different approaches on the Brain data set. Note that the selection size has to be large enough to extract known biological information from manually curated databases.
Unsurprisingly, given the variety of approaches used, there were not many genes in common: there were between 12 and 30 genes shared between sPLS-DA, sDDA, sLDA and SPLDA - sDDA and sLDA shared the most important number of genes (30). The gene selection from SGPLS grandly differed from the other multivariate approaches (between 2 and 9 genes). This may explain why the performance of SGPLS was pretty poor compared to the other approaches on the Brain data set. RF seemed to be the approach that selected the highest number of genes in common with all approaches except with NSC (between 10 and 23 genes). A fact to be expected was that there were very few commonly selected genes between the exploratory approaches and the wrapper approaches (between 2 and 10 genes).
We then investigated further the biological meaning of the selected genes. This analysis was performed with the GeneGo software [4] that outputs process networks, gene ontology processes as well as the list of diseases potentially linked with the selected genes.
It was interesting to see that in all these gene lists (except NSC and RFE), between 3 to 5 genes were linked to networks involved in neurogenesis, apoptosis, as well as DNA damage (sPLS-DA, sDDA) and neurophysiological processes (OFW-cart). Most of the lists that were selected with the wrapper approaches generated interesting gene ontology processes, such as degeneration of neurons (RF), synaptic transmission or generation of neurons (OFW-svm). On the contrary, the sparse exploratory approaches seemed to pinpoint potential biomarkers linked with relevant diseases: central nervous system and brain tumor (sPLS-DA), Sturge Weber syndrome, angiomatosis, brain stem (sDDA, sLDA), neurocutaneous syndrome (sDDA), neurologic manifestations and cognition disorders (SGPLS).
This preliminary analysis shows that the different approaches are able to select relevant genes linked to the biological study and are able to select complementary information. This was also the conclusion drawn in [10].
Further biological interpretation with the sPLS-DA list
Using the GeneGo software, known biological networks were generated from the list of genes selected with sPLS-DA - 26 genes in total for the first two dimensions. For example, the network represented in Figure 9(b) is based on 12 of these selected genes (indicated with a red dot), which are involved in biological functions such as cell differentiation, cellular developmental process and central nervous system development. These genes are organised around two transcription factors, ESR1 and SP1. SP1 can activate or repress transcription in response to physiological and pathological stimuli and regulates the expression of a large number of genes involved in a variety of processes such as cell growth, apoptosis, differentiation and immune responses.
Interestingly, all 12 genes present in the network were also found to be highly correlated to the sPLS-DA dimensions 1 and 2 (indicated in green for the ESR1 network, magenta for the SP1 network and red for common genes in both subgraphs). This latter result suggests a. that the first (second) dimension of sPLS-DA seems to focus on the SP1 (ESR1) network and b. that the genes selected with sPLS-DA are of biological relevance (see Table 3 for a description of most genes). Further investigation would be required to give more insight into the sPLS-DA gene selection.
Table 3. Brain data: Biological relevance of some of the selected genes
Conclusions
In this article, we showed that sPLS could be naturally extended to sPLS-DA for discrimination purposes by coding the response matrix Y with dummy variables. sPLS-DA often gave similar classification performance to competitive sparse LDA approaches in multiclass problems. Undoubtedly, the sparse approaches that we tested are extremely competitive to the wrapper methods, which are often considered as black boxes with no intuitive tuning parameters (such as the kernels to use in the SVM). The preliminary biological analysis showed that some tested approaches brought relevant biological information. The PLS-based approaches such as the sPLS-DA approach that we propose have a well established framework for class prediction. The computational efficiency of sPLS-DA as well as the valuable graphical outputs that provide easier interpretation of the results make sPLS-DA a great alternative to other types of variable selection techniques in a supervised classification framework. We also showed that a stability analysis could guide the parameter tunings of sPLS-DA. On the Brain data set, we showed that sPLS-DA selected relevant genes that shed more light on the biological study. For these reasons, we believe that sPLS-DA provides an interesting and worthwhile alternative for feature selection in multiclass problems.
Methods
In this section, we introduce the sparse Partial Least Squares Discriminant Analysis (sPLS-DA) to perform feature selection. sPLS-DA is based on Partial Least Squares regression (PLS) for discrimination analysis, but a Lasso penalization has been added to select variables. We denote X the n × p sample data matrix, where n is the number of patients or samples, and p is the number of variables (genes, SNPs, ...). In this supervised classification framework, we will assume that the samples n are partitioned into K groups.
Introduction on PLS Discriminant Analysis
Although Partial Least Squares [13] was not originally designed for classification and discrimination problems, it has often been used for that purpose [38,51]. The response matrix Y is qualitative and is recoded as a dummy block matrix that records the membership of each observation, i.e. each of the response categories are coded via an indicator variable. The PLS regression (now PLS-DA) is then run as if Y was a continuous matrix. Note that this might be wrong from a theoretical point of view, however, it has been previously shown that this works well in practice and many authors have used dummy matrice in PLS for classification [30,37,51,52].
PLS constructs a set of orthogonal components that maximize the sample covariance between the response and the linear combination of the predictor variables. The objective function to be solved can be written as
where uh and vh are the hth left and right singular vector of the singular value decomposition (SVD) of XT Y respectively [53] for each iteration or dimension h of the PLS. These singular vectors are also called loading vectors and are associated to the X and Y data set respectively.
In the case of discrimination problems, the PLS model can be formulated as follows:
where β is the matrix of the regression coefficients and E is the residual matrix. To give more details, β = W*V T, where V is the matrix containing the loading vectors (or right singular vectors from the SVD decomposition) (v1, ..., vH ) in columns, W* = W (UT W )-1, where W is the matrix containing the regression coefficients of the regression of X on the latent variable , and U is the matrix containing the loading vectors (or left singular vectors from the SVD decomposition) (u1, ..., uH ) in columns. More details about the PLS algorithm and the PLS model can be found in the reviews of [53,54]. The prediction of a new set of samples is then
The identity of the class membership of each new sample (each row in Ynew ) is assigned as the column index of the element with the largest predicted value in this row.
Discriminant PLS for large data sets
Numerous variants of PLS-DA have been proposed in the literature to be adapted to classification problems for large data sets such as microarray. Iterative Reweighted PLS was first proposed by [31] to extend PLS into the framework of generalized linear models. In the same context, [51,55,56] proposed a two-stage approach, first by extracting the PLS-DA latent variables to reduce the dimension of the data, and then by applying logistic discrimination or polychotomous discrimination in the case of multiclass problems. To avoid infinite parameters estimates and non convergence problems, other authors [32] extended the work of [31] by applying Firth's procedure to avoid (quasi) separation, whereas [33] combined PLS with logistic regression penalized with a ridge parameter. The response variables Y is modelled either as a dummy matrix [51,55,56], or as a pseudo-response variable whose expected value has a linear relationship with the covariates [33]. The approach proposed by [32] updates the adjusted dependent variable as the response rather than working with the original outcome. While these authors propose to address the problem of dimension reduction, they still require to perform gene filtering beforehand, with, for example, t-statistics or other filtering criterion such as the BSS/WSS originally proposed by [2].
sparse PLS Discriminant Analysis
sparse PLS for two data sets
The sparse PLS proposed by [25,26] was initially designed to identify subsets of correlated variables of two different types coming from two different data sets X and Y of sizes (n × p) and (n × q) respectively. The original approach was based on Singular Value Decomposition (SVD) of the cross product . We denote uh (vh) the left (right) singular vector from the SVD, for iteration h, h = 1 ... H where H is the number of performed deflations - also called chosen dimensions of the PLS. These singular vectors are named loading vectors in the PLS context. Sparse loading vectors were then obtained by applying l1 penalization on both uh and vh. The optimization problem of the sPLS minimizes the Frobenius norm between the current cross product matrix and the loading vectors:
(1)
where Pλ1 (uh) = sign(uh)(|uh| - λ1)+, and Pλ2 (vh) = sign(vh)(|vh| - λ2)+ are applied componentwise in the vectors uh and vh and are the soft thresholding functions that approximate Lasso penalty functions [21]. They are simultaneously applied on both loading vectors. The problem (1) is solved with an iterative algorithm and the Xh and Yh matrices are subsequently deflated for each iteration h (see [25] for more details). For practical purposes, sPLS has been implemented in the R package mixOmics such that the user can input the number of variables to select on each data set rather than the penalization parameters λ1 and λ2.
sPLS extended to sPLS-DA
The extension of sparse PLS to a supervised classification framework is straightforward. The response matrix Y of size (n × K) is coded with dummy variables to indicate the class membership of each sample. Note that in this specific framework, we will only perform variable selection on the X data set, i.e., we want to select the discriminative features that can help predicting the classes of the samples. The Y dummy matrix remains unchanged. Therefore, we set and the optimization problem of the sPLS-DA can be written as:
with the same notation as in sPLS. Therefore, the penalization parameter to tune is λ. Our algorithm has been implemented to choose the number of variables to select rather than λ for practical reasons. For the class prediction of test samples, we use the maximum distance as presented above for the PLS case as it seemed to be the one that worked better in practice for multiclass problems. Note that other distances such as the centroids or Malhanobis distances are also implemented in the mixOmics package [42,43]. In the results section, we illustrated how to tune the PLS dimension H as well as the number of X variables to select.
sPLS-DA for multiclass classification
In binary problems, sPLS-DA was shown to bring relevant results in microarray cancer data sets (see [57]). In this paper, we investigated the use of sPLS-DA in the more complex multiclass case, as PLS-DA and sPLS-DA are naturally adapted to multiclass problems. In this paper, we did not attempt to address the specific problem of unbalanced classes, that would require the development of appropriately weighted multiclass objective functions for wrapper classification approaches (see for example [58]).
Parameters to tune in sPLS-DA
There are two parameters to tune in sPLS-DA: the number of dimensions H, and the number of variables to select on each dimension. In the Results Section, we showed that for most cases, the user could set H = K - 1, similar to what is advised in a LDA case. The number of variables to select is more challenging given the complexity of such data sets and is still as an open question. The tuning of such parameter can be guided through the estimation of the generalisation classification error and a stability analysis. However, these analyses might be seriously limited by the small number of samples. Most importantly, the user should keep in mind that a close interaction with the biologists is necessary to carefully tune this parameter in order to answer biological questions. Sometimes, an optimal but too short gene selection may not suffice to give a comprehensive biological interpretation, and experimental validation might be limited in the case of a too large gene selection.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
KALC performed the statistical analysis, wrote the R functions and drafted the manuscript. SB preprocessed the SNP data and helped to draft the manuscript. PB participated in the design of the manuscript and helped to draft the manuscript. All authors read and approved the final manuscript.
Acknowledgements
We would like to thank Dr. Dominique Gorse (QFAB) for his advice on using GeneGo. We are indebted to Pierre-Alain Chaumeil (QFAB) for his support on using the QFAB cluster. We thank the referees for their useful comments that helped improving the manuscript. This work was supported, in part, by the Wound Management Innovation CRC (established and supported under the Australian Government's Cooperative Research Centres Program).
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Research article
Quantitative characterization and analysis of the dynamic NF-κB response in microglia
Patrick W Sheppard1, Xiaoyun Sun2, John F Emery2, Rona G Giffard2 and Mustafa Khammash1*
Author Affiliations
1 Department of Mechanical Engineering, University of California, Santa Barbara, Engineering II Bldg., Santa Barbara, CA, 93106-5070, USA
2 Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, 94305-5117, USA
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BMC Bioinformatics 2011, 12:276 doi:10.1186/1471-2105-12-276
Published: 5 July 2011
Abstract
Background
Activation of the NF-κB transcription factor and its associated gene expression in microglia is a key component in the response to brain injury. Its activation is dynamic and is part of a network of biochemical species with multiple feedback regulatory mechanisms. Mathematical modeling, which has been instrumental for understanding the NF-κB response in other cell types, offers a valuable tool to investigate the regulation of NF-κB activation in microglia at a systems level.
Results
We quantify the dynamic response of NF-κB activation and activation of the upstream kinase IKK using ELISA measurements of a microglial cell line following treatment with the pro-inflammatory cytokine TNFα. A new mathematical model is developed based on these data sets using a modular procedure that exploits the feedback structure of the network. We show that the new model requires previously unmodeled dynamics involved in the stimulus-induced degradation of the inhibitor IκBα in order to properly describe microglial NF-κB activation in a statistically consistent manner. This suggests a more prominent role for the ubiquitin-proteasome system in regulating the activation of NF-κB to inflammatory stimuli. We also find that the introduction of nonlinearities in the kinetics of IKK activation and inactivation is essential for proper characterization of transient IKK activity and corresponds to known biological mechanisms. Numerical analyses of the model highlight key regulators of the microglial NF-κB response, as well as those governing IKK activation. Results illustrate the dynamic regulatory mechanisms and the robust yet fragile nature of the negative feedback regulated network.
Conclusions
We have developed a new mathematical model that incorporates previously unmodeled dynamics to characterize the dynamic response of the NF-κB signaling network in microglia. This model is the first of its kind for microglia and provides a tool for the quantitative, systems level study the dynamic cellular response to inflammatory stimuli.
