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Bibliography: The Oz Bookshelf (The Baum Bugle, Autumn 2001)
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Title: The Oz Bookshelf (The Baum Bugle, Autumn 2001)
Authors: Phyllis Ann Karr and David Maxine and Jane Pigney and Richard R. Rutter and Sean P. Duffley
Year: 2001
Type: ESSAY
ISFDB Record Number: 1176869
User Rating: This title has fewer than 5 votes. VOTE
Current Tags: None Add Tags
Publications:
Copyright (c) 1995-2011 Al von Ruff.
ISFDB Engine - Version 4.00 (04/24/06)
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The free office suite
Download LibreOffice
LibreOffice Linux - rpm (x86), version 3.6.4, Xhosa. Not the version you wanted? Change System, Version or Language
You need to download and install these files in order:
• Source code
LibreOffice is an open source project and you can therefore download the source code to build your own installer.
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Int. J. Mol. Sci. 2012, 13(5), 5700-5705; doi:10.3390/ijms13055700
Short Note
Development of Nine Markers and Characterization of the Microsatellite Loci in the Endangered Gymnogobius isaza (Gobiidae)
Center for Ecological Research, Kyoto University, Hirano 2-509-3, Otsu 520-2113, Japan
* Author to whom correspondence should be addressed.
Received: 5 April 2012; in revised form: 28 April 2012 / Accepted: 7 May 2012 / Published: 11 May 2012
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
Download PDF Full-Text [176 KB, uploaded 11 May 2012 11:27 CEST]
Abstract: Gymnogobius isaza is a freshwater goby endemic to Lake Biwa, Japan. They experienced a drastic demographic bottleneck in the 1950s and 1980s and slightly recovered thereafter, but the population size is still very small. To reveal dynamics of genetic diversity of G. isaza, we developed nine microsatellite markers based on the sequence data of a related goby Chaenogobius annularis. Nine SSR (Simple Sequence Repeats) markers were successfully amplified for raw and formalin-fixed fish samples. The number of alleles and expected heterozygosities ranged from one to 10 and from 0.06 to 0.84, respectively, for the current samples, while one to 12 and 0.09 to 0.83 for historical samples. The markers described here will be useful for investigating the genetic diversity and gene flow and for conservation of G. isaza.
Keywords: bottleneck; formalin-fixed samples; Gymnogobius isaza; Lake Biwa; microsatellite
Article Statistics
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Cite This Article
MDPI and ACS Style
Araki, K.S.; Nakazawa, T.; Kawakita, A.; Kudoh, H.; Okuda, N. Development of Nine Markers and Characterization of the Microsatellite Loci in the Endangered Gymnogobius isaza (Gobiidae). Int. J. Mol. Sci. 2012, 13, 5700-5705.
AMA Style
Araki KS, Nakazawa T, Kawakita A, Kudoh H, Okuda N. Development of Nine Markers and Characterization of the Microsatellite Loci in the Endangered Gymnogobius isaza (Gobiidae). International Journal of Molecular Sciences. 2012; 13(5):5700-5705.
Chicago/Turabian Style
Araki, Kiwako S.; Nakazawa, Takefumi; Kawakita, Atsushi; Kudoh, Hiroshi; Okuda, Noboru. 2012. "Development of Nine Markers and Characterization of the Microsatellite Loci in the Endangered Gymnogobius isaza (Gobiidae)." Int. J. Mol. Sci. 13, no. 5: 5700-5705.
Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
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Cells 2012, 1(3), 464-491; doi:10.3390/cells1030464
Review
Autophagy Contributes to the Death/Survival Balance in Cancer PhotoDynamic Therapy
Department of Biological and Environmental Science and Technology (Di.S.Te.B.A.), University of Salento, Lecce 73100, Italy
* Author to whom correspondence should be addressed.
Received: 15 June 2012; in revised form: 9 July 2012 / Accepted: 19 July 2012 / Published: 3 August 2012
(This article belongs to the Special Issue Autophagy)
Download PDF Full-Text [582 KB, uploaded 3 August 2012 10:51 CEST]
Abstract: Autophagy is an important cellular program with a “double face” role, since it promotes either cell survival or cell death, also in cancer therapies. Its survival role occurs by recycling cell components during starvation or removing stressed organelles; when damage becomes extensive, autophagy provides another programmed cell death pathway, known as Autophagic Cell Death (ACD). The induction of autophagy is a common outcome in PhotoDynamic Therapy (PDT), a two-step process involving the irradiation of photosensitizer (PS)-loaded cancer cells. Upon tissue oxygen interaction, PS provokes immediate and direct Reactive Oxygen Species (ROS)-induced damage to Endoplasmic Reticulum (ER), mitochondria, plasma membrane, and/or lysosomes. The main biological effects carried out in cancer PDT are direct cytotoxicity to tumor cells, vasculature damage and induction of inflammatory reactions stimulating immunological responses. The question about the role of autophagy in PDT and its putative immunological impact is hotly controversial and largely studied in recent times. This review deals with the induction of autophagy in PDT protocols and its dual role, also considering its interrelationship with apoptosis, the preferential cell death program triggered in the photodynamic process.
Keywords: photodynamic therapy (PDT); autophagy; cancer therapy; Atg proteins; immunogenic cell death; cell death
Article Statistics
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Cite This Article
MDPI and ACS Style
Inguscio, V.; Panzarini, E.; Dini, L. Autophagy Contributes to the Death/Survival Balance in Cancer PhotoDynamic Therapy. Cells 2012, 1, 464-491.
AMA Style
Inguscio V, Panzarini E, Dini L. Autophagy Contributes to the Death/Survival Balance in Cancer PhotoDynamic Therapy. Cells. 2012; 1(3):464-491.
Chicago/Turabian Style
Inguscio, Valentina; Panzarini, Elisa; Dini, Luciana. 2012. "Autophagy Contributes to the Death/Survival Balance in Cancer PhotoDynamic Therapy." Cells 1, no. 3: 464-491.
Cells EISSN 2073-4409 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
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Moderate Activity
Contributors : ari64
Analyzed 1 day ago based on code collected 1 day ago.
Activity on Yabause by ari64
All-time Commits: 14
12-Month Commits: 0
30-Day Commits: 0
Overall Kudo Rank:
First Commit: 09-Nov-2011
Last Commit: 21-Feb-2012
Names in SCM: ari64
Commit history:
Recent Kudos...
... for Yabause given by:
Guillaume
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Project Commits
Approximately one year of commit activity shown
Project Languages
Language Aggregate Coding Time Total Commits Total Lines Changed Comment Ratio
C 4m 11 198 7.8%
Assembly 3m 4 220 38.9%
CMake 1m 1 11 -
C++ 1m 1 2 -
All Languages 4m 14 431 23.6%
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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19 Bible Verses about Family Problems
Jeremiah 33:3 ESV / 33 helpful votes
Call to me and I will answer you, and will tell you great and hidden things that you have not known.
Ephesians 6:1-4 ESV / 28 helpful votes
Children, obey your parents in the Lord, for this is right. “Honor your father and mother” (this is the first commandment with a promise), “that it may go well with you and that you may live long in the land.” Fathers, do not provoke your children to anger, but bring them up in the discipline and instruction of the Lord.