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Research article
Widespread horizontal genomic exchange does not erode species barriers among sympatric ducks
Robert HS Kraus1,2*, Hindrik HD Kerstens3, Pim van Hooft1, Hendrik-Jan Megens4, Johan Elmberg5, Arseny Tsvey6, Dmitry Sartakov7, Sergej A Soloviev8, Richard PMA Crooijmans4, Martien AM Groenen4, Ronald C Ydenberg1,9 and Herbert HT Prins1
Author Affiliations
1 Resource Ecology Group, Wageningen University, P.O. Box 47, 6700 AA Wageningen, The Netherlands
2 Conservation Genetics Group, Senckenberg Research Institute and Natural History Museum, D-63571 Gelnhausen, Germany
3 Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands
4 Animal Breeding and Genomics Centre, Wageningen University, Marijkeweg 40, 6709 PG Wageningen, The Netherlands
5 Aquatic Biology and Chemistry, Kristianstad University, SE-291 88 Kristianstad, Sweden
6 Biological Station Rybachy of the Zoological institute RAS, 238535 Kaliningrad region, Russia
7 Ecological Watch of Siberia, Komarova street 27/6/5, 644074 Omsk, Russia
8 Department of Chemistry, Omsk State University, St. Prospect Mira 55a, 644077 Omsk, Russia
9 Centre for Wildlife Ecology, Simon Fraser University, V5A 1S6 Burnaby, BC, Canada
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BMC Evolutionary Biology 2012, 12:45 doi:10.1186/1471-2148-12-45
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2148/12/45
Received:8 November 2011
Accepted:2 April 2012
Published:2 April 2012
© 2012 Kraus 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
The study of speciation and maintenance of species barriers is at the core of evolutionary biology. During speciation the genome of one population becomes separated from other populations of the same species, which may lead to genomic incompatibility with time. This separation is complete when no fertile offspring is produced from inter-population matings, which is the basis of the biological species concept. Birds, in particular ducks, are recognised as a challenging and illustrative group of higher vertebrates for speciation studies. There are many sympatric and ecologically similar duck species, among which fertile hybrids occur relatively frequently in nature, yet these species remain distinct.
Results
We show that the degree of shared single nucleotide polymorphisms (SNPs) between five species of dabbling ducks (genus Anas) is an order of magnitude higher than that previously reported between any pair of eukaryotic species with comparable evolutionary distances. We demonstrate that hybridisation has led to sustained exchange of genetic material between duck species on an evolutionary time scale without disintegrating species boundaries. Even though behavioural, genetic and ecological factors uphold species boundaries in ducks, we detect opposing forces allowing for viable interspecific hybrids, with long-term evolutionary implications. Based on the superspecies concept we here introduce the novel term "supra-population" to explain the persistence of SNPs identical by descent within the studied ducks despite their history as distinct species dating back millions of years.
Conclusions
By reviewing evidence from speciation theory, palaeogeography and palaeontology we propose a fundamentally new model of speciation to accommodate our genetic findings in dabbling ducks. This model, we argue, may also shed light on longstanding unresolved general speciation and hybridisation patterns in higher organisms, e.g. in other bird groups with unusually high hybridisation rates. Observed parallels to horizontal gene transfer in bacteria facilitate the understanding of why ducks have been such an evolutionarily successful group of animals. There is large evolutionary potential in the ability to exchange genes among species and the resulting dramatic increase of effective population size to counter selective constraints.
Background
Biology has seen the proposition of several species concepts. Of these, the biological species concept [1] is historically the most influential; according to it all individuals belong to the same species if they produce viable and fertile offspring in nature, i.e., they share a common gene pool. To account for inherent difficulties to test this concept in practice, especially in allopatric populations that never encounter each other, biologists tend to supplement it by elements of the morphospecies concept (which is as old as the study of nature). With the advance of molecular genetic data over the past decades many researchers now define species by genetic characteristics rather than morphological ones because genetics provides a means of actually measuring recent or ongoing genetic connectivity between species [2]. Species boundaries are strengthened by accumulation of genomic incompatibilities preventing formation of zygotes, so called Dobzhansky-Muller incompatibilities [3-5]. Once evolved, post-zygotic isolation is irreversible, in contrast to pre-zygotic barriers such as mate recognition. There is much evidence that post-zygotic barriers evolve slowly in birds [5,6], potentially contributing to the high rates of hybridisation observed in this group [7] and explaining why genetic distances can be low in spite of large morphological differences [8].
When populations diverge into species their gene pools become disconnected, and even in the absence of ecological differentiation stochastic effects, i.e., genetic drift, will drive each new species towards increased differentiation. If introgression of genetic material of one species into another occurs regularly enough in the absence of genomic incompatibility, one would expect that these events oppose genetic drift by exchange of alleles that the two subsequently will have in common. Such potential sharing of alleles at genetic loci through genetic admixture can directly be observed by the study of genetic markers. One type of genetic marker that has recently received a lot of attention is the 'single nucleotide polymorphism' (SNP) [9]. Due to the abundance of SNPs in genomes and suitability for high automation in genotyping, SNPs can be characterised in large numbers, yielding a representative image of an entire genome. With SNP data from multiple species, one can study the sharing of genetic material at the same loci, providing a new means of studying species divergence by the speed of loss of genetic coherence.
While persistent genetic admixture can lead to the merging of species [10,11] this does not generally seem to be the case in some taxonomic groups. For example, ducks (family Anatidae) show much hybridisation in the wild, with viable and fertile offspring [7,12,13]. In spite of this, duck species remain morphologically distinct. Males especially display species-specific plumage, ornamentation, and courtship behaviour (Figure 1). In the present study, we utilise a recently developed SNP set for the mallard (Anas platyrhynchos) [14] to infer the degree of genomic connectivity among five species of closely related, ecologically similar and morphologically well differentiated duck species, among which interspecific hybridisation is commonplace. With this example we set out to illustrate how analysis of "SNP persistence time" facilitates the understanding of the evolutionary impact of ongoing hybridisation, how it can reveal the existence of superspecies complexes, and how it sheds light on longstanding unresolved puzzles of speciation processes.
Figure 1. The studied duck species. Male and female of each of the studied duck species: a) Anas platyrhynchos (mallard), b) Anas acuta (northern pintail), c) Anas crecca (teal), d) Anas penelope (Eurasian wigeon), e) Anas strepera (gadwall), f) Aythya fuligula (tufted duck). Except for c) the more colourful male is in the front. Evidently, plumage ornamentation in these ducks is very distinctive among species. Drawings are from the artwork stocks of the WWT, Slimbridge, UK, and used with permission.
Results and Discussion
Genotypic differentiation between Anas platyrhynchos and other duck species
We screened 364 SNPs developed for the mallard, Anas platyrhynchos, [14] in the genomes of six duck species, five of genus Anas and one of Aythya, the latter mainly for outgroup comparison: Anas platyrhynchos (N = 197), Anas acuta (northern pintail, N = 7), Anas crecca, (common teal, N = 9), Anas penelope (Eurasian wigeon, N = 14), Anas strepera (gadwall, N = 10) and Aythya fuligula (tufted duck, N = 17). The SNPs were evaluated for minor allele frequency (MAF) spectrum, Hardy-Weinberg equilibrium and linkage disequilibrium in Anas platyrhynchos from nine localities on three continents. The great majority of SNPs does not significantly deviate from neutrality and are unlinked.
We plotted the results of a series of principal component analyses (PCAs) for several combinations of individual of Anas platyrhynchos and other species genotypes. All plots are based on the first and second PCA axes. Other axes were investigated visually but did not provide further insight. No clear genetic clusters among specimens of Anas platyrhynchos were discernible in this analysis when analysed separately, and the evident absence of genetic structure in mallards is reflected by low values of explained variance in the first and second PCAs (Figure 2a). Geography had no influence on genetic similarity. Even after correcting for potential mislabelling or outliers (see methods for details) a few individuals seem to lie a bit outside the main cluster, but note that the scaling of differences between Anas platyrhynchos individuals in this PCA is different from the scaling in analyses involving other duck species (see below). Interestingly, a lack of population structure in mallards has also been described on a continent-scale for mitochondrial data [15] and on a global scale using SNPs (Kraus et al., manuscript submitted). The other species form distinct clusters if analysed together (Figure 2b): Anas penelope and Anas strepera form one cluster and are hard to distinguish from each other. Anas acuta and Anas crecca each form their own specific clusters. Aythya fuligula is of a different genus and hence not a dabbling duck. It serves as outgroup here and clearly lies outside these clusters. When individuals of all species are analysed jointly in this way (Figure 2c), Anas platyrhynchos is clearly distinct from the other species. A putative hybrid between Anas acuta and Anas platyrhynchos is placed exactly in between its assumed parental species, thereby confirming its supposed hybrid status.
Figure 2. PCA analysis of duck genotypes. The program smartpca from the Eigenstrat package was used to calculate multivariate eigenvectors of the duck genotypes. The first two eigenvectors for each individual are plotted and colour coded by locality or species. The percent variation explained by PCA axes 1 and 2 is given in brackets. a) only Anas platyrhynchos individuals, colour coded by locality (see additional file 4). b) other ducks, colour coded by species: An. acuta (Anas acuta, ANAC), An. crecca (Anas crecca, ANCR), An. penelope (Anas penelope, ANPE), An. strepera (Anas strepera, ANST), Ay. fuligula (Aythya fuligula, AYFU). c) A joint calculation of PCA axes including all ducks analysed in this study. Additionally, a hybrid between Anas acuta and Anas platyrhynchos was included (ANACPLA), which is placed between the Anas platyrhynchos and Anas acuta cluster as expected. Anas platyrhynchos clearly forms an own cluster and the genetic similarity to the other species clusters reflects phylogenetic placements (i.e., Anas platyrhynchos is more closely related to Anas acuta and Anas crecca than to Anas penelope or Anas strepera).
SNP sharing among duck species is unexpectedly high
Genotyping was successful in the non-Anas platyrhynchos species with only 14-24% missing genotypes while within Anas platyrhynchos (for which the SNP set was originally designed) this number was 4%. Of 364 Anas platyrhynchos SNPs, 86 (24%) were polymorphic in Anas acuta, 102 (28%) in Anas crecca, 60 (16%) in Anas penelope, 41 (11%) in Anas strepera, and 11 (3%) in Aythya fuligula (Figure 3). The proportion of shared SNPs between the Anas species are high compared with those reported in studies comparing other species with similar evolutionary distances. Bovines (cattle, bison and yak), for instance, have a relatively recent, Pleistocene radiation 2.5 million years ago (Mya), yet SNP sharing does not exceed 5% [16]. SNP sharing in the genus Gallus (chickens and relatives), another taxon with putative Pleistocene speciation and recent introgression from domestic animals, is also estimated at 5%[17], while in sheep (divergence time ~ 3 Mya) it is estimated at only 1% [18]. The same low levels of SNP sharing also occur in invertebrate and plant species. The flies Drosophila pseudoobscura and D. miranda show 2.9% SNP sharing [19] (divergence time 3.7 Mya [20]) while the plant pairs Arabidopsis halleri/A. lyrata petraea and A. lyrata lyrata/A. l. petraea share 4.7% and 1.6%, respectively [21] (divergence times < 5 Mya). Given the divergence time of Anas platyrhynchos from, e.g., Anas acuta and Anas crecca of at least 6.4 Mya [22] (Figure 4) they share up to an order of magnitude more SNPs than shown in these previous reports.
Figure 3. Venn diagram of shared SNPs with mallard by the four other Anas species. A core of 18 SNPs was polymorphic in all four Anas species. The closer phylogenetic relationship of Anas acuta and Anas crecca to Anas platyrhynchos is reflected in their polymorphism sharing pattern. Abbreviations as in Figure 2.
Figure 4. Schematic phylogram of the studied duck species. Branch lengths are scaled to Mya. Aythya fuligula was added as outgroup (branch length shortened at the split of the genus). Redrawn from [22] and Javier Gonzales (pers. comm.). An. codes for the genus Anas, and Ay. for Aythya.
Generally, the rate of SNP sharing in closely related species, as reported thus far, appears to be in the order of a few percent, at maximum. Random genetic drift usually purges polymorphisms as a function of time (generations), effective population size (Ne) and initial MAF, allowing an approximation of the time to fixation of allele frequencies under genetically neutral conditions [23]. For Anas platyrhynchos we estimate the mean persistence time (i.e., how long the polymorphisms segregate) for alleles with the highest possible MAF to be 5.3 million years, assuming a generation time of one year and Ne being constant at the present-day number. In the other duck species studied here it ranges between 0.8 and 2 million years. Rare alleles, e.g. MAF < 0.1, are lost more quickly (Table 1). The probability distribution for this loss has a long tail towards longer persistence times, with 5% of the shared polymorphisms with a MAF = 0.5 expected to be retained after a calculated threshold of 3.8Ne generations [24]. For Anas platyrhynchos this would equate to 7.2 million years (at a divergence from Anas crecca/Anas acuta of 6.4 Mya [22]). Thus, Anas platyrhynchos could have retained some of the ancestral shared polymorphisms since that split. However, Anas acuta and Anas crecca currently have much smaller Ne, and are unlikely to have retained more than 5% of their ancestral polymorphisms for periods longer than 2 and 2.6 million years (on the basis of 3.8Ne generations), if these species were reproductively fully isolated. Even with three times higher Ne or generation time, the number of shared SNPs between the studied duck species is higher than expected: the persistence times of the 5% fraction of SNPs with MAF = 0.5 for Anas acuta and Anas crecca (6.2 and 7.9 Mya) just exceed their divergence time from Anas platyrhynchos (6.4 Mya [22]). On the other hand, under these scenarios Anas penelope and Anas strepera would not have retained more than 5% of SNPs with MAF = 0.5 after 3.8 and 4.3 million years, respectively, at a minimum divergence time from Anas platyrhynchos of 8 Mya [22]. In conclusion, it seems the number of shared SNPs between the studied duck species exceeds what is likely under the neutral theory even when conservatively high estimates of Ne (from the upper bounds of the official counts) and conservatively low divergence times (mean times minus standard deviation of the values presented in [22]) are assumed.
Table 1. Interaction between population size and persistence time
Increased population size by ongoing interspecific hybridisation
What can then explain the high level of shared polymorphisms? We argue that these (and other closely related) duck species are part of a superspecies complex, here defined as a group of distinct species that frequently hybridise, with fertile offspring as the result. The superspecies concept was put forward by Mayr in 1931 [25], as a translation of the German expression Artenkreis, based on the work of Rensch [26]. Initially, it was used to assign species status to allopatric "races" that were too distinct to be lumped into the same species [27-29] (superspecies sensu stricto). Later, the definition was widened by Kiriakoff [30] and Mayr and Short [31] to be no longer exclusive to allopatric populations. For the Anas platyrhynchos complex this concept has previously been used by Scherer [13]. Being aware that "superspecies" is not an official taxonomic category we here choose to use the term superspecies (sensu lato) to embrace the sympatric distribution of interbreeding duck species. In doing so, we do not attempt to redefine nomenclatural classification schemes, nor do we propose to change current nomenclature. The term superspecies is clearly "an evolutionary taxonomy category but not nomenclatural rank" [32], thus to be preferred when studying biological systems rather than nomenclature.
There is longstanding anecdotal, morphological and experimental evidence for high hybridisation rates in ducks [7,12,22], but molecular proof has been limited thus far. Two studies using mitochondrial DNA in the Anas rubripes/platyrhynchos [33] and Anas zonorhyncha/platyrhynchos [34] complexes confirm hybridisation between these species. These findings were corroborated by studies investigating one to two nuclear markers [35,36]. Our study, using shared polymorphisms at hundreds of independent loci across the entire genome provides a more powerful means of analysing gene pool connectivity between closely related species and our results are consistent with a high level of genetic transfer between species via hybrid production and backcrossing.
A STRUCTURE [37] analysis identified several cases where genetic admixture from other species seems supported by their genotypes. When all six duck species were analysed jointly with the genetic clustering software STRUCTURE, all non-Anas platyrhynchos individuals were assigned to the same cluster (Additional file 1). Anas acuta individuals in particular showed partial Anas platyrhynchos genome admixture, and many Anas platyrhynchos individuals displayed some admixture from other species. When Anas platyrhynchos individuals were excluded, STRUCTURE assigned Anas penelope, Anas strepera and Aythya fuligula individuals to their species specific clusters, although one Anas strepera individual (ANST001) was almost fully assigned to Anas penelope. Anas acuta and Anas crecca were lumped into one cluster, and the hybrid was correctly assigned to that cluster by only 50% of its genome (Additional file 2). Excluding the hybrid from analysis did not alter the assignment of these two species to the same cluster. The same data sets were analysed with comparable settings in the software InStruct [38], which does not assume Hardy-Weinberg equilibrium in the inferred populations, and yields qualitatively similar results as the STRUCTURE analysis. This may be direct evidence of partial gene pool sharing between species, hence the establishment of a superspecies complex.
Additional file 1. Bar graph of the genetic admixture analysis of individual ducks. All duck species in one admixture analysis. Each bar represents one individual and colours indicate membership in a certain cluster as identified with STRUCTURE without using prior information. Individual IDs are explained in the text and additional file 4 and additional file 6. On the y-axis the percentage of membership in a certain cluster is given. For instance, individual ATHO001 (individual 1 from the Anas platyrhynchos locality in Austria) is almost 100% assigned to the light blue cluster, while individual CARM009 (from a Canadian locality) is mainly assigned to the light blue, but also with about 15% to the purple cluster (an effect of genetic admixture between these two otherwise discrete clusters). This file is scalable in order to retrieve details if needed.
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Additional file 2. Bar graph of the genetic admixture analysis of individuals: Anas platyrhynchos excluded. See additional file 1 for details.
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For example, a superspecies complex comprising Anas platyrhynchos, Anas acuta and Anas crecca would have a joint census population size of 31 million individuals and hence an Ne of 3.1 million (see methods for sources and assumptions), although sub-division of this possible superspecies due to assortative mating makes this an over-estimate[39]. However, an Ne of 3.1 million results in a mean persistence time of almost 9 million years (for initial MAF = 0.5). With an estimated most recent common ancestor at 6.4 Mya, these species could have on average retained even SNPs of lower MAF = 0.2. We refer to this analysis as 'persistence time analysis'.
Species status and the supra-population concept
The ducks studied here have not only remained morphologically distinct, their genetic cluster species designation [2] is strongly supported by principal component analysis of SNP genotypes: we find clear genetic differentiation between Anas platyrhynchos and the other duck species, as well as among these (Figure 2c). Even though all these species live in sympatry, such a combined population is highly structured by assortative mating. While geographical substructure would be indicated by the term "meta-population", the situation in ducks leads us to define a new term that does not have a geographical connotation: "supra-population". We define a supra-population as a group of individuals that are part of the same sympatric superspecies complex and within which natural hybridisation occurs. Individuals of a superspecies complex are genetically-connected hybridising species, in which species barriers are primarily maintained by pre-zygotic factors.
A new model of speciation in ducks
Genomic incompatibilities usually lead to irreversible post-zygotic isolation of populations, but other, reversible, barriers can also be strong drivers of speciation. Visual cues have been identified as drivers of speciation in sexually dimorphic bird species [8,40] while sexual imprinting alone can explain assortative mating in modeling studies [41]. An empirical example from another Anatid species, the snow goose Anser caerulescens, which has two wide ranging colour morphs, nicely illustrates the case [42]. At any rate, a model for speciation in ducks must be able to explain the observed pattern of genetic and morphological differentiation in spite of the high degree horizontal gene exchange.
Paleogeographic and paleoclimatic evidence suggest that ecological conditions have been favourable for a duck radiation 6-12 Mya. This late Miocene period was warm and humid [43,44], but in transition towards a colder climate. Precipitation remained relatively high [45-47], making wetlands abundant and turning large inland salt water bodies brackish or even freshwater (e.g., Lake Pannon in Eurasia [48-50]). Globally, during this transition towards a colder, wet climate tropical forests were largely replaced by open grasslands [51-53], a habitat well suited for ducks. The fossil record of ducks beyond the Pleistocene is still very poor [54] but the few studies on the subject suggest that morphological change in respective duck species has been very limited over the last few million years [55,56], after a larger waterfowl species turn-over 15-23 million years ago [57]. The first fossil that resembles Anas platyrhynchos is thought to be from the late Pliocene, about 5 Mya [58]. This is close to the suggested lower bound of divergence times of some Anas species in the latest phylogeny of Anatidae [22]. We propose that an Anas-like duck split into multiple sister morphs sympatrically and simultaneously at that time, subsequently diverging by assortative mating. Our results indicate that the resulting cluster of species still exchanges portions of their genomes. We argue that since branching off of the Anas clade at least 6 Mya these mostly sympatric species remain separate by isolating mechanisms other than genetic incompatibilities, mostly by assortative mating. Though we acknowledge that this speciation scenario rests on the assumption of widespread sympatry for millions of years, we feel comfortable in making this claim. Although we only sampled five species for the present study, our model system sensu lato is the specious genus Anas, and even though species distributions change over time there certainly have always been several Anas species living in sympatry.
Theoretical studies suggest that sexual imprinting can drive speciation even in sympatry [59]. Moreover, experimental manipulations clearly demonstrate that individuals of Anas platyrhynchos can be imprinted on nearly any species of waterfowl but when raised in isolation they recognise conspecifics as mates [60]. This suggests that imprinting is important but incomplete in ducks; genetic factors also contribute to mate recognition. The presence of assortative mating and recognition mechanisms are prerequisites for sympatric speciation leading to a superspecies complex around Anas platyrhynchos.
Conclusions
The amount of shared polymorphism between the studied duck species cannot be explained by large population sizes of the respective species only. We suggest extraordinary and evolutionarily sustained hybridisation rates as drivers of ongoing gene pool mixing. Gene flow continues and will allow the transfer of genetic material among duck species. At present, extensive hybridisation still occurs. The genetic compatibility of different duck species, combined with mixed effects of genetically determined and imprinted mate choice leads to speciation reversals [11] despite genotypically and morphologically defined species boundaries. Present-day occurrence of Anas platyrhynchos in large numbers and wide geographical extent may even drive some of their close relatives to extinction by hybridisation [61]. This is a major concern in many parts of the world, especially where Anas platyrhynchos is not indigenous [62]. Many species of the genus Anas are hard to fit into the biological species concept because their evolution has rather led to a superspecies complex with discernable lineages. Besides the five dabbling duck species studied here, it is likely that many more of the ca. 40 Anas species are part of the global supra-population.
Besides conservation implications, this creates large evolutionary potential, comparable to bacteria, which are able to exchange genes among different species by horizontal gene transfer. Further, increasing effective population sizes into the millions may allow non-adaptive evolutionary processes to act, opening up additional degrees of evolutionary freedom [63]. SNP-based analysis at hundreds of independent loci across the entire genome, as done here, may serve to re-evaluate long-standing puzzling patterns of speciation and hybridisation in several bird groups, such as other waterfowl, galliforms, hummingbirds and woodpeckers [7], as well as in many other organisms where species pairs exhibit unusually high levels of hybridisation.
Methods
Samples
In total, 212 individuals of Anas platyrhynchos obtained from nine localities representing Eurasian and North American populations were sampled and their blood was stored on FTA cards [64] at room temperature until DNA isolation. Numbers of samples with abbreviation codes in brackets: Eurasian samples were from Austria (25, ATHO), Estonia (22, EETA), Portugal (32, PTDJ), and three Russian localities: Yaroslavl (25, RUYA), Omsk (12, RUOM) and Tomsk (32, RUTO). North America was represented by Ontario (7, CALM), Manitoba (20, CARM) and Alaska (22, USMF). Preliminary multivariate clustering of SNP genotypes (see below) positioned 15 of these individuals far outside the Anas platyrhynchos species cluster, sometimes well within the clusters of other duck species (Additional file 3). We discarded these 15 individuals as mislabelled because they showed obvious deviation from their putative genotypic species cluster. Details are available in Additional file 4.
Additional file 3. Vector graph of a PCA analysis of genotypes of all duck species. First and second axes are plotted against each other (explained variation in brackets). Grey dots represent individuals designated as Anas platyrhynchos at sampling. Other colours indicate other duck species. A tentative hybrid between Anas acuta and Anas platyrhynchos is in red. Labels next to the dots represent individual study IDs. This file is scalable in order to retrieve details if needed.
Format: PDF Size: 23KB Download file
This file can be viewed with: Adobe Acrobat Reader
Additional file 4. List of all Anas platyrhynchos samples analysed in this study. Includes information on specific ID, collection date, country of origin, names of collectors, sampling locations, and further additional info.
Format: PDF Size: 16KB Download file
This file can be viewed with: Adobe Acrobat Reader
A set of 67 samples from other duck species were obtained world wide from various sources (hunting bags, live-trapped, zoos) and localities. Most often blood on FTA cards was used, sometimes other tissues stored in ethanol, and also previously isolated DNA from collections. The cross species testing was applied to ducks of the following Anas and Aythya species (numbers of samples and abbreviation code in brackets): Anas acuta (7; ANAC), Anas crecca (9; ANCR), Anas penelope (14; ANPE), Anas strepera (10; ANST), Aythya fuligula (17; AYFU) and one F1 hybrid between Anas acuta and Anas platyrhynchos (ANACPLA). Using the same procedure as with the Anas platyrhynchos set, we identified nine of these samples as apparently mislabelled. These were excluded from all subsequent analyses (Additional file 5). Details are available in Additional file 6.
Additional file 5. PCA analysis of genotypes of all non-Anas platyrhynchos individuals. Details as in additional file 3, but without Anas platyrhynchos.
Format: XLS Size: 46KB Download file
This file can be viewed with: Microsoft Excel Viewer
Additional file 6. List of all other duck species samples analysed in this study, Details similar those given in additional file 4.