Colossians 3:13 ESV / 26 helpful votes
Bearing with one another and, if one has a complaint against another, forgiving each other; as the Lord has forgiven you, so you also must forgive.
2 Thessalonians 3:6 ESV / 24 helpful votes
Now we command you, brothers, in the name of our Lord Jesus Christ, that you keep away from any brother who is walking in idleness and not in accord with the tradition that you received from us.
Luke 12:51-53 ESV / 19 helpful votes
Do you think that I have come to give peace on earth? No, I tell you, but rather division. For from now on in one house there will be five divided, three against two and two against three. They will be divided, father against son and son against father, mother against daughter and daughter against mother, mother-in-law against her daughter-in-law and daughter-in-law against mother-in-law.”
Matthew 5:4 ESV / 16 helpful votes
“Blessed are those who mourn, for they shall be comforted.
Psalm 23:1-6 ESV / 16 helpful votes
A Psalm of David. The Lord is my shepherd; I shall not want. He makes me lie down in green pastures. He leads me beside still waters. He restores my soul. He leads me in paths of righteousness for his name's sake. Even though I walk through the valley of the shadow of death, I will fear no evil, for you are with me; your rod and your staff, they comfort me. You prepare a table before me in the presence of my enemies; you anoint my head with oil; my cup overflows. ...
Proverbs 1:8 ESV / 15 helpful votes
Hear, my son, your father's instruction, and forsake not your mother's teaching,
Proverbs 13:22 ESV / 13 helpful votes
A good man leaves an inheritance to his children's children, but the sinner's wealth is laid up for the righteous.
Psalm 27:1-14 ESV / 13 helpful votes
Of David. The Lord is my light and my salvation; whom shall I fear? The Lord is the stronghold of my life; of whom shall I be afraid? When evildoers assail me to eat up my flesh, my adversaries and foes, it is they who stumble and fall. Though an army encamp against me, my heart shall not fear; though war arise against me, yet I will be confident. One thing have I asked of the Lord, that will I seek after: that I may dwell in the house of the Lord all the days of my life, to gaze upon the beauty of the Lord and to inquire in his temple. For he will hide me in his shelter in the day of trouble; he will conceal me under the cover of his tent; he will lift me high upon a rock. ...
Luke 14:28 ESV / 10 helpful votes
For which of you, desiring to build a tower, does not first sit down and count the cost, whether he has enough to complete it?
Proverbs 16:1-33 ESV / 10 helpful votes
The plans of the heart belong to man, but the answer of the tongue is from the Lord. All the ways of a man are pure in his own eyes, but the Lord weighs the spirit. Commit your work to the Lord, and your plans will be established. The Lord has made everything for its purpose, even the wicked for the day of trouble. Everyone who is arrogant in heart is an abomination to the Lord; be assured, he will not go unpunished. ...
Proverbs 21:20 ESV / 8 helpful votes
Precious treasure and oil are in a wise man's dwelling, but a foolish man devours it.
Psalm 127:1-5 ESV / 8 helpful votes
A Song of Ascents. Of Solomon. Unless the Lord builds the house, those who build it labor in vain. Unless the Lord watches over the city, the watchman stays awake in vain. It is in vain that you rise up early and go late to rest, eating the bread of anxious toil; for he gives to his beloved sleep. Behold, children are a heritage from the Lord, the fruit of the womb a reward. Like arrows in the hand of a warrior are the children of one's youth. Blessed is the man who fills his quiver with them! He shall not be put to shame when he speaks with his enemies in the gate.
Joshua 24:15 ESV / 8 helpful votes
And if it is evil in your eyes to serve the Lord, choose this day whom you will serve, whether the gods your fathers served in the region beyond the River, or the gods of the Amorites in whose land you dwell. But as for me and my house, we will serve the Lord.”
John 10:10 ESV / 6 helpful votes
The thief comes only to steal and kill and destroy. I came that they may have life and have it abundantly.
Proverbs 22:7 ESV / 5 helpful votes
The rich rules over the poor, and the borrower is the slave of the lender.
Genesis 1:26-27 ESV / 5 helpful votes
Then God said, “Let us make man in our image, after our likeness. And let them have dominion over the fish of the sea and over the birds of the heavens and over the livestock and over all the earth and over every creeping thing that creeps on the earth.” So God created man in his own image, in the image of God he created him; male and female he created them.
Romans 8:1 ESV / 2 helpful votes
There is therefore now no condemnation for those who are in Christ Jesus.
Suggest a Verse
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Changes for document China Open Source Week
From version 92.1
edited by Cedric Thomas
on 2012/09/27 20:11
To version 93.1
edited by Cedric Thomas
on 2012/11/05 21:46
Content changes
<H2 align="center"><a href="http:~//www.ow2.org/xwiki/bin/download/China-Open-Source-Week-2012/WebHome/COSW12-Prospectus-v5.pdf">[[image:http://skins.ow2.org/skins/skinOW2/images/PdfIconOSmall.png||style="position:relative;top:5px"]]Download the <b> Sponsorship Prospectus</a></b></H2>
== See the [[**Announcement**>>China-Open-Source-Week-2012.Announcement]] ==
== See the [[**announcement**>>China-Open-Source-Week-2012.Announcement]] ==
== Check out the [[**pictures here**>>http://www.ow2.org/view/Events.Photos/China_Open_Source_Week_2012Photos#Attachments]]==
Platinum Sponsors
Gold Sponsors
Silver Sponsors
Legal Notice
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This work is licensed under a Creative Commons Attribution-ShareAlike 3.0 United States License.
An XML version of this text is available for download, with the additional restriction that you offer Perseus any modifications you make. Perseus provides credit for all accepted changes, storing new additions in a versioning system.
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Citation URN: urn:cts:latinLit:phi1056.phi001.perseus-lat1:10.8.5
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Excel Software Announces AppProtect 3 for Mac and Windows
Printer-friendly versionPDF version
AppProtect applies protection to a compiled Mac or Windows application using a computer unique password or online serial number activation. Protect MAX multi-media applications, Unity games or Excel spreadsheets.
Henderson, NV, United States., March 13, 2013 - (PressReleasePoint) - Excel Software announced AppProtect 3.0 to protect Mac or Windows software. AppProtect applies protection with a human controlled or automated online activation process to a compiled application in minutes without programming. It supports MAX multi-media applications or Unity games. AppProtect 3.0 works with OfficeProtect 2.0 to generate a protected application from an Excel spreadsheet.
AppProtect 3.0 is LicenseCard enabled for drag and drop activation. Protected Windows applications can now passthru command line parameters. The developer interface has enhancements to save and reorganize records.
AppProtect wraps a Mac or Windows application with an activation process that requires a computer unique password or Serial Number on first launch. The software vendor can generate passwords from AppProtect or automate the process with an online activation server. Excel Software offers vendor accounts on the Safe Activation service or a vendor can self-host an activation server using WebActivation.