Format: XLS Size: 21KB Download file
This file can be viewed with: Microsoft Excel Viewer
DNA isolation
DNA isolation was done using the Gentra Systems Puregene DNA purification Kit according to the manufacturer's instructions, with modifications when handling of FTA cards. Appropriate amounts of tissue or blood on FTA cards were digested with 9 μg Proteinase K (Sigma) in Cell Lysis Solution (Gentra Systems) at 65°C over night, or longer in case of some tissues. Proteins were subsequently precipitated with Protein Precipitation Solution (Gentra Systems) and spun down together with the FTA card material. DNA from the supernatant was precipitated with isopropanol and washed twice with 70% ethanol. DNA quantity and purity were measured using the Nanodrop ND1000. Samples with 260/280 nm absorption ratios less than 1.8 were purified again.
SNP genotyping
We used Illumina's GoldenGate Genotyping assay, on the Illumina BeadXpress. The marker set consisted of 384 SNPs [14] ("mallard 384 SNP set"), which are numbered according to their dbSNP accession numbers from ss263068950 (SNP 0) to ss263069333 (SNP 383). Raw genotyping results were analysed in GenomeStudio (Illumina), and SNP clusters adjusted by hand. The respective OPA (oligo pooled assay) and cluster files can be found online with this paper (Additional file 7 and Additional file 8).
Additional file 7. 'Oligo pooled assay (OPA)' summary file. Contains all necessary information for genotyping the presented SNPs on an Illumina BeadXpress system.
Format: OPA Size: 229KB Download file
Additional file 8. 'Cluster file' for use with GenomeStudio software. These configuration settings are used by the SNP genotyping software to convert raw signal into genotypes.
Format: EGT Size: 169KB Download file
SNP set evaluation
We assessed technical and biological properties of the SNP set in Anas platyrhynchos:
i) Minor allele frequencies and heterozygosity
For each of the nine localities we counted the occurrences of each of the two alleles. The count of the allele occurring less frequently (minor allele) was divided by the total number of alleles, giving the population wide frequency of minor alleles per locus (minor allele frequency, MAF). Additionally, we counted heterozygote individuals as a fraction of all individuals (observed heterozygosity, Hobs).
ii) Hardy-Weinberg equilibrium
Each locus was tested for deviation from Hardy-Weinberg equilibrium in each locality with the software Arlequin 3.5.1.2 [65] using the analog to Fisher's exact test for arbitrary table size [66] (1,000,000 Markov chain steps, 100,000 dememorisation steps).
iii) Linkage disequilibrium
Per locality, pairs of SNP loci were tested for presence of linkage disequilibrium (LD) in Arlequin. The implemented likelihood-ratio test [67] employs the EM algorithm [68] to infer haplotypes from unphased genotypic data to test for statistical significance of LD. Repeated use of a SNP in multiple statistical tests requires a correction of the significance level α. In our 364 SNP data set each SNP is involved in 66066 pairwise tests, significance levels for LD are thus Bonferroni corrected.
iv) Physical SNP locations inferred from chicken genome
We searched the SNP positions on the chicken genome (from Kraus et al. [14]) in Ensembl [69] for chicken gene information using Bioconductor [70] with biomaRt in R [71]. We recorded if a SNP was situated in a gene, or even intron.
Persistence times of SNPs
The equation for mean persistence time t(p) is a combination of the time to loss and to fixation [72,73]. It can be written as -4Ne[(1-p) ln(1-p) + pln(p)] where p denotes the initial MAF and Ne the effective population size (for derivation see ref. [23], page 112, eqn. 3.10). To calculate the persistence time t(p) of a SNP, an estimate of the effective population size (Ne) from the census population size (Nc) is thus required. Estimates of current census population sizes (Nc) of the investigated duck species were taken from the BirdLife species fact sheets [74]. Upper estimates were used when a range was given. The ratio between Ne and Nc for species of dabbling ducks has to our knowledge not been studied, but it is probably fairly low as most census estimates are based on winter counts made several months before the breeding season starts and most mortality may occur before breeding [75]. Further, dabbling ducks are generally r-selected and their population sizes fluctuate greatly by swift responses to benign and detrimental conditions [76,77], with Ne being dominated by the smallest values [23]. Estimated Ne: Nc ratios from white-winged wood ducks (Asarcornis scutulata, formerly Cairina scutulata) range between 0.052 (genetic measurements) and 0.094 (demographic measurements) [78]. Thus, we use a ratio of 0.1 as a conservative estimate (on the high side) for the ratio of Ne to Nc.
The generation time has been set to one year for clarity. As mentioned above, many individuals do not reproduce at all, and those that do are in the vast majority of the cases first-years [75]. The actual generation time value should lie in the range between 1.1 and 1.2 years, and this has no effect on our interpretations.
Interspecific, genetic admixture
A Bayesian genetic clustering algorithm as implemented in the software STRUCTURE [37] (version 2.3.3) was used to test for genetic admixture, i.e., the incorporation of genes from one discrete population/species into another. Two datasets were analysed: i) all Anas platyrhynchos and other duck species (the same individuals as analysed by PCA, see Figure 2c); ii) only the other species (cf. Figure 2b) plus the putative hybrid between Anas platyrhynchos and Anas acuta. A value of K = 6 simulated clusters (as many clusters as species) was chosen in the analysis of all ducks (i), and consequently K = 5 when Anas platyrhynchos was excluded (ii). Default settings were used with the admixture model of STRUCTURE, run for 300,000 steps (the first 100,000 discarded as burn-in). Additionally, we compared the results of the STRUCTURE analysis with those of the program InStruct [38] which is designed to perform the same analysis as STRUCTURE but not depending on Hardy-Weinberg equilibrium. The same datasets and settings were used, including the default settings, with the same values for K. Mode 1 - "infer population structure only with admixture" - in InStruct was chosen because it is most comparable to the program STRUCTURE as explained in its manual. The dataset containing only non-Anas platyrhynchos ducks (K = 5) was also run for the same amount of iteration steps. The larger dataset, all ducks combined (K = 6), was run substantially longer because the Markov chain converged very slowly (2,000,000 steps, of which 1,000,000 were discarded as burn-in).
Multivariate genetic clustering of genotypes
We tested for genetic similarity of individuals using principal component analysis (PCA) on their genotypes with the program smartpca from the Eigenstrat package [79] with default settings, but outlier removal switched off. The analysis was repeated for every new subset of the data.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
RHSK designed the study, coordinated sample collection, prepared DNA, analysed and interpreted data, and wrote the manuscript. PvH analysed and interpreted the data, and revised the manuscript. HHDK analysed data. H-JM interpreted data and revised the manuscript. RCY interpreted data, co-wrote the manuscript, and coordinated sample collection. JE co-wrote the manuscript. RPMAC, MAMG, AT and HHTP revised the manuscript. AT, DS and SAS coordinated sample collection and discussed the paper. All authors read and approved this paper.
Acknowledgements
We are thankful to the following persons and institutions for providing Anas platyrhynchos samples: Ernst Niedermayer, Hans Jörg Damm (Stiftung Fürst Liechtenstein, Austria), David Rodrigues (Escola Superior Agrária de Coimbra, Portugal), Brandt Meixell, Danielle Mondloch, Jonathan Runstadler (University of Alaska Fairbanks, USA), V.N. Stepanov, O. Tutenkov, V.I. Zalogin, Sergey Gashkov, Sergey Fokin (State Informational-Analytical Centre of Game Animal and Environment of Hunting Department of Russia), Urmas Võro, David Lamble, Garry Grigg, Aaron Everingham, Holly Middleton (Simon Fraser University, Vancouver, Canada). Rolik Grzegorz (Zoo Opole, Poland), Magnus Hellström (Ottenby Bird Observatory, Sweden), Michael Wink, Javier Gonzales (University of Heidelberg, Germany), Dirk Ullrich (Alpenzoo Innsbruck, Austria), Kamil Čihák (Zoo Dvur Kralove, Czech Republic), Marina Euler (Tierpark Lange Erlen, Switzerland), Sascha Knauf (Opel Zoo, Germany), Yang Liu (University of Bern, Switzerland), Mathieu Boos (CNRS Strasbourg, France), Crystal Matthews (Virginia Aquarium, USA), Timm Spretke (Zoologischer Garten Halle, Germany) and Valery Buzun provided samples from duck species other than Anas platyrhynchos. Technical assistance with genotyping was provided by Bert Dibbits. Daniël Goedbloed helped with the software package Eigenstrat. We thank Michael Turelli and Carlo Dietl for discussions. Javier Gonzales provided unpublished data on divergence times of duck species, and Brian Cade helped with statistics. The WWT, Slimbridge, UK, provided drawings for Figure 1. This work was financially supported by the KNJV (Royal Netherlands Hunters Association), the Dutch Ministry of Agriculture, the Faunafonds and the Stichting de Eik trusts (both in The Netherlands) and the Swedish Environmental Protection Agency, grants V-220-08 and V-205-09.
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Research article
Type 1 Diabetes in the Spanish Population: additional factors to Class II HLA-DR3 and -DR4
Elena Urcelay1*, José L Santiago1, Hermenegildo de la Calle2, Alfonso Martínez1, Julián Méndez1, José M Ibarra3, Carlos Maluenda4, Miguel Fernández-Arquero1 and Emilio G de la Concha1
Author Affiliations
1 Immunology Department, Hospital Universitario San Carlos, Madrid, Spain
2 Endocrinology Department, Hospital Ramón y Cajal, Madrid, Spain
3 Diabetes Unit, Hospital Universitario San Carlos, Madrid, Spain
4 Department of Paediatrics, Hospital Universitario San Carlos, Madrid, Spain
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BMC Genomics 2005, 6:56 doi:10.1186/1471-2164-6-56
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2164/6/56
Received:15 November 2004
Accepted:20 April 2005
Published:20 April 2005
© 2005 Urcelay 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
The Major Histocompatibility Complex is the main genetic contributor to susceptibility to type 1 diabetes (T1D); genome-wide scans have consistently mapped increased predisposition to this region. The highest disease risk has been associated with HLA-DR3 and HLA-DR4. In particular, the DR3-positive ancestral haplotype 18.2 was reported as highly diabetogenic. We aimed to corroborate whether this haplotype increases the susceptibility conferred by the DQ2-DR3 alleles in a Mediterranean population. We also searched for additional susceptibility factors to the classic DQ2-DR3 and DQ8-DR4.
Results
Genetic MHC markers were analysed in a case-control study with 302 T1D patients and 529 ethnically matched controls. DR3-TNFa1b5 carrier rate was significantly higher in DR3-positive heterozygous T1D patients than in DR3-positive heterozygous controls (p = 0.0019; odds ratio OR [95% confidence interval CI] = 2.26 [1.3–3.93]). This data was confirmed analysing the allelic frequency, which includes the information corresponding to the DR3-homozygous individuals (p = 0.001; OR = 2.09) and by using the Arlequin software to check the DR3-positive haplotypes (p = 0.004;OR = 1.93). The present results provide strong evidence of a second susceptibility region in the ancestral haplotype 18.2 in the Spanish population.
Moreover, we searched for T1D susceptibility factors in addition to the MHC classical ones, within the DR2-DQ6/DR3-DQ2/DR4-DQ8 negative population. Several genetic markers in both MHC class II (DQA1*0101-DQB1*0501 [p = 0.007;OR = 2.81], DQA1*0201-DQB1*0202 [p = 0.03; OR = 2.35]) and III (TNFa2b1 [p = 0.01 OR = 2.74], BAT-2*2 [p = 0.004; OR = 3.19]) were found. These different alleles associated with T1D were not independent and we observed linkage disequilibrium among them leading us to describe two new risk haplotypes (DQA1*0101-DQB1*0501-TNFa2b1 and DQA1*0201-DQB1*0202- BAT-2*2). Finally, we studied a T1D susceptibility/protection marker located in extended class I, D6S2223; however, no association was observed in our population.
Conclusion
Our results suggest that other associated MHC haplotypes might present susceptibility factors in loci different from HLA-class II and that the class II molecules are not necessarily the universal etiologic factor in every MHC haplotype.
Background
Type 1 diabetes is a multifactorial autoimmune disease characterised by insulin deficiency, due to the T cell mediated destruction of pancreatic β-cells [1]. Among the genetic determinants of susceptibility, with more than 18 putative loci identified to date, a region in chromosome 6p21 (IDDM1) containing the Major Histocompatibility Complex (MHC) is the only one consistently associated with T1D in genome-wide screenings. The MHC spans approximately 4 Mb and consists of over 200 genes arranged in three subregions named class II, III and I. More than 90% of Caucasoid type 1 diabetic patients have at least one copy of the class II HLA-DR3 or DR4 allele, as compared to the 45% present in the general population and the genotype frequency of the DR3/DR4 heterozygote in T1D patients is 40% vs. 3% in controls [2]. In fact, the strongest susceptibility haplotypes described are DQB1*0201-DQA1*0501-DRB1*03 (DQ2-DR3) and DQB1*0302-DQA1*0301-DRB1*04 (DQ8-DR4), especially when both appear together in the genotype. However, not all HLA-DR3 or -DR4 positive haplotypes are equally predisposing [3,4]. This might suggest the role of other MHC loci responsible for modifying the susceptibility to diabetes conferred by class II genes, but their search has been difficult due to the strong linkage disequilibrium (LD) present in this chromosomal region. The term ancestral, extended haplotype was coined referring to continuous sequence derived with little, if any, change from an ancestor of all those now carrying all or part of the haplotype [5]. A published report stated that the DQ2-DR3-B18 AH 18.2 significantly increased risk compared to other haplotypes with the same class II alleles, but LD between markers hampered a more precise localisation of the presumed susceptibility gene [6]. Taking into account that this AH 18.2 is more frequent in Southern European populations, we decided to assess the possible role of other loci in the MHC region besides DQ-DR within this haplotype. We evaluated several genetic markers along the MHC in a case-control study with 302 Spanish T1D patients and 529 healthy controls. This study reproduced the especially strong association of the AH 18.2 with T1D in the Spanish population, supporting the existence of a second susceptibility locus within this haplotype. The present work extended the search to other T1D risk factors in the MHC besides DQ2-DR3/DQ8-DR4. Additional MHC haplotypes question the paradigm of class II genes as sole responsible for the association and open up the possibility that class III susceptibility factors would be also involved.
Results
We first aimed to corroborate in the Spanish population the published increased risk to autoimmune diabetes of the AH 18.2, as compared to other DR3-positive haplotypes [6]. Microsatellites TNFa and TNFb, located in the untranslated region upstream of the LTA gene, exhibit extensive polymorphism and are good haplospecific markers. In order to identify the extended haplotype AH 18.2, we selected both microsatellites TNFab, which are conveniently close to HLA-B and easier to genotype than the latter. The microsatellites TNFa1b5 tag the AH18.2 defined by the characteristic alleles of five markers (D6S273*2, BAT2*2, TNFa1b5, MICA*4) in our families with IgA deficiency [7] and celiac disease [8]. These AH 18.2 markers were also confirmed by the computer program Arlequin, by linkage disequilibrium studies and by analysis of homozygous individuals. As we are dealing with patients and controls with no families at our disposal, the DR3-TNFa1b5 phase was uncertain. However, due to heavy linkage disequilibrium between these alleles, most of the times they will probably be in cis. This proportion can be estimated based upon the presence of TNFa1b5 in DR3-negative individuals: 8 carriers out of 109 DR3-negative T1D patients, and 13 carriers out of 376 DR3-negative healthy controls. These numbers yield allelic frequencies of TNFa1b5 on DR3-negative haplotypes of 7 and 3%, respectively. The assumption can therefore be made that, most of the time; a DR3 heterozygous sample carrying TNFa1b5 will in fact carry these alleles in the same haplotype.
Once the AH 18.2 was defined, we looked for the already described different distribution of this haplotype between T1D patient and control cohorts. Initially, we compared the carrier rate of TNFa1b5 among DR3-positive individuals. In T1D patients, the ratio of DR3 homozygous subjects out of the total DR3-positive individuals is much higher than the observed in controls (47 out of 193 vs. 8 out of 153 in controls; p = 1 × 10-6; OR = 5.83). This makes necessary to calculate the TNFa1b5 carrier rate exclusively in DR3 heterozygous individuals to avoid the cumulative effect of those individuals. When the TNFa1b5 carrier rate was compared, it was significantly higher in DR3-positive heterozygous T1D patients than in DR3-positive heterozygous controls (66 out of 143 vs. 33 out of 120; p = 0.0019; OR (95% CI) = 2.26 [1.3–3.93]). If we do not want to discard the information corresponding to the DR3-homozygous individuals, the comparison should be made counting allelic rather than phenotypic frequency and then normalising these counts by the total number of DR3-positive haplotypes present in the DR3-positive individuals (112/123 vs. 40/92, p = 0.001, OR = 2.09) (Table 1).
Table 1. Comparison of the TNFa1b5 allelic frequency in the DR3-positive T1D patient and control cohorts.
The results strongly suggest that the haplotype AH 18.2 is over represented among DR3 haplotypes. To formally elucidate whether this is the case, we observed that the allelic frequency of DR3-TNFa1b5 (AH 18.2) is higher than that of the DR3-positive abundant haplotype AH 8.1, which carries TNFa2b3, (112/40 vs. 64/51, p = 0.002, OR (95% CI) = 2.23 [1.29–3.86]). Moreover, when the allele frequencies of TNFa1b5 and TNFa2b3 were compared to the total of TNFab alleles excluding the two aforementioned, the AH18.2 showed significant difference (112/59 vs. 40/41, p = 0.01, OR = 1.95) whereas TNFa2b3, AH8.1, did not (64/59 vs. 51/41, p = 0.62, OR = 0.87). An alternative approach would consist of applying an expectation-maximisation algorithm, as the one implemented by the Arlequin program to the sample genotypes. Table 2 shows the DR3 three-loci haplotypes generated by this software sorted into TNFa1b5 positives, TNFa2b3 positives and other haplotypes. Again, TNFa1b5 is significantly different from other DR3 haplotypes, while TNFa2b3 behaves similarly to the rest.
Table 2. Frequency and number of DR3-positive haplotypes estimated by the Arlequin software.
In our Spanish sample this DR3-TNFa1b5 positive haplotype was present in a 33% T1D patients (98/298) vs. 7% controls (37/504). The haplotypes ascertained by the Arlequin software yielded an AH 18.2 almost five times more frequent in the Spanish patient than control cohorts (Table 2). Moreover, almost one half (46%, 66/142) of the DR3 heterozygous diabetic patients vs. one forth (27%, 33/120) of the controls displayed a DR3-TNFa1b5 positive phenotype. On the contrary, in this subpopulation the distribution of the other main DR3-positive haplotype, AH 8.1, was similar between patients (43/142, 30%) and controls (47/120, 39%).
Therefore, these results confirmed the reported specific diabetogenic role of the AH 18.2 in a Mediterranean population and are compatible with published observations that established the presence of a second susceptibility gene in the AH 18.2 [6,9] possibly located in either class III or class I.
The second aim of this work was searching for additional T1D susceptibility factors to the classical DQ2-DR3 and DQ8-DR4 in the MHC region. Obviously, the subjects studied should belong to DR3- and DR4-negative populations to eliminate the underlying genetic risk attributable to these known risk factors and they were also stratified by DR2, to avoid the effect of this allele negatively associated with the disease. We tested the predisposition determined by alleles of the five genetic markers in HLA class III already studied (Table 3), and we also compared the distribution of the DQA1-DQB1 alleles (Table 4). Then, alleles TNFa10b4, DQA1*0501-DQB1*0301 and DQA1*0103-DQB1*0603 for protection, and TNFa2b1, BAT-2*2, DQA1*0101-DQB1*0501 and DQA1*0201-DQB1*0202 for susceptibility, displayed statistical significant difference when T1D patients and healthy controls were compared in the DR3, DR4 and DR2- negative population. These different alleles associated with T1D were not mutually independent and linkage disequilibrium was observed between TNFa2b1 and DQA1*0101-DQB1*0501 (p = 9 × 10-5; D' = 0.34), BAT-2*2 and DQA1*0201-DQB1*0202 (p = 4 × 10-7; D' = 0.36) and weak LD between TNFa10b4 and DQA1*0103-DQB1*0603 (p = 0.09; D' = 0.16). These results would suggest the presence of extended haplotypes increasing the risk to autoimmune diabetes in these conditions, although the exact location of the susceptibility gene remains undetermined. The allele 2 of microsatellite BAT-2 within the haplotype DQA1*0201-DQB1*0202 is the same present in the AH 18.2, and therefore a common susceptibility region could potentially be shared by both haplotypes. To test this possibility two adjacent markers to BAT-2 were analysed, one telomeric, MN6S1879 and other centromeric, N3-2-3. The MN6S1879*14 allele present in the AH 18.2 is the same found in LD with BAT-2*2 in the DR2-DQ6/DR3-DQ2/DR4-DQ8 negative patients (p = 7 × 10-5; D' = 0.33). Curiously, provided the extensive LD displayed by the AH 18.2, there are two different alleles (7 and 9) in the N3-2-3 marker corroborated in our deficit IgA and celiac disease families, in homozygous individuals and by Arlequin software. The allele N3-2-3*7 did not show LD with BAT-2*2 in the triple negative population (p = 0.87, D' = 0.014), but N3-2-3*9 (p = 0.052, D' = 0.26) showed a trend for association. Although this latter allele seemed to mark higher risk than N3-2-3*7, the difference did not reach statistical significance. There was indirect evidence supporting the role of the allele N3-2-3*9 in T1D susceptibility. In two DR3-TNFa1b5 homozygous control individuals there were three alleles N3-2-3*7 and one N3-2-3*9, while in nine T1D patients, there were nine alleles each. Moreover, in DR3-DQ2/DR4-DQ8 individuals carrying TNFa1b5, the allele present in N3-2-3 is 9 (41 out of 83 vs. 0 from 14, p = 0.0012) instead of 7 (25 out of 83 vs. 7 out of 12, p = 0.06, OR = 0.31). Of notice the different trend shown for the allele 9 conferring susceptibility and for the allele 7 conferring protection. However, one must be cautious in the interpretation of these data, as allele 9 is much more haplospecific for AH 18.2 than allele 7, which appear in several other haplotypes. Any ulterior analysis was prevented given the lack of DR3-DQ2/DR4-DQ8 control subjects displaying the AH 18.2.
Table 3. Comparison of the carrier rate of HLA class III genetic markers in the DR2-DQ6/DR3-DQ2/DR4-DQ8 negative diabetic and control cohorts.
Table 4. DQA1-DQB1 haplotypes in DR2-DQ6/DR3-DQ2/DR4-DQ8 negative T1D patients and controls.
Finally, we tried to ascertain the role as T1D susceptibility/protection marker of the microsatellite located 4.9 Mb telomeric of DQ in extended class I, D6S2223. In Northern European countries allele D6S2223*3 was associated with a reduction in risk independent of the class II effect [9,10] and allele D6S2223*1 accounted for susceptibility to T1D [6]. These associations were not observed in Sardinia [11]. In our DR3, DR4 and DR2-negative study group we did not find any association (allele D6S2223*3 for protection: 28/29 in T1D patients vs. 223/234 in healthy controls, OR = 1.38, p = 0.61; allele D6S2223*1 for susceptibility: 0/29 vs. 2/234, p = 0.79). However, the limited number of patients after stratification decreases the statistical power of detection for a positive association in our population.
Discussion
Our observations support the distinctive effect on type 1 diabetes susceptibility of the AH 18.2 among all the other DR3-positive haplotypes in the Spanish population. Both, allelic and phenotypic frequencies showed the increased risk conferred by the DR3-TNFa1b5 haplotype. Moreover, the different behaviour in terms of T1D predisposition of both DR3-positive main haplotypes, AH 8.1 and 18.2, argues in favour of a second susceptibility locus besides the standard class II molecules (DR and DQ) in the latter.
Previous studies reported the contribution to T1D susceptibility of a second region in the MHC besides DQ-DR genes. Among them, one concluded that this second region extended between HLA-B and BAT-3 in the highest risk DR3/DR4 genotype [12], while other mapped the critical region around the microsatellite D6S273 centromeric to TNF [13]. TNF-α has been identified as a diabetogenic effector molecule synergistic with IFN-γ in the induction of β-cell apoptosis [14-16] and therefore, it was of interest to consider the TNF region located in class III MHC as a candidate susceptibility locus. Transfected cells containing BAT1 promoter fragments from the 8.1 AH exhibited lower reporter activity compared to the 7.1 AH. Since the 7.1 and 8.1 AH are associated with resistance and susceptibility to T1D respectively, the observed effects are claimed to have significant implications for the pathogenesis of this disease [17]. We decided to study this region in our population. Our findings of BAT-2*2, TNFa2b1 and TNFa10b4 as genetic markers of the risk conferred by the DQ-DR locus agrees with those previous reports in terms of location. Most probably the etiological variant(s) will be in linkage disequilibrium with the BAT-2*2 allele. However, given the low recombination rate of the haplotype 18.2 (shown by the TNFa1b5 present in a DR3-negative context, see Table 3), and being BAT-2*2 a common allele, this microsatellite could mark a different susceptibility gene in the AH 18.2 and in other haplotypes. Clearly, the analysis of genetic markers in class II and class III provided an emerging pattern of susceptibility/protection haplotypes in addition to the classical DR3/DR4/DR2 determinants. In this sense, one could speculate that the traditional emphasis on class II alleles alone as responsible for increasing the T1D risk could be an oversimplification of a more complex reality where class III markers remained in the background.
Population studies provide invaluable information helping to map predisposition loci. A good example is the role of D6S2223 as a marker of autoimmune diabetes in several Nordic populations [9] which has been reproduced neither in Sardinia [11] nor in Spain (present data).
A large number of studies from different populations including the Spanish one [18] have indicated that common allelic variants at the class II HLA-DRB1, -DQA1 and -DQB1 loci are associated with T1D. These MHC class II molecules play an important role in the presentation of peptide antigens after intracellular processing to CD4 T- lymphocytes. The correlation between the relative T1D predisposition of class II alleles and the structure of their proteins has also been described [19]. However, the presence of HLA class II molecules alone does not by itself cause disease. The HLA transgenic mice develop diabetes when there is an islet "insult", even if the islet "insult" is, itself, not sufficient to precipitate disease [17].