AppProtect on Windows has the ability to embed static data files into the executable with performance enhancements to support applications up to 1 GB in size with a faster launch time. For an application constructed from an interpreted language or that requires external data files, the unprotected files are no longer visible to the user. This process protects the source code, allows a secure license to be applied and simplifies the user experience since the entire application is distributed as one file.
AppProtect on Mac or Windows supplements the standard protection available to all applications with additional, optional layers of protection. Each protection layer works independently so the developer can customize the protection for a specific application.
AppProtect can be used to protect a standard Mac OS X application (.app), Windows executable (.exe) or Microsoft Excel spreadsheet (.xlsm). A Single User license is $295 on either Windows (XP, Vista, 7 or 8) or Mac OS X and includes royalty-free distribution rights for any number of protected products or licenses. The tool includes a printed and PDF User Guide with popup help screens that allow anyone to protect and license an application without programming skills.
Visit the Excel Software web site for demonstration videos, product information and secure online ordering for an integrated family of software protection and license management tools.
Excel Software
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User:LeeMartin
Family Trees
Default (view) (launch FTE)
people: 41
Martin-Strimple (view) (launch FTE)
people: 5559
Users Researching
Martin
Adams
Holcombe
Howland
Whitmeyer
Strimple
Pritchard
Sterling
I'm currently researching My Dad's side of the family. They came from France and I would like to learn more about the Martin family from France. I'm also interested in Adams, Holcombe, Pritchard, Sterling, Austin, Gorham and other lines. I'm facinated with my Puritan roots oddly enough. I started doing genealogy back in Elementary school but laid dormant for several years until I signed up on ancestry.com and have been going ever since. I have somewhat a large collection of primary sources from various probate courts, death certificates, birth records, etc. I finished the first six generations on both sides of the family. Now I'm trying to do further digging. I haven't started writing a family history until I can get more documents and more than likely it'll be a multi-volume work.
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Australian Bureau of Statistics
Celebrating the International Year of Statistics 2013
ABS Home > Statistics > By Release Date
6202.0 - The Labour Force, Australia, Preliminary, Feb 1996
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41 reputation
3
bio website abhi1one@tumblr.com
location India
age 25
visits member for 1 year, 10 months
seen Oct 21 '11 at 9:43
stats profile views 6
Hey I am abhishek, a consulting dev who loves to experiment and learn thing. Till now i have concentrated on just on input and processing of info in my learning my curve. But form now I am also going to list my learning and experimenting experience. Lately, I have enrolled my self on stanford open course learning offers for AI, ML and DB and am quiet enjoying my self revising concept of DB and learning new thing with AI and ML. Cheers.
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Connexions
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You are here: Home » Content » Social Change
About: Social Change
Module by: OpenStax College. E-mail the author
View the content: Social Change
Metadata
Name: Social Change
ID: m42948
Language: English (en)
Summary:
• Explain how technology, social institutions, population, and the environment can bring about social change
• Discuss the importance of modernization in relation to social change
Subject: Social Sciences
Keywords: Modernization, Social change
License: Creative Commons Attribution License CC-BY 3.0
Authors: OpenStax College (info@openstaxcollege.org)
Copyright Holders: Rice University (daniel@openstaxcollege.org)
Maintainers: OpenStax College (info@openstaxcollege.org), Sociology Cap (dcwill@rice.edu)
Latest version: 1.2 (history)
First publication date: Jan 30, 2012 9:52 am -0600
Last revision to module: Jun 4, 2012 5:17 pm -0500
Downloads
PDF: m42948_1.2.pdf PDF file, for viewing content offline and printing. Learn more.
XML: m42948_1.2.cnxml XML that defines the structure and contents of the module, minus any included media files. Can be reimported in the editing interface. Learn more.
Version History
Version: 1.2 Jun 4, 2012 5:17 pm -0500 by Sociology Cap
Changes:
initial content publication
Version: 1.1 Jan 30, 2012 2:54 pm -0600 by OSC Physics Maintainer
Changes:
Created module
How to Reuse and Attribute This Content
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• the title of the work: Social Change
• the Connexions URL where the work can be found: http://cnx.org/content/m42948/1.2/
See the citation section below for examples you can copy.
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We can’t let educators off the hook
Steve Dembo said:
I don’t see it as teachers spurning technology, or choosing not to take advantage of those new ideas and tools. I think most teachers don’t even realize that there’s a decision to be made. It’s not a matter of choosing the red pill or the blue pill… if you don’t know that there are even two pills available as options.
… A teacher that has never heard of Blabberize or Glogster or Prezi, has never been introduced to the new world of online applications that are available to them. They likely don’t follow blogs or listen to podcasts. They have probably never been to an EdTech conference or seen a TED talk. In short, they’re just ordinary, average educators who aren’t aware that there’s a whole other world that they have easy access to… if they just ‘take the blue pill’.
… I’m all for conversations about ‘big’ change. And yes, I agree, it’s not the technology, it’s the pedagogy. However, I also think that you need at least a minimal base to build from before you can have those conversations. And the vast majority of the educators in this country do NOT have that base yet.
Every day that I present for educators, I have a greater appreciate for how distorted the view is as seen through the eyes of a typical EduBlogger. In fact, the majority of the voices in the EdTech Community are so far ahead of the curve that it doesn’t even seem like their on the same road anymore. Most educators have never listened to a podcast, much less created one. They’ve never edited a wiki, much less started one of their own. So how on earth could they be expected to have a rational conversation about the impact new technologies are having on the skill sets our students need? Simply put, they can’t. The majority of the voices many of us listen to on a regular basis… actually represent just a tiny fraction of the educators out there. We’re the minority, the outsiders, the ones who talk using strange terms involving words with far too many missing vowels.
Darren Draper said:
the large majority of teachers that I know are very caring individuals that believe firmly in life-long learning. Most love teaching because making a difference in the lives of our youth can be the most rewarding profession on the planet. Most love kids, love community, and want to share. It’s not that they don’t want to try new things, it’s not that they’re lazy, and it’s not that they’re incapable. Rather, it’s that their priorities don’t always line up with those of other progressive educators in and out of the blogosphere. I’m not saying it’s right, but I am trying to describe the reality that so many in the blogosphere seem to misunderstand.
Darren also said:
Those content to lurk but still hesitant (or unable, for whatever reason) to contribute.
The fact of the matter is that there exist a very large number of effective educators that are simply not able to contribute in any significantly recurrent amount to online discussion. All told, it’s not that they’re incapable of participating and it’s not that they’re unwilling. Rather, this group maintains perceived silence online because their professional priorities prohibit them from spending the time or energy required to provide plausible contribution.
To which I say, NO, WE CAN’T LET EDUCATORS OFF THE HOOK. Whether they’re teachers or administrators or librarians or education professors, they have a voluntarily-assumed, paid responsibility to be relevant to the needs of children and education TODAY and to prepare graduates as best they are able for TOMORROW. ‘Professional priorities’ must be aimed at preparing students for the world as it is and will be. Otherwise, what are educators there for?
You can’t ‘firmly believe in life-long learning’ and simultaneously not be clued in to the largest transformation in learning that ever has occurred in human history. Those two don’t co-exist. Being a ‘life-long learner’ is not ignoring what’s going on around you; you don’t get to claim the title of ‘effective educator’ if you do this.