Conclusion
Our data prove that there are additional susceptibility/protection factors besides DR3/DR4/DR2 in HLA in the Spanish population and particular combinations of these minor risk factors could have important effects on susceptibility. The results of the present study provide evidence of the importance of the whole HLA in T1D risk gradient after stratification for the DR3, DR4 and DR2 determinants. The accent placed on class II in the canonical DQ2-DR3/DQ8-DR4 haplotypes is not necessarily extensive to other associated haplotypes where susceptibility might map to different MHC loci.
Methods
302 T1D patients and 529 healthy unrelated controls, both groups composed of Caucasian individuals from the same Madrid area, were consecutively recruited after informed consent obtained from the indexed subjects or their parents when the patient was a child. The T1D patients were diagnosed at two hospitals in Madrid and the control subjects were collected among healthy blood donors. The age at onset for the T1D patients (150 men and 152 women) range 1–55 years old (median onset 15 years old). Diagnosis was based on patients' clinical features and laboratory data according to the criteria of the American Diabetes Association (ADA). All subjects were insulin-dependent at the time of the study. Ab-positivity was studied for GAD, IA-2, insulin and ICA. The protocol followed the principles expressed in the Declaration of Helsinki and was approved by the Hospital Ethics Committee.
Both patients and controls were genotyped for HLA-DQB1, DQA1 and DRB1 alleles [20] for 6 microsatellite markers (D6S273, BAT-2, TNFa, TNFb, MICA and D6S2223) as previously described [20-25]. Microsatellite alleles were ascertained using an ABI Prism™ 310 automatic sequencer (Applied Biosystems, Foster City, CA, USA). Each sample included an internal size standard (TAMRA 500, Applied Biosystems) to achieve a highly consistent measure.
Allelic distribution and frequencies of the haplotypes present in the control and diabetic cohorts were determined using a software for population genetics data analysis (Arlequin ver 2.000. Schneider S, Roessli D and Excoffier L. University of Geneva, Switzerland). Haplotypes were also corroborated by our previous findings in families affected by other immune related diseases, by LD studies in controls, and by the recent literature [6].
The frequencies of each marker allele in patients versus controls were compared by a standard chi-square test using a statistical software package (EPI-INFO v. 6.02; Center for Disease Control & Prevention CDC, U.S.A.) and a result was considered significant if p < 0.05. Statistics are performed upon the individuals with available data in the markers under comparison; therefore the final number could differ among different analyses. As our working hypothesis was to verify in the Spanish population the presumed special association with T1D of the characteristic alleles of the AH 18.2, there was no need for Bonferroni corrections in these initial comparisons.
Abbreviations
T1D type 1 diabetes
MHC Major Histocompatibility Complex
HLA human leukocyte antigen
AH ancestral haplotype
LD linkage disequilibrium
TNF tumor necrosis factor
OR odds ratio
LTA lymphotoxin alpha.
Freq. frequency
Authors' contributions
EU carried out the genotyping of some samples, participated in the statistical analysis and drafted the major part of the manuscript.
JLS carried out the genotyping of most of the patients and a great part of the controls, participated in the statistical analysis and drafted the manuscript. He participated in the design and coordination of the study.
HdlC made the diagnosis, and collaborated in the statistical analysis
AM carried out a great part of the genotyping of control samples and participated in the statistical analysis and drafted the manuscript
JM participated in the genotyping and recollection of samples, and in the statistical analysis.
JMI made the diagnosis, and collaborated in the statistical analysis
CM made the diagnosis, and collaborated in the statistical analysis
MFA participated in the design and coordination of the study and helped to collect the DNA samples.
EgdlC conceived of the study and helping its coordination, participated in the statistical analysis and drafted the manuscript
All authors have red and approved the final manuscript.
Acknowledgements
We thank Carmen Martínez for expert technical assistance. Elena Urcelay is recipient of a "Ramón y Cajal" contract of the Spanish Science and Technology Ministry. Alfonso Martínez is a recipient of a FIS contract (CP04/00175).
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< Previous
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: Wow, what a great deal! On the way home from work I stopped by a yard sale and picked up an old DOD 8-track mixer for $25. I got a guitar stand for $1 too.
Finally, the fact that browser/OS integration is a dumb idea gets submitted to the general public.
[Main] [Edit]
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under a Creative Commons License.
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Rate This Article
Average: 3/5
Angular momentum
Physics & Chemistry:
Angular momentum
This article has been reviewed by the following Topic Editor: Andy Jorgensen
Angular momentum is the product of mass times the perpendicular distance from the axis of rotation times the rotation velocity. The angular momentum about the Earth’s axis of rotation can be expressed as the sum of the angular momentum of the solid Earth’s rotation plus the angular momentum of zonal air motion relative to the surface of the Earth. Were this quantity to be absolutely conserved, a parcel of air with the angular momentum of the Earth’s surface at the Equator would have a westerly zonal wind speed of 134 m/s at 30o latitude.
Scale of definition
The concept of angular momentum is used in the practical world around us to quantify the spin momentum of figure skaters, merry-go-rounds and any other object in circular motion; the concept is also very useful in planetary and galactic level motions of celestial bodies, such as the moon's motion around the Earth. In addtion the notion of angular momentum is useful in analyzing the atomic. molecular and subatomic world, where elementary particles are the objects of interest. In those cases it is more difficult to realize an intuitive picture of many of the subatomic uses of angular momentum, due to the role of the Heisenberg Uncertainty principle.
Further Reading
• Dennis L. Hartmann. Global Physical Climatology. Academic Press, 1994.
Citation
Steve Baum, C Michael Hogan (Contributing Author);Andy Jorgensen (Topic Editor) "Angular momentum". In: Encyclopedia of Earth. Eds. Cutler J. Cleveland (Washington, D.C.: Environmental Information Coalition, National Council for Science and the Environment). [First published in the Encyclopedia of Earth March 29, 2010; Last revised Date September 2, 2011; Retrieved May 18, 2013 <http://www.eoearth.org/article/Angular_momentum?topic=49557>
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PR Update
Newbie Member
2Mar2009,00:36 #1
Does anyone know about google's next PR update time?
Thanks
Go4Expert Founder
2Mar2009,00:47 #2
I would be in the next quarter
Go4Expert Member
4Mar2009,00:49 #3
Hi,
I think it was just yesterday. I saw PR updates in my couple of blogs and in few sites too. And, backlinks of my blogs are also increased.
Go4Expert Founder
4Mar2009,09:14 #4
I don't see anything
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About this Journal Submit a Manuscript Table of Contents
Journal of Ophthalmology
Volume 2012 (2012), Article ID 397178, 11 pages
doi:10.1155/2012/397178
Review Article
Clinical Applications of the Photopic Negative Response to Optic Nerve and Retinal Diseases
Department of Ophthalmology, Iwate Medical University School of Medicine, 19-1 Uchimaru, Iwate, Morioka 020-8505, Japan
Received 18 July 2012; Accepted 16 September 2012
Academic Editor: Suresh Viswanathan
Copyright © 2012 Shigeki Machida. 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.
How to Cite this Article
Shigeki Machida, “Clinical Applications of the Photopic Negative Response to Optic Nerve and Retinal Diseases,” Journal of Ophthalmology, vol. 2012, Article ID 397178, 11 pages, 2012. doi:10.1155/2012/397178
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Int. J. Mol. Sci. 2011, 12(9), 5672-5683; doi:10.3390/ijms12095672
Review
The Important Molecular Markers on Chromosome 17 and Their Clinical Impact in Breast Cancer
Wei Zhang 1,* and Yingyan Yu 2
1 Department of Surgery, School of Medicine, The Ninth People’s Hospital of Shanghai Jiao Tong University, Shanghai 200011, China 2 Department of Surgery, School of Medicine, Shanghai Ruijin Hospital of Shanghai Jiao Tong University, Shanghai 200025, China
* Author to whom correspondence should be addressed.
Received: 13 July 2011; in revised form: 16 August 2011 / Accepted: 31 August 2011 / Published: 5 September 2011
(This article belongs to the Special Issue Biomarkers 2011)
Download PDF Full-Text [318 KB, uploaded 5 September 2011 11:10 CEST]
Abstract: Abnormalities of chromosome 17 are important molecular genetic events in human breast cancers. Several famous oncogenes (HER2, TOP2A and TAU), tumor suppressor genes (p53, BRCA1 and HIC-1) or DNA double-strand break repair gene (RDM1) are located on chromosome 17. We searched the literature on HER2, TOP2A, TAU, RDM1, p53, BRCA1 and HIC-1 on the Pubmed database. The association of genes with chromosome 17, biological functions and potential significance are reviewed. In breast cancer, the polysomy 17 (three or more) is the predominant numerical aberration. HER2 amplification is widely utilized as molecular markers for trastuzumab target treatment. Amplified TOP2A, TAU and RDM1 genes are related to a significant response to anthracycline-based chemotherapy, taxane or cisplatin, respectively. In contrast, p53, BRCA1 and HIC-1 are important tumor suppressor genes related to breast carcinogenesis. This review focused on several crucial molecular markers residing on chromosome 17. The authors consider the somatic aberrations of chromosome 17 and associated genes in breast cancer.
Keywords: chromosome 17; biomarkers; breast cancer
Article Statistics
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Cite This Article
MDPI and ACS Style
Zhang, W.; Yu, Y. The Important Molecular Markers on Chromosome 17 and Their Clinical Impact in Breast Cancer. Int. J. Mol. Sci. 2011, 12, 5672-5683.
AMA Style
Zhang W, Yu Y. The Important Molecular Markers on Chromosome 17 and Their Clinical Impact in Breast Cancer. International Journal of Molecular Sciences. 2011; 12(9):5672-5683.
Chicago/Turabian Style
Zhang, Wei; Yu, Yingyan. 2011. "The Important Molecular Markers on Chromosome 17 and Their Clinical Impact in Breast Cancer." Int. J. Mol. Sci. 12, no. 9: 5672-5683.
Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
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Int. J. Mol. Sci. 2008, 9(12), 2622-2638; doi:10.3390/ijms9122622
Article
Potential Use of Quantum Dots in Flow Cytometry
1 Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, Australia 2 Department of Molecular Medicine & Pathology, University of Auckland Medical School, Auckland, New Zealand 3 Department of Earth Sciences, Macquarie University, Sydney, Australia 4 Department of Physics, Macquarie University, Sydney, Australia 5 School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia
* Author to whom correspondence should be addressed.
Received: 4 July 2008; in revised form: 20 November 2008 / Accepted: 10 December 2008 / Published: 17 December 2008
Download PDF Full-Text [458 KB, uploaded 17 December 2008 11:37 CET]
Abstract: QDs may offer significant advantages in environmental and bead-based applications where the target cells need to be discriminated above background fluorescence. We have examined the possible applications of QDs for flow cytometric measurements (FCM) by studying their excitation - emission spectra and their binding to paramagnetic beads. We labelled beads with either QDs or a commonly-used fluorochrome (FITC) and studied their fluorescence intensity by FCM. Flow cytometric comparisons indicated that the minimum fluorophore concentration required for detection of QDs above autofluorescent background was 100-fold less than for FITC.
Keywords: Quantum dots; flow cytometry; fluorescent detection; detection limit; autofluorescence
Article Statistics
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Cite This Article
MDPI and ACS Style
Ibáñez-Peral, R.; Bergquist, P.L.; Walter, M.R.; Gibbs, M.; Goldys, E.M.; Ferrari, B. Potential Use of Quantum Dots in Flow Cytometry. Int. J. Mol. Sci. 2008, 9, 2622-2638.
AMA Style
Ibáñez-Peral R, Bergquist PL, Walter MR, Gibbs M, Goldys EM, Ferrari B. Potential Use of Quantum Dots in Flow Cytometry. International Journal of Molecular Sciences. 2008; 9(12):2622-2638.
Chicago/Turabian Style
Ibáñez-Peral, Raquel; Bergquist, Peter L.; Walter, Malcolm R.; Gibbs, Moreland; Goldys, Ewa M.; Ferrari, Belinda. 2008. "Potential Use of Quantum Dots in Flow Cytometry." Int. J. Mol. Sci. 9, no. 12: 2622-2638.
Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
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Google Doesn't Pay Forum "Top Contributors"
Sep 17, 2010 • 7:39 am | (4) by | Filed Under SEO & SEM Forum News
I spotted an unusual thread at the Google Webmaster Help forums. The thread had an individual ask how he can a job as a "top contributor" in the Google Forums.
Top contributors are those who spend a nice amount of time helping others in the Google support forums. It can range from the webmaster forum, web search forum, AdSense forum, Chrome forum and so on. Anyone who spends a lot of time helping webmasters and Google deems they worthy are labeled "top contributors."
I believe top contributors have special privileges, such as being able to flag certain posts for a real Google employee to review. I suspect they also have their own private discussion forum to chat with Google employees. Plus they get the label, "top contributor" added to their names. I also believe they may receive a t-shirt or something, as a thank you.
Outside of that, they get zero compensation. Google doesn't pay them in any way.
So the guy looking to get paid to be a top contributor is out of luck. At first this guy didn't believe they didn't get paid. He said:
Why people spend so much of valuable time on browsing scrap sites and write hundreds of pages. That too for 24x7x365. All this just for a title "Top Contributor"? It's not convincing...
Yes, it is true. As Sasch, a top contributor said:
We're here to help webmasters... that's it.
It is true, most are there to help - like it or not.
But that doesn't mean Google doesn't pay people to help their users. For example, if you want to help webmasters with their Google problems, you can and you can get paid. You have to apply to be a Google Webmaster Trends Analyst, which is a job based in Zurich, Switzerland. I believe they may make exceptions for certain people to work from other Google offices. I suspect many do already.
Forum discussion at Google Webmaster Help.
Previous story: Daily Search Forum Recap: September 16, 2010
blog comments powered by Disqus
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Place:Tokoname, Aichi, Japan
Watchers
NameTokoname
TypeCity
Coordinates34.833°N 136.833°E
Located inAichi, Japan
source: Getty Thesaurus of Geographic Names
the text in this section is copied from an article in Wikipedia
is a city located in Chita District, Aichi Prefecture, Japan. As of 2011, the town had an estimated population of 55,322 and a population density of 994 persons per km². The total area was 55.63 km².
Research Tips
This page uses content from the English Wikipedia. The original content was at Tokoname, Aichi. 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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Australian Bureau of Statistics
Celebrating the International Year of Statistics 2013
ABS Home > Statistics > By Release Date
1302.6 - Tasmanian Pocket Year Book, 1999
Previous ISSUE Released at 11:30 AM (CANBERRA TIME) 07/07/1999
Page tools: Print Page Print All RSS Search this Product
• About this Release
ABOUT THIS RELEASE
Presents the majority of the 1301.6 statistics, but in less detail. This pocket-size publication presents a basic summary of Tasmania.
© Commonwealth of Australia 2013
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Australian Bureau of Statistics
Celebrating the International Year of Statistics 2013
ABS Home > Statistics > By Catalogue Number
9217.0 - Experimental Estimates of Freight Movements, Australia, Sep 1995
Latest ISSUE Released at 11:30 AM (CANBERRA TIME) 18/06/1996 Ceased
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• About this Release
Provides statistics on tonnes of freight moved in Australia between selected statistical divisions by mode (road, rail, sea and air). Information on tonnes moved by broad commodity grouping (based on the Australian Transport Freight Commodity Classification), and dissections of freight classified by bulk, dangerous, refrigerated or containerised are also included.
This publication has been converted from older electronic formats and does not necessarily have the same appearance and functionality as later releases.
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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.
This question is a follow up to another question but it stands as a question by itself so i decided to ask it separately..
i am a single-founder starting a company and hence looking for investments/incubator/YC. clearly i can't go through it alone, i need some one. So i asked the above linked question as to should i add a novice founder (that is all i can find right now being where i am) because investors tend to avoid single founder companies and i might need a hand at small day to day stuff. The response was that i shouldn't and i agree with it. Make no mistake, he is just novice in tech startup industry but is a brilliant person, i just believe in a fast paced tech startup industry, it just won't be worth it to teach him enough so that he can be a founder. Currently, as it stands, he does not bring anything to the table.
But i need someone, that's a given, so i decided to hire him a a sort of employee but since the company is very early stage, 'employee' really does not make any sense because he won't be doing a particular task. So the question is what should i title this said guy who is not a founder/co-founder and won't be playing a key role in business development but still plays VERY important role in company, the first non-founder.
I know title is something that i should not worry about but there has to be something that i introduce him to every body with, that i tell my investors, that i tell him.
Also should i give him equity? if yest then how much? (I think i should give him equity but i would really like to know what you think, how much equity is something i don't know yet, i need help on it too)
Please help, it will be much appreciated
Thanks!
share|improve this question
2 Answers
up vote 1 down vote accepted
Technologist?
Lead Developer?
Technology Director?
Senior Coder? (or, Senor Coder?) ;)
Architecture Lead
share|improve this answer
show 1 more comment
How about employee #1
A bit tongue in cheek, but hey it can be useful in conversations. I've learnt that humour goes a long way when trying to connect with people.
share|improve this answer
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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.
Most bloggers are saying you should release early, iterate often, and fail fast.
But some companies are notorious for releasing early, but then getting a bad reputation which led to their failure. Sometimes they corrected the problems but couldn't redirect the reputation.
What companies do you know like this?
And then: What should we learn from those specific stories?
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8 Answers
I think the "release early, iterate often, and fail fast" is often misquoted and misused. The origin of this phrase can be attributed to Eric Raymond. The release early, release often makes perfect sense, particularly since we as the developers don't always know what the consumer really wants.
So the idea is to release a minimal version which provides the basic functionality, and then to get users on board as early as possible. And observing the users closely will tell you what the additional functionality should be.
This is very different from just throwing a buggy broken version into the user's hands. Buggy is not equal to minimal.
My main take away - Focus on building the absolute basic functionality, but make it robust, non-buggy. Release it when you know it runs without too many crashes. Even though it doesn't have all the functionality that you would be proud of. Then observe the users, and iterate often to add incremental functionality.
Here is a set of learnings from Paul Graham on why startups succeed / fail
And another set from Jason Fried on why startups fail.
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One startup that comes to mind is theglobe.com. They are essentially what MySpace and Facebook are today. Their failure is rooted in the dotcom bust of 2000, being that they went the IPO route and so forth. But I see it as a social media site as we know it today being way ahead of its time.
But for a textbook example of failing due to an early release, Pownce.com comes to mind. It was founded by Kevin Rose and band of his buddies. With his name attached it had all the typically SV press coverage it needed, but it failed because it was hard to distinguish what it was. Was it a Twitter clone, or a Facebook for co-workers? The execution of it fits the classic example of "let's get it out there, then think of a business strategy next".
I look at Pownce and it makes me realize that a startup, on launch, should solve exactly one problem first, and that problem should actually exist in the real world. They could have focused on a niche, such as office co-workers. When Google created a search engine, they did so to solve the problem that "search isn't smart enough, let's make it smarter".
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This one is infamous, though probably not the type of software you are looking for
One of the problems with your question, Jason, is that many of the failed releases we know about are because they are companies we know and which exist today, so the data will be skewed to show that releasing early is not so bad - companies can survive.
The companies that fail after their first (too early) product launch are not going to be remembered for too long.
But this is still a good question. It certainly gathered a lot of discussion on Jeff's blog/SO blog.
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Sorry, don't have any specific examples to point to, but certain ideas come before their time. It may be hard to gauge whether it's time for your idea, but you can try to get a sense by looking at the cost of some fundamental materials you need to build.
Some examples - Apple Newton was a great device that just was ahead of its time - its price point / interface / speed wasn't such that became a huge hit. If it was designed today (and I am sure the rumored Apple Pad is a grand-child of that), it would be much different. I am sure there were lots of video startups in late nineties, but bandwidth cost too much and the idea of user-generated content wasn't as ingrained in average user's mind. There are a lot of services right now that would not work 10 years ago, because, for example not enough people had computers or internet / broadband access. One of the reasons so much software is SaaS now is because you can assume that your users will be able to connect - doing that even in early 2000 might be a harder sell in some industries. Same thing with mobile - lots of people have been trying to do stuff in that space five years ago, but the technology was too klunky for people to really use.
So release early, release often is valuable. I read it as release as quickly as possible with a minimal feature set (that works well), so you can start getting users and learning more about what they are interested in, so you can iterate to your eventual product.
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"Release often" and "Iterate Fast" only work AFTER you reach a minimum viable product threshold. If you release a crab, you will get bad feedback that you deserve and unless you have enough resource & run way, you will die. Again, don't confuse rushing product out to market with reaching the minimum viable product threshold which vary drastically by businesses. For example, if you launch an enterprise focused product that needs to be sold by salesforce behind firewall, you better not release often. Also, would anyone want to buy infrastructure hardware and software that are missing some common features and constantly having updates? I don't.
One might argue that SaaS approach would enable customers to adopt this mantra but it's all relative. I guarantee you that the release cycle at Salesforce.com or even other brand new enterprise focused SaaS company delivering mission critical service is a lot longer than a consumer facing website that is launching another "community" site or twitter mashup app with no mission criticality.
The "lean" start-up mantra is admirable but you need to take it a grain of salt. Don't offload your sxxt to your customers. Define value and deliver them with the minimum viable product AND then iterate fast & release often.
I get antsy when some people keep saying "we have to release often!" Remember there is another much more time-tested advice...don't fix what's not broken.
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I can think of two languages that were ahead of their time and so they may have been seen as being released early, since developers weren't ready for them.
The first is Smalltalk. It was one of the first OO languages, but there didn't seem to be any need for developers to change their paradigm, so it languished for over a decade.
The other was Erlang. It was developed at the same time as Java, but it required a paradigm shift, and since Eriksson wasn't ready to actively promote it, it's release was probably too early, so it is relatively recent in becoming more popular, as other FP languages become more mainstream.
There are some ideas, such as Cuil, http://en.wikipedia.org/wiki/Cuil, that should have been better tested and they should not have set expectations so high. If they had just come out, and had people try it, then, if it was better than Google, which they could have iterated before their was such a bad experience with it, then it would have spread by word-of-mouth.
Oftentimes it seems that new ideas will fail because of unmet expectations or the idea is too new and people don't truly see the use of it.
An example of that is the Wardenclyffe tower, http://en.wikipedia.org/wiki/Wardenclyffe_Tower, by Nikolai Tesla. If he had finished it we would have had pagers in the 1920's, but it was too far ahead of it's time.
I think there is less risk from releasing too early than too late. Generally, if an idea is ready then there will be several competing products in development at the same time, and if you wait too long, perfecting it, before releasing, then you may have lost your chance at a large segment of the market.
I think if you follow the customer development approach then, as long as expectations weren't set too high, and you can react very quickly to problems and reasonable feature requests, then too early won't be a problem.
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I believe in Release often and Iterate Fast. Release early is subjective. If you release too early with bugs and missing important features, your product will get a bad rap and people will shy away from it and you will have to do damage control. When people visit a new site and get a bad first impression, it's hard to revisit the site in the future unless the site is getting a lot of good reviews, and which you are going to be aware of, which have to erase your first impression.
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I think there is also the strong possibility of some randomness and luck in the equation - things that can't generally be attributed to one reason or another why some site or product failed and a similar one took off.
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Sunday, March 14, 2010
Cloud rant
For the last two posts, I've had a pop at the term "cloud", I'd like to now explain my reasoning in more detail.
First, as always, some background information.
What we know
The transition from a product to a services world in I.T. is very real. It's happening now because of the confluence of concept, suitability, technology and a change it business attitude. Overall it's driven by the process of commoditisation and it is the very ubiquity of specific I.T. activities that makes them potentially suitable for volume operations. I say potentially because volume operations is only viable for activities which are both well defined and ubiquitous.
Fortunately ubiquity has a relationship to certainty (or in other words how well understood, defined and therefore certain an activity is) which is why these activities are suitable for provision on the basis of volume operations through large computer utilities.
Lifecycle
For many years I've talked about lifecycle and the evolution of business activities. Any activity goes through various stages from its first innovation (as per the use of computer resources in the Z3 in 1941) to custom built examples to products which describe the activity. Usually, the activity ends up becoming a ubiquitous and well defined commodity (assuming there are no natural limits or constraints).
During this lifecycle, as the activity becomes more defined in the product stage, service models can often arise (for example the rental model of the managed hosting industry for computing infrastructure or the early subscription like models of electricity provision). As the activity becomes more of a commodity the existence of these service models tends to lead to the rise of utility services (as with electricity provision).
An essential requirement for the growth of the utility model (and the type of volume operations necessary to support it) is that consumers view that what's provided is a commodity. It's little more than a cost of doing business and a standardised version is good enough.
The latter is why a change of attitude is critical in development of the utility service model. If, for example, consumers still view the activity as creating some form of competitive advantage (whether true or not), they are unlikely to adopt a utility model of standard services.
The change in attitude
Over the last decade the attitude of business towards certain I.T. activities has changed dramatically. Recently, a group of 60 odd CIOs & Architects highlighted that many of the I.T. related activities they undertook were commonplace and well defined, particularly across their industry & geography.
Now that doesn't mean they did things the same way, quite the reverse.
Taking just one activity, ERP, then all of these companies agreed that whilst they gain no competitive advantage in ERP, it was an essential cost of doing business. They also agreed that they all had their own customised processes for ERP which they invested heavily in. The shock was their agreement that these different processes provided no differential benefit. It was estimated that for this one activity alone, across this small group of companies, then $600 million p.a. was spent maintaining differences which provided no value.
By reducing customisation through the provision of ERP as standardised services, then each company would significantly benefit in terms of cost savings. Standardisation of processes and removing costs associated with customisation is seen as one of the major benefits of the transition from an "as a Product" to an "as a Service" world.
Let's be clear here, "as a Service" was considered shorthand for "provision of a commodity activity through standardised services via a competitive marketplace of computer utilities". These companies were not looking for an outsourcing arrangement for a highly customised service for their needs, they were looking for a commodity to be treated as a commodity.