Look, it’s not like those of us who now ‘get it’ were born with this knowledge. We weren’t like this at the beginning. At some point in our personal histories we were the same as these educators that for some reason now get to be labeled as ‘unable’ to do this. Unable to do this? Poppycock. At no time in the personal computer / Internet era has this technology and social media stuff been easier to initiate. It’s not like back when you needed to know computer coding. Want to use a wiki? Click Edit; type; click Save. Want to leave a comment on a blog? Click on Comments; type in your name, e-mail, school web site, and comment; click on Save. There isn’t an educator alive who ‘can’t do that.’ They engage in similarly-easy activity every time they search or order something online.
The reason many of us now ‘get it’ is because we realized that the world is changing, we recognized our responsibility to our students and schools, and we dived in and learned as we went along. Changing inertia into momentum, not waiting for someone to hand us the answer, taking responsibility ourselves rather than blaming others for our own inactivity – that’s what life-long learners do. That’s what effective educators do. That’s what we owe our children.
If you’re a teacher / administrator / librarian / education professor that somehow ‘doesn’t even realize [yet] that there’s a decision to be made,’ should you even be working in a school or university? Don’t our children and our school systems need and deserve someone who’s in a different place than you are? It’s one thing to still be a learner; heck, we’re all learners with this technology stuff. It’s another to opt out or not even recognize the choice. If we look at what our kids need, shouldn’t we replace you with someone else?
It’s not about us. It’s not about our personal or professional priorities and preferences, our discomfort levels, or any of that other stuff that has to do with us. It’s about our students: our children and our youth who deserve at the end of their schooling experience to be prepared for the world in which they’re going to live and work and think and play and be. That’s the obligation of each and every one of us. No educator gets to disown this.
We can’t let educators off the hook. Not a single one. So keep that fishhook firmly wedged in their mouths. Keep tugging them along on the line. Keep scooping them up in our nets. Feed them tasty tidbits if need be. Do whatever it takes to make this happen. But insist on them doing the same.
Image credits: My fish hook; Slide – Should teachers get to choose?
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Converting Data Table / Dataset Into JSON String
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Converting Data Table / Dataset Into JSON String (Unpublished)
JSON (Java Script Object Notation), is a light weight, easily understandable to read and write string. It is also easly parseable by machine. It is introduced on two structues A collection (key/value pair) And ordered list of values.
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Wikia
SRD:Rod of Nightmares
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Revision as of 06:37, August 11, 2009 by Surgo (Talk | contribs)
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This material is published under the OGL
NightmaresEdit
Anyone who comes within 20 feet of the wielder of this rod feels a grave sense of unease. Each person so affected must make a Will save (DC 17) or suffer the effects of a nightmare spell the next time he or she falls asleep. The wielder is immune to this effect. Three times per day, the wielder can utter a command word that causes the rod to emit a horrid, inhuman scream. Up to twenty of the closest creatures within a 30-foot radius who hear this terrible wail believe that their worst nightmares have become reality and suffer the effects of a wail of the banshee spell (DC 23).
Caster Level: 21st; Prerequisites: Craft Rod, Craft Epic Rod, nightmare, permanency, wail of the banshee; Market Price: 284,000 gp.
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SMALL FIRE ELEMENTALEdit
Small Fire Elemental
Size/Type: Small Elemental (Fire, Extraplanar)
Hit Dice: 2d8 (9 hp)
Initiative: +5
Speed: 50 ft. (10 squares)
Armor Class: 15 (+1 size, +1 Dex, +3 natural), touch 12, flat-footed 14
Base Attack/Grapple: +1/–3
Attack: Slam +3 melee (1d4 plus 1d4 fire)
Full Attack: Slam +3 melee (1d4 plus 1d4 fire)
Space/Reach: 5 ft./5 ft.
Special Attacks: Burn
Special Qualities: Darkvision 60 ft., elemental traits, immunity to fire, vulnerability to cold
Saves: Fort +0, Ref +4, Will +0
Abilities: Str 10, Dex 13, Con 10, Int 4, Wis 11, Cha 11
Skills: Listen +2, Spot +3
Feats: Dodge, Improved InitiativeB, Weapon FinesseB
Environment: Elemental Plane of Fire
Organization: Solitary
Challenge Rating: 1
Treasure: None
Alignment: Usually neutral
Advancement: 3 HD (Small)
Level Adjustment:
A fire elemental cannot enter water or any other nonflammable liquid. A body of water is an impassible barrier unless the fire elemental can step or jump over it.
Fire elementals speak Ignan, though they rarely choose to do so.
COMBATEdit
A fire elemental is a fierce opponent that attacks its enemies directly and savagely. It takes joy in burning the creatures and objects of the Material Plane to ashes.
Burn (Ex): A fire elemental’s slam attack deals bludgeoning damage plus fire damage from the elemental’s flaming body. Those hit by a fire elemental‘s slam attack also must succeed on a Reflex save or catch on fire. The flame burns for 1d4 rounds. The save DC varies with the elemental’s size (see the table below). A burning creature can take a move action to put out the flame. The save DC is Constitution- based.
Creatures hitting a fire elemental with natural weapons or unarmed attacks take fire damage as though hit by the elemental’s attack, and also catch on fire unless they succeed on a Reflex save.
Fire Elemental Sizes
Elemental Height Weight Burn Save DC
Small4 ft.1 lb.11
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Difference between revisions of "ECE497 Contributions and Project Status"
From eLinux.org
Jump to: navigation, search
(Project Status)
Line 61: Line 61:
|-
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| [[User:chris.good | Christopher A Good]]
| [[User:chris.good | Christopher A Good]]
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+
| [[Special:Contributions/Chris.good|contrib]]
| [[ECE497 Project Template | My Beagle Project]]
| [[ECE497 Project Template | My Beagle Project]]
| [https://github.com/goodca/ goodca]
| [https://github.com/goodca/ goodca]
Revision as of 04:32, 24 September 2012
Embedded Linux Class by Mark A. Yoder
Contents
Fall 2012
Project Status
Please edit this page and add your project to this list. Copy my ECE497 Project Template to your own eLinux page and include the title of your project in the name of the page.
Please make the list alphabetical by family name.
Take a look at what you and others have contributed.
Name Contributions Project git repository
Tom Atnip My Beagle Project atniptw
Greg Larmore My Beagle Project larmorgs
Jesse Brannon My Beagle Project brannojs
Xinyu Cheng My Beagle Project [1]
Bryan Correll contrib My Beagle Project Correlbn
Alex Drane My Beagle Project draneaw
Josh Dugan My Beagle Project duganje
Kevin Geisler My Beagle Project geislekj
Christopher A Good contrib My Beagle Project goodca
Ross Hansen contrib My Beagle Project Hansenrl
Michael Junge contrib My Beagle Project Jungeml
Xia Li contrib My Beagle Project xiali
Matthew Moravec My Beagle Project
Peter Ngo My Beagle Project ngop
Stephen Shinn contrib Project TBD shinnsm
Mark A. Yoder contrib My Beagle Project MarkAYoder
James Popenhagen My Beagle Project popenhjc
Elias White My Beagle Project whiteer
Ruffin White My Beagle Project ruffsl
Sean Richardson My Beagle Project Sean Richardson
Andrew Miller My Beagle Project millerap
Yue Zhang My Beagle Project Yue Zhang
John Lobdell My Beagle Project jtlobdell
Winter 2011-2012
Contributions
1. Yuming Cao
2. Yifei Li
3. Greg Harrison
4. Jack Ma
5. Guanqun Wang
6. Mona Yan
7. Mark A. Yoder
8. Michael Yuhas
9. Ziyi Zhang
10. David Zitnik
11. Alex Drane
12. Jesse Brannon
13. Greg Larmore
14. Michael Junge
15. Andrew Miller
16. Bryan Correll
Project Status
1. Mark A. Yoder, My Beagle Project
2. Mona Yan and Greg Harrison, Playstation Eye Audio with Qt
3. Yuming Cao and Ziyi Zhang, Node.js Weather Station
4. Yifei Li and Guanqun Wang, Play games using Kinect on Beagleboard
5. Michael J. Yuhas and Jack Ma, Multiple Partitions via U-boot
6. David Zitnik, Twitter Java Application
Embedded Linux Class by Mark A. Yoder
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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.
Sunday, 13 April 2008
Format shifting: the MBG responds
Last week, the IPKat belatedly notes, the Music Business Group unveiled its collective submission to the UKIPO on private copying and format shifting, in response to the proposed changes to copyright exceptions as recommended by the Gowers Review -- the most contentious of which is the proposal to implement an exception for format shifting without compensation. The MBG is an informal cross industry body comprising the BPI, AIM, BACS, BMR, MPA, MCPS-PRS, MMF, MPG, MU and PPL. According to the British Phonographic Industry (BPI) press release
"We acknowledge that consumers clearly want to format shift and also place enormous value on the transferability of music. Music fans clearly deserve legal clarity in this area as well as the freedom to enjoy any music they have legitimately obtained.
But it is not only music lovers who benefit here. Enormous value is derived by those technology companies and manufacturers who enable consumers to copy. UK creators and rights owners are legally entitled to share in this value – as they hold the exclusive right to reproduce their music – but are currently excluded from the value chain.
The UK IPO’s current recommendation also leaves the UK at odds with the rest of Europe. In every other major European territory, an exception for private copying is counterbalanced by mechanisms that compensate creators and rights holders.
...
To restore a balance of copyright – one that allows consumers to enjoy their music, that drives technological innovation, and reinstates music creators’ and rights owners’ place in the value chain – the MBG is proposing to UK IPO an easily-implemented, flexible, future-proofed and transparent solution: an exception subject to licence.
The purpose of this proposal would not be to legitimise the wholesale copying and sharing of music, but to allow consumers to transfer music they have purchased onto their portable devices, while ensuring that a fraction of the value is enjoyed by those who create music and invest in its creation. The licensing scheme would be restricted to copying in the offline world".
The IPKat notes the reasoned and measured tones of this response, which compare favourably with some of the more apocalyptic "end of the world" utterances that could be heard at an earlier stage of the debate. Merpel adds: it's certainly tidy-minded to go for a solution that is not out of step with the rest of Europe, but would the failure to achieve a pan-European solution create the sort of economic imbalances that the European Commission so fears, rather than mere injustices with which it feels it can cope?
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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.
Saturday, 28 June 2008
Judge not rash in psoriasis ruling
On Wednesday the Court of Appeal for England and Wales (Lords Justices Mummery, Jacob and Wilson) heard the appeal in Leo Pharma and another v Sandoz Ltd, a decision of Mr Justice Mann this March (see earlier IPKat post, "Dangerous to use common sense" Says Patent Judge, here). The Court of Appeal is not yet available on BAILII, though it has been briefly noted on the LexisNexis Butterworth subscription-only service.
Right: the IPKat is working on a new process for making calcipotriol monohydrate ...
Leo, the first claimant, held a patent for calcipotriol monohydrate, a new crystalline form of calcipotriol used to treat psoriaris, the second claimant being Leo's subsidiary. Sandoz, a big player in the generic pharmaceutical market, secured market authorisation for a cream containing the monohydrate version of the calcipotriol molecule, whereupon Leo roared "patent infringement!" and applied for an interim injunction to stop the distribution of the cream.
The question arose as to whether damages would be an adequate compensation for Leo if Sandoz were allowed to sell the cream up till the time of the trial, and as to the adequacy of a cross-undertaking in damages for Sandoz if that company were banned from selling a cream which, if it later turned out, they were allowed to trade in. On top of this, Leo's own financial difficulties were relevant, particularly in the light of its potential loss of sales and the need to reduce its own prices in order to combat the presence of a competitor in what would otherwise have been its monopoly market. Sandoz, on the other hand, wanted to protect itself against the loss of the benefit of being the first generic supplier to market the cream. Finally, the effect of the balance of convenience and the status quo fell to be determined.
Mann J allowed Leo's application. On the evidence, Leo would not adequately be compensated by damages and the balance of convenience meant that the injunction should be granted. Sandoz appealed, complaining that Mann J had erred in principle by taking into account the likelihood of Leo having to cut its prices before trial.
The Court of Appeal dismissed the appeal. In its view it was important to bear in mind precisely what it was that the judge had to consider. He did not have to decide on a balance of probabilities whether there would be price cuts if the injunction were not granted. His job was to undertake an entirely different exercise -- to consider the various possibilities that might happen before the trial, disregarding those possibilities which were fanciful. If there was any chance of a circumstance occurring, the judge was entitled to consider whether that circumstance affected the question of whether damages were an adequate remedy. That's what Mann J and his judgment could not be faulted.
The IPKat, who regarded the original decision as impeccable, naturally agrees with the Court of Appeal too.
Psoriasis here, here and here
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ECONOMIC APPROACH TO OPTIMIZING DESIGN PARAMETERS
W. Edgar Watt, Kenneth C. Wilson
Abstract
For coastal engineering works, as for other structures, the designer must search for the economic optimum point. This point represents the minimum in the sum of direct cost and cost of possible future damage. By setting up functional representations of these costs the optimum can be obtained directly. This approach is illustrated by models developed independently in the Netherlands and in Canada. At this stage the output of the models may be denoted as the 'perfect knowledge' optimum, in the sense that parameters of the cost functions are assumed to be known with complete accuracy. In the 'real world' case, however, the estimated values of the parameters will be subject to considerable uncertainty. It is shown that because of this uncertainty the 'real world' design optimum will generally be shifted to give a structure larger than that indicated by the 'perfect knowledge' assumption. The novel contribution of the present paper consists of analyzing this shift to obtain simple expressions for the apparent overdesign due to uncertainty and for the resulting cost increase. An illustrative example is presented.
Keywords
economic approach; design optimization
Full Text: PDF
This work is licensed under a Creative Commons Attribution 3.0 License.
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Quotation added by staff
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Say not you know another entirely till you have divided an inheritance with him. Lavater, Johann Kaspar
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Johann Kaspar Lavater (November 15, 1741 - January 2, 1801), was a poet and physiognomist.
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Quotation added by staff
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A big leather-bound volume makes an ideal razor strap. A thin book is useful to stick under a table with a broken caster to steady it. A large, flat atlas can be used to cover a window with a broken pane. And a thick, old-fashioned heavy book with a clasp is the finest thing in the world to throw at a noisy cat. Twain, Mark
This quote is about books - reading · Search on Google Books to find all references and sources for this quotation.
A bit about Twain, Mark ...
Samuel Langhorne Clemens (November 30, 1835 April 21, 1910), better known by his pen name Mark Twain, was a famous and popular American humorist, novelist, writer and lecturer.
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Have the courage to live. Anyone can die. Cody, Robert
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If you don't know how great this country is, I know someone who does; Russia. Frost, Robert
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Robert Lee Frost (March 26, 1874 January 29, 1963) was an American poet. Frost received four Pulitzer Prizes.
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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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The best way to procure insults is to submit to them. Hazlitt, William
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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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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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Mathematics alone make us feel the limits of our intelligence. For we can always suppose in the case of an experiment that it is inexplicable because we don't happen to have all the data. In mathematics we have all the data and yet we don't understand. We always come back to the contemplation of our human wretchedness. What force is in relation to our will, the impenetrable opacity of mathematics is in relation to our intelligence. Weil, Simone
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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°
Click here to buy this »
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There is no way to success in art but to take off your coat, grind paint, and work like a digger on the railroad, all day and every day. Emerson, Ralph Waldo
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212 - The Extra Degree
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God bless us every one! said Tiny Tim, the last of all. Dickens, Charles
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212 - The Extra Degree
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Click here to buy this »
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Much ingenuity with a little money is vastly more profitable and amusing than much money without ingenuity. Bennett, Arnold
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Click here to buy this »
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Quotes about choice
These are quotes tagged with "choice". You can also search for quotes containing the word choice.
"The more equally attractive two alternatives seem, the harder it can be to choose between them -- no matter that, to the same degree, the choice can only matter less."
Paradox, Edward Fredkin's on choice
"The highest order of mind is accused of folly, as well as the lowest. Nothing is thoroughly approved but mediocrity. The majority has established this, and it fixes its fangs on whatever gets beyond it either way."
Pascal, Blaise on choice
"If you choose not to decide, you still have made a choice."
Peart, Neil on choice
6 fans of this quote
"Choice strengthens all."
Prescot, Neal on choice
"As simple as it sounds, we all must try to be the best person we can: by making the best choices, by making the most of the talents we've been given."
Retton, Mary Lou on choice
"Inhabit ourselves that we may indeed do what we want to do."
Richards, Mary Caroline on choice
"Look for your choices, pick the best one, then go with it."
Riley, Pat on choice
"You see, it's never the environment; it's never the events of our lives, but the meaning we attach to the events -- how we interpret them -- that shapes who we are today and who we'll become tomorrow."
Robbins, Anthony on choice
"We can change our lives. We can do, have, and be exactly what we wish."
Robbins, Anthony on choice
"We are the only beings on the planet who lead such rich internal lives that it's not the events that matter most to us, but rather, it's how we interpret those events that will determine how we think about ourselves and how we will act in the future."
Robbins, Anthony on choice
"A man either lives life as it happens to him, meets it head-on and licks it, or he turns his back on it and starts to wither away."
Roddenberry, Gene on choice
"One's philosophy is not best expressed in words; it is expressed in the choices one makes. In the long run, we shape our lives and we shape ourselves. The process never ends until we die. And, the choices we make are ultimately our own responsibility."
Roosevelt, Eleanor on choice
8 fans of this quote
"I think there is a choice possible to us at any moment, as long as we live. But there is no sacrifice. There is a choice, and the rest falls away. Second choice does not exist. Beware of those who talk about sacrifice."
Rukeyser, Muriel on choice
"The Great Way is not difficult for those who have no preferences."
Saying, Zen on choice
"You cannot be anything if you want to be everything."
Schechter, Solomon on choice
"The perfect way is without difficulty, for it avoids picking and choosing. Only when you stop liking and disliking will all be clearly understood. Be not concerned with right or wrong, for the conflict between right and wrong is the sickness of the mind."
Seng-Ts'an on choice
"Every single moment of your life you must choose from a number of alternatives. What you choose determines where you will end up."
Sinha, Shall on choice
"I am not a sound bite person. I prefer to run at the mouth."
Sirtis, Marina on choice
"If you want to sing out, sing out, and if you want to be free, be free, cause there's a million ways to be, you know that there are..."
Stevens, Cat on choice
"Be careful the environment you choose for it will shape you; be careful the friends you choose for you will become like them."
Stone, W. Clement on choice
7 fans of this quote
"If there are things you don't like in the world you grew up in, make your own life different."
Thomas, David on choice
"You can do what you want to do. You can be what you want to be."
Thomas, David on choice
"All my life, whenever it comes time to make a decision, I make it and forget about it."
Truman, Harry S on choice
"There are always two choices. Two paths to take. One is easy. And its only reward is that it's easy."
Unknown, Source on choice
"Of all earthly creatures, humans alone have the power to choose."
Unknown, Source on choice
"Nine out of ten people who change their minds are wrong the second time too."
Unknown, Source on choice
"You are led through your lifetime by the inner learning creature, the playful spiritual being that is your real self. Don't turn away from possible futures before you're certain you don't have anything to learn from them. You're always free to change your mind and choose a different future, or a different past."
Unknown, Source on choice
"You have the power to think what you want. No matter what the circumstance."
Unknown, Source on choice
"There is an election going on all the time... the Lord votes for you and Satan votes against you, and you must cast the deciding vote."
Unknown, Source on choice
"You must give up the way it is... to have it the way you want it"
Unknown, Source on choice
3 fans of this quote
"No poet sings because he must sing. At least no great poet does. A great poet sings because he chooses to sing."
Unknown, Source on choice
"Everything is something you decide to do, and there is nothing you have to do."
Waitley, Denis on choice
"There are two primary choices in life: to accept conditions as they exist, or accept the responsibility for changing them."
Waitley, Denis on choice
19 fans of this quote
"Nine-tenths of the people were created so you would want to be with the other tenth."
Walpole, Horace on choice
"Whenever I have to choose between two evils, I always like to try the one I haven't tried before."
West, Mae on choice
5 fans of this quote
"For what human ill does dawn not seem to be alternative?"
Wilder, Thornton on choice
"When you can't have what you choose, you just choose what you have."
Wister, Owen on choice
"There has never been another you. With no effort on your part you were born to be something very special and set apart. What you are going to do in appreciation of that gift is a decision only you can make."
Zadra, Dan on choice
But wait... There are more: prev 1, 2, 3, 4 next
Take a look at recent activity on QB!
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Antoine Walker pleads guilty to felony in casino case
RedsArmyAdmin June 29, 2011 Uncategorized 4 Comments
Antoine Walker's financial implosion is now well documented. His NBA legacy will now always be the guy who made over $100 million and went broke.
And now, in a move that is either a step closer to rock bottom or putting his problems behind him… Antoine pleaded guilty to stiffing a casino
Pro-basketball player Antoine Walker pleaded guilty Tuesday to one felony count of passing a bad check stemming from his failure to repay about $1 million in gambling debts he owed to three Las Vegas casinos.
A sentencing date for Walker, who did not appear in court, was scheduled for Nov. 1 before Judge Valorie Vega.
The 34-year-old faces probation or one to four years in prison. Prosecutor Sam Bateman said he is not seeking prison time as long as Walker pays back the $750,000 he still owes.
As part of the negotiations, prosecutors dropped two other counts of passing bad checks.
This could be the step closer to rock bottom because if 'Toine doesn't pay back the $750,000, then he's going to jail. But he could also be closer to a recovery if he pays the money back, moves on, and starts living a normal life.
Antoine has been playing ball wherever he can. $750,000 is a lot of money. I'm not exactly sure where he's going to get it. Somehow, I still get the feeling this won't end well.
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Paul Pierce
GreenLight Madness: Final Four – Seed #2 vs Seed #14
The second final four matchup features two huge three-pointers at different yet equally important times. One was by The Truth, the other by Rondo. I know which one I would vote for (hint: the ECF, on the road, is far more significant). #2 Seed: Paul Pierce’s Cold-Blooded Three: The Celtics dropped the first two games [...]
October 3, 2012 Jay MrTrpleDouble10 Videos, Paul Pierce, Rajon Rondo 2
Photo Gallery: Celtics first practice in Istanbul
Doc Rivers wasted no time in getting the Celtics back out on the court. A few hours after a grueling 11-hour flight from Boston to Istanbul, they were back to business. Despite the lack of rest, KG and Darko were all smiles. Enjoy some photos of their practice session via Sina. [...]
October 2, 2012 KWAPT Avery Bradley, Brandon Bass, Celtics News, Darko Milicic, Dionte Christmas, Jared Sullinger, Jason Terry, Jeff Green, Kevin Eastman, Kevin Garnett, Paul Pierce, Rajon Rondo, Red's Army Multimedia, The Team 5
Pictures from the Celtics arrival in Istanbul
The Celtics arrived at their hotel in Turkey a few hours ago. I think the immediate plan involves some relaxation before an afternoon practice. I’m not sure if rookie Fab Melo is enamored with his arrival in a new nation: CSNNE’s Sherrod Blakely also shared a picture of his view: [...]
October 2, 2012 Chuck - Red's Army Celtics News, Paul Pierce 3
So it begins..
This is fantastic. Paul Pierce just tweeted this great team pic as the C’s embark to Istanbul, Turkey to begin the 2012 NBA Preseason. Check out KG on the far right with those glasses. Man this is going to be a fun season…UBUNTU! And we r off to Istanbul ill holla twitter.com/paulpierce34/s… — Paul Pierce [...]
October 1, 2012 KWAPT Celtics News, Paul Pierce, Red's Army Multimedia, The Team 8
Celtics Gangnam Style
A very creative Celtics fan put together this video set to PSY’s “Gangnam Style”. It features Shaq, Big Baby, the Celtics Dancers and other Celtics-past and present. Enjoy: [...]
September 29, 2012 KWAPT Celtics Dancers, Keyon Dooling, Marquis Daniels, Mickael Pietrus, Past, Paul Pierce, Rajon Rondo, Ray Allen, Red's Army Multimedia, Videos 3
Celtics Media Day: pics and kicks
Another Media Day has come and gone, and as usual, we saw some sweet kicks. Veterans like Paul Pierce brought out some great shoes, as did newcomers like Courtney Lee. Here’s Paul in his Nike “P2 V” from the 2008-09 season. They feature a replica of his “Gift/Curse” tattoo on them. We also saw Jeff [...]
September 29, 2012 KWAPT Avery Bradley, CeltKicks, Courtney Lee, Dionte Christmas, Fab Melo, Jason Terry, Jeff Green, Kevin Garnett, Paul Pierce, Rajon Rondo, Red's Army Multimedia 7
GreenLight Madness: Elite Eight Seed #5 vs Seed #29
Paul Pierce and Avery Bradley went head-to-head in the previous matchup and today they go right back at it. This time, it’s The Truth reaching a huge milestone versus AB’s monster rejection on Dwyane Wade. Will AB take down the captain this time? You be the judges. Seed #5 – Avery Bradley owns Dwyane Wade: Riding [...]
September 27, 2012 Jay Avery Bradley, MrTrpleDouble10 Videos, Paul Pierce 2
GreenLight Madness: Elite Eight Seed #2 vs Seed #7
The second matchup of the elite eight continues with two polarizing plays for two very different scenarios. Watch as The Truth executes some of the finest hero ball you’ll ever see, while Avery Bradley executes one of the best guard-attacks-superstar dunks you’ll ever see. #2 Seed: Paul Pierce’s Cold-Blooded Three: The Celtics dropped the first [...]
September 25, 2012 Jay Avery Bradley, MrTrpleDouble10 Videos, Paul Pierce 2
GreenLight Madness: Elite Eight Seed #1 vs Seed #9
We’re reached the remaining eight plays that you, the readers, have voted on in the 2012 GreenLight Madness tournament. The first matchup of the group will be interesting as the top seeded play by Rajon Rondo goes head to head with Paul Pierce’s dominating Game 2 performance in Atlanta. Previous results are also listed and [...]
September 23, 2012 Jay MrTrpleDouble10 Videos, Paul Pierce, Rajon Rondo 2
GreenLight Madness Sweet Sixteen: Seed #8 vs Seed #9
Just like the penultimate matchup of the sweet sixteen, the final matchup features Paul Pierce versus Rajon Rondo. It’s one of Rondo’s best assists of his career going against Pierce’s best playoff game of the year when he saved Rondo (via suspension) and carried the Celtics on his back, 2002 style. This should be a [...]
September 21, 2012 Jay MrTrpleDouble10 Videos, Paul Pierce, Rajon Rondo 3
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Recent blog entries for psychlotron
25 Jul 2006 (updated 26 Jul 2006 at 14:39 UTC) »
http://www.m-w.com/dictionary/robot
Main Entry: ro·bot
Pronunciation: 'rO-"bät, -b&t
Function: noun
Etymology: Czech, from robota compulsory labor; akin to Old High German arabeit trouble, Latin orbus orphaned -- more at ORPHAN
1 a : a machine that looks like a human being and performs various complex acts (as walking or talking) of a human being; also : a similar but fictional machine whose lack of capacity for human emotions is often emphasized b : an efficient insensitive person who functions automatically
2 : a device that automatically performs complicated often
repetitive tasks
3 : a mechanism guided by automatic controls
I'm going to Robobusiness next week. I'll get some pictures if I see anything cool. Anyone else going?
My site has a link to my final presentation for Spidar. This doesn't mean that I'm finished with the robot, it just means that I've accomplished what I set out to do for the class. Anyway, check it out. I'll have some walking videos up soon.
I have a new look for my site and a new look for my robot...more details there. There's also a new video. I've got some crude walking motions but not good enough, in my opinion, to post. Check it out.
I'm working on a piece of hardware that will interface with my software which will make servo sequencing much faster. Hopefully the time that I have spent making this controller will decrease the amount of time that I spend sequencing servo motions. I'll put some pics up soon.
Today is my presentation that marks a half-way point in my project.
20 Feb 2006 (updated 20 Feb 2006 at 22:33 UTC) »
I posted a screenshot of my current Spidar Sequencer. This software will allow you to sequence up to 16 servos with four positions each. I am currently giving this program a bit of a makeover though. The next version will look more like a Yamaha RM1X sequencer. I am modelling the software after this music sequencer for a few reasons. First of all, I am trying to carry over some of the cool things about musical editing to robotic movement sequencing because I have experience with that. Second, the RM1X and other similar sequencers are pretty intuitive pieces of equipment to use. Therefore, it should be pretty easy to open the Spidar Sequencer and start using it. Hopefully, it will be something that can be used for more than just my robot.
13 Feb 2006 (updated 13 Feb 2006 at 22:58 UTC) »
I posted a video on my site that shows my robot standing up. I just finished the body, which is made of foamed pvc, and attached the legs. I added some springs to simulate muscles and help balance the load. Next I'm going to put a second level on the body and try over-volting the servos a bit for some extra strength. Oh yeah, the DS in the video does nothing...just got done with some MKDS that's all.
I assembled Spidar's legs today. I have a video posted of one of the legs in motion. It's a bit jerky, but that's due to my unsteady hand on the controls(a set of VB sliders). Next, I will be cutting a body out of plexiglass and attaching the legs. Then the real fun will begin! My website for Spidar has a bit of a new look, too.
I've finished most of the code for my Servo Sequencer, which is based on a music sequencer and sampler. The program allows you to create four-position sequences for up to sixteen channels(servos). These groups of sequences can be assigned to six different buttons, like a sampler. This allows you to make walk, run, sequences. I also received my leg brackets in the mail today, which I will be assembling soon.
6 older entries...
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Skip to content
MMVR17: Shooting Prison Break
This is the second day of the Medicine Meets Virtual Reality 17 conference and the day started with a real surprise. They are shooting the Prison Break series outside the hotel. Those who were expecting to see some interesting reviews and slides please forgive me, but there have been only a few presentations and posters so far. So let’s see now how they are shooting Prison Break (I uploaded the images in better quality to Flickr):
At the elevator
At the entrance
I tried to get closer to the actors
They changed Hyatt to Panda Bay Hotel.
Michael Rapaport talks with William Fichtner
William Fichtner alone
It’s not that hard to shoot with such a background…
If you want to follow the conference live, please follow my account on Twitter or the #mmvr17 hash tag.
Feel free to join the discussion on Twitter and share your slideshows on Slideshare.net.
The next post will focus on the conference, I promise.
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Help Wikitravel grow by contributing to an article! Learn how.
Northern Sulawesi
From Wikitravel
Indonesia : Sulawesi : Northern Sulawesi
Jump to: navigation, search
Northern Sulawesi consists of the provinces of North Sulawesi and Gorontalo in Indonesia.
[edit] Regions
[edit] Cities
• Manado - the largest city and main gateway to the north
• Gorontalo - Gateway to the Togeans.
• Tomohon - cool off in the central highlands
• Bitung - the main deep-water port and access to the Lembeh Strait
[edit] Other destinations
• Bunaken - world-famous diving site
[edit] Understand
Inhabited by the Minahasa, Hulontalangio, Bantik, and Sangirese, much of Northern Sulawesi is a solidly Christian (mostly but not entirely Protestant) enclave in mostly Muslim Indonesia. A center of Dutch settlement in colonial times the region still retains many traces of Western influence.
[edit] Talk
The local language is Manado Malay (bahasa manado), also known as Minahasa Malay.
[edit] Get in
[edit] By plane
Manado has an International airport with numerous flights a week to Singapore, Kuala Lumpur, Davao (in the Philippines), and just about all the big cities in Indonesia.
Air Asia, Asia's budget airline now run three flights a week direct from Kuala Lumpur to Manado [Update as of October2010 this Service seems to be terminated/suspended]. Silk Air run direct from Singpore but a quite a lot more expensive.
[edit] By boat
• Manado has a harbour with ships going to and from the more Northern Islands (Sangir Talaud area).
• Bitung is the major port of North Sulawesi and you can get on board a Pelni ship to sail towards other area's of Indonesia. Some of the larger cruise ships that travel from Australia towards Thailand or other Asian countries also make a stop at Bitung.
[edit] By car or bus
You can travel by car or bus from South Sulawesi towards Manado, however due to security issues in Central Sulawesi this is currently not recommended. So, if you plan on travelling by land, check the local situation first!
[edit] Get around
[edit] By motorcycle
[edit] By car
Rental cars are available in Manado, but like most other areas of Indonesia, hiring a car with driver is advisable because of traffic woes and knowledge of local conditions. That wiggly line on the map may or may not be passable. A bilingual driver with a car in condition may cost approximately Rp 500,000 per day, or self drive may cost Rp 300,000 per day.
[edit] By mikrolet
You won't go far without seeing a torrent of light blue Mitsubishi Colts (aka bemos elsewhere) trolling the streets for customers. Though usually used within towns, you can take mikrolets intercity as well.
[edit] By bus
[edit][add listing] See
[edit][add listing] Do
Scuba diving is the main draw for tourists to North Sulawesi. Famous diving areas are:
• Bunaken National Marine Park
• Lembeh Strait, for it's excellent muck diving
• Bangka area, for it's brilliant soft coral and diversity in dive sites (from beginner to very advanced)
You can also visit the Minihasan Highlands to climb some of the volcanoes in the area. Taxis can be arranged from your hotel in Manado to the town of Kinilow and Tomohon. From here it is easy to reach the nearby peaks. Also worth a visit is the local market in Tomohon, not for the faint hearted locals choose from delicacies dog, bat and the rather boring pig (North Sulawesi is largely Christian).
[edit][add listing] Eat
Minahasan cuisine from North Sulawesi features heavy use of meat such as pork, fowl, and seafood. Woku is a type of seafood dish with generous use of spices, often making up half the dish. Ingredients of woku include lemongrass, lime leaves, chili peppers, spring onion, shallots, either sautéed with meat, or wrapped around fish and grilled covered in banana leaves. Other ingredients such as turmeric and ginger are often added to create a version of woku. Foreign colonial influence has also played a role in shaping Minahasan cuisine. Brenebon (from Dutch "Bruin" (brown) and "Boon" (bean)) is a pork shank bean stew spiced with nutmeg and cloves. Roast pork similar to lechon in the Philippines or pig roast in Hawaii is served at special occasions, especially weddings. Other unusual and exotic meats such as dog, bat, and forest rat are also regularly served in North Sulawesi region. Paniki is the bat dish of Minahasa. Manado is best known for Minahasan cuisine.
[edit][add listing] Drink
Being largely Christian