The concepts of computer utilities offering elastic and infinite supply on demand, provision of activities through services and commoditisation are all tightly coupled.
The benefits & risks of "cloud"
The benefits of this shift towards service provision via large computer utilities has been discussed extensively for the last 40 years :-
• economies of scale (volume operations)
• focus on core activities (outsourcing to a service provider)
• pay per use (utility charging)
• increased consumer innovation ( componentisation)
However, one critical benefit that gets missed is standardisation itself.
The risks associated with this change (ignoring the disruptive effect on the product industry) can be classified into transitional risks (related to the change in business relationship) and generic outsourcing risks. I've categorised these below for completeness.
Transitional Risks
• Confusion over the new models.
• Trust in the new providers.
• Transparency of relationships.
• Governance of these new models (including auditing, security & management).
• Security of supply
Outsourcing Risks
• Suitability of the activity for service provision.
• Vendor lock-in (& exit costs).
• The availability of second sourcing options.
• Pricing competition.
• Loss of strategic control.
Transitional risks can be mitigated through standard supply chain management techniques. For example with electricity we often combine both public and private sources of provision (a hybrid option). However outsourcing risks require the formation of competitive marketplaces in order to mitigate. Whilst the latter is a genuine concern for companies, even without these marketplaces the benefits of this change are still attractive.
The problem with the term "Cloud"
This change in I.T. is all about standardised service provision of commodity activities through a competitive marketplace of computer utilities. The notion of utility conjures up easily understood and familiar models.
Few would have a problem in understanding how access to a standardised form of electricity through a marketplace has allowed for a huge range of new innovations built upon consuming electricity. Few would have a problem in understanding how the providers themselves have sought new innovative ways of generating electricity. Few would ever consider electricity itself as a form of innovation, to most it comes from a plug and it is critical that it is standardised.
The problem with the term "cloud" beyond being fuzzy, it is often used to describe this change in I.T. as something new and innovative. The term helps disguise a fundamental shift towards a world where the bits don't matter and it's all about services. The term allows for all manner of things to be called cloud, many of which have little to do with the standardisation of an activity and its provision through utility services.
You could easily argue the term is misleading as it encourages customisation and distracts the consumer from what should be their focus - standardised services through a competitive marketplace of computer utilities.
Alas, as I said we ALL have to use the term today because of its momentum.
At Ubuntu we focus on commodity provision of activities (common workloads), providing our users with the technology to build a private computer utility (nee "Cloud", as part of a hybrid strategy), the adoption of the defacto standard of EC2 & S3 and we also provide all the technology as open source to encourage the formation of competitive markets.
We use the term "cloud" because it's what customers, analysts and others expect to hear. This of course doesn't stop us from explaining what is really happening and busting the "cloud" myths that exist.
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Mozilla Service Week: How to help!
Mary Colvig
1
Wondering how you can get a head start on Mozilla Service Week (Sept. 7 – 21, 2009)? You can roll up your sleeves and help an organization in need of technology-related service now or help get the word out! This summer it will be critical to not only expose Mozilla Service Week to would-be volunteers worldwide, but help identify and approach non-profits or local organizations that can use our help.
That’s where you come in — the Mozilla community has always been adept at spreading the word! Help drive thousands of privileges to serve and hundreds of opportunities by taking a few moments to promote Mozilla Service Week. Here’s how:
• Download site badges, banners, and buttons to add to your blog, your social network profile, or your email signature.
• Download a Mozilla Service Week flyer. Print it out and hand it out at a local event or post at work, at school, or at your community center.
• Start planning your service activity and challenge your friends to join you using PledgeBank.
• Get the word out by posting news, video or pictures on your blog, twitter, or social network site. Tag your posts with “mozservice09″ so they’re easy to find.
• Share your story of what you’re planning to do for Mozilla Service Week here or on your favorite social networking site.
• Flaunt your support for Mozilla Service Week with a customized Persona, a skin for Firefox.
Everyone should have the opportunity to know how to use the Internet, have easy access to it, and have a good experience when they’re online. So if you have a talent for writing, designing, programming, developing, all-around technical know-how or a knack for spreading the word, join the Mozilla Service Week effort today.
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Users/KevinWan
Info
Search:
Hello.
I own a little restaurant and bar in town.
During the warmer months in Davis, I book live shows 3-4 nights a week.
Many people just know me as "The Quizmaster" from a weekly Trivia Night on Tuesdays. I write the quiz, ask the questions, grade the papers, and make fun of the answers and scores. It's sometimes obnoxious, often pretentious, mostly fun. If you have a good question, feel free to let me know so I can take credit for it as my own.
You can email me if you want. I might even reply.
Comments:
Note: You must be logged in to add comments
2012-08-08 16:04:38 Thanks! Yeah, I like it a lot so far. I haven't been by when they've been out grilling since moving in, but I'm looking forward to checking that situation out. And they've got a surprisingly solid beer selection. I also liked the pastries at Stonegate quite a bit this weekend. It's a great little shopping center. —TomGarberson
2012-08-08 18:46:03 Hi —StevenDaubert
2012-12-27 00:19:47 When is Sophia's going to start serving drinks in decanters? The time has come! —JeffSpeckles
2013-02-13 14:56:26 "Gnomonic device" - well played. —TomGarberson
This is a Wiki Spot wiki. Wiki Spot is a 501(c)3 non-profit organization that helps communities collaborate via wikis.
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CELinux 040304 Release
From eLinux.org
Jump to: navigation, search
This page describes the CELinux source tree currently under construction.
Contents
Integrated Tree
See http://tree.celinuxforum.org/source/celinux-040304.tar.bz2
Supported Platforms:
Supported Platforms
i386 generic
VIA Eden board
TI OMAP Innovator
Renesas SH7751 board
Toshiba RBXTX4927 board
Patchset File
CELinux is also provided in patchset form so that individual technology patches may be examined, modified and used independently from the base source tree.
See http://tree.celinuxforum.org/source/celinux-040304.patchset.tar.bz2
To apply the patches, follow these instructions:
- download the base kernel (see the link in the table below)
- download the patchset tarfile (see the link above)
- unzip and untar the patchset tarfile (tar -xjvf celinux-040304.patchset.tar.bz2)
- run the "tpm" command from the patchset file:
patches.release/tpm -i linux-2.4.20.tar.bz2 -f patches.release/patchlist -o celinux-040304
Base Kernel
The base kernel is Linux version 2.4.20 from kernel.org.
See http://www.kernel.org/ for details.
Sources List
Kernel Version .
http://tree.celinuxforum.org/source/linux-2.4.20.tar.bz2 2.4.20 see http://www.kernel.org/
Patch Donor Patch Status
base-2.4.20-8.patch Sony/Panasonic baseline patch (see CELinux_031030_Release)
ulinux-i386-refactored-01.patch Lineo Solutions platform patch
ulinux-kgdb-i386-refactored-01.patch Lineo Solutions bugfixes for kgdb for i386
ulinux-kgdb_031219.patch Lineo Solutions introduce kgdb support - OK
ulinux-sh-refactored-1.patch Lineo Solutions Add Renesas SH support
toshiba-rbtx4927.celf20031030.patch Toshiba Add RBTX4927 support
arm-celf-integrator-040301.patch ARM Fix some integrator structure defs - OK
mips-lasat-clean-fix.patch Sony Fix a problem with 'make distclean' for mips
embedded-menu-1.patch Sony Added "embedded options" menu
preset-lpj-1.patch Sony Isolated preset LPJ patch - result of BTWG activity
extraversion-celf2.patch Sony change EXTRAVERSION to celf2
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Category:Duplin County, North CarolinaEdit This Page
From FamilySearch Wiki
Pages in category "Duplin County, North Carolina"
This category contains only the following page.
D
Media in category "Duplin County, North Carolina"
The following 2 files are in this category, out of 2 total.
• This page was last modified on 25 November 2012, at 03:54.
• This page has been accessed 342 times.
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Changes related to "Great Mills, Maryland"
From FamilySearch Wiki
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GlobalVoices in Learn more »
Kazakhstan Joins the Ban on Anti-Islam Film
This post also available in:
Malagasy · Miditra Ho Firenena Mandrara Ny Horonantsary Manohitra An'Islam I Kazakhstan
Español · Kazajistán se une a la prohibición de la película anti-Islam
Kazakhstan has joined a number of other countries in banning the controversial anti-Islamic film “The Innocence of Muslims.” On October 4, a court in Astana, the country's capital, declared [ru] the film “extremist” and ruled to ban the import and distribution of “The Innocence of Muslims” across Kazakhstan. Prior to the court ruling, the authorities had blocked access to the movie trailer on YouTube.
The film that many Muslims across the world view as offensive has been banned in Egypt, Libya, Malaysia, Indonesia, Pakistan, India, and Philippines. Among Kazakhstan's neighbors in Central Asia, as reported earlier by Global Voices Online, Afghanistan and Kyrgyzstan prohibited the distribution of the movie on their territories.
Although a series of violent bomb blasts attributed to Muslim extremists rocked the country in the past 12 months, indicating the growing influence of radical interpretations of Islam in this Central Asian nation, Kazakhstan has seen no angry riots or protests over “The Innocence of Muslims”.
In Kazakhstan, the latest country so far to ban the controversial film, Muslims comprise about half of the population. This image depicts the central mosque in Astana, the country's capital. Image by Flickr user Msykos (CC BY 2.0), uploaded June 6, 2008.
Many Internet users in the country support the court ruling. For example, commenting under a report about the ban on Tengrinews.kz website, an anonymous user wrote [ru]:
Правильно сделали, а то какой то отморозок выпустил фильм и мог довести до третьей мировой. Его запрет будет лучше для всех…
They've done a right thing. Some idiot produced the movie and could provoke the third world war. The ban is good for everyone…
Yet, some netizens suggest that there was no need to ban the film. Umka opined [ru] that Kazakhstanis were different from the nationals of those countries where the film had prompted angry demonstrations:
Никакой фильм меня не заставит выходить на улицу. Я знаю что это фильм…
No movie can cause me to take to the streets. I know that this is just a movie…
On the same website, another anonymous user proposed [ru] that the ban will make the film more popular by giving it higher exposure in the country:
Этот так называемый “фильм” – на него бы внимания никто не обратил… Так нет же – надо было на весь мир привлечь внимание запретами, чтобы и те, кому вообще пофигу – а таких в мире процентов 99 – обязательно посмотрели…
Nobody would have paid attention to this so-called ‘movie'… But what they've done is they drew global attention to the film by banning it and thus making sure that those who didn't care [about the movie] before, watch it…
The ban has also led some netizens in the country to focus on the film itself. Blogger Tenebrant likened [ru] “The Innocence of Muslims” to “a new form of trolling“, arguing that any reaction to the film should have been avoided:
Вообщем, я тут поразмышлял и понял, что это ни что иное, как новый тип троллинга. Вот сидит народ на всяких блог-платформах и от безделия и скуки пытается вызвать баттхерт своими откровенно тупыми комментариями, постами и высказываниями, а тут один чувак взял и затроллил треть мира.
I've been thinking and I've come to realize that this is nothing but a new type of trolling. Many people in general are spending time on blogging platforms, trying to cause butthurt by writing obviously stupid comments, posts, and statements out of idleness and boredom; and here you have one person who has trolled one-third of the world.
Others are thinking about the broader implications of the ban. Assel suggested [ru] that the court ruling to ban the film might be a prelude to further internet restrictions in the country:
Готовьтесь, теперь доступ к youtube перекроют =(
Get ready, they will now block access to YouTube =(
Kazakhstan's government blocks a number of websites it deems dangerous to the internal security of the country. It has also recently restricted religious freedoms in response to the rise of extremist Islam.
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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, 27 May 2005
ARE THERE ANY ADIDAS STRIPE PUNS LEFT?
The IPKat thanks Gino van Roeyen of Netherlands firm Banning for tipping him off about another adidas two stripe/three stripe case.
As no doubt all the IPKat’s readers know, adidas owns the three-stipes trade mark in the Netherlands. H&M used two stripes on its clothing in 1996. adidas’ response was to bring infringement action under (in Directive terms) Arts 5(1)(b) and 5(2) which ended up in the 's-Hertogenbosch Court of Appeal. However, adidas failed on both claims.
Regarding confusion-based infringement, the visual difference between three and two stripes would stand out to consumers and prevent them from being confused.
Regarding dilution-style infringement, the court followed the ECJ’s decision in Adidas v Fitnessworld, finding that under the relevant provision, the degree of similarity between a mark with a reputation and a conflicting sign must be such that the relevant section of the public establishes a link between the sign and the mark. Here the evidence produced by adidas did not establish this since it examined the position at present, rather than proving that consumers made a link between the two sets of stripes in 1996. However, the court acknowledged that the scope of protection of a trade mark is not static and can be affected by changes in circumstances.
The IPKat models the latest in adidas knock-off gear
The IPKat notes that the Dutch court seems to be taking a different approach to similarity of marks under Arts 5(1)(b) and 5(2) respectively, otherwise the failure of the Art.5(1)(b) would have killed off the Art.5(2) claim. This has got to be the right approach following Adidas v Fitnessworld.
More things to make adidas angry here, here, here and here
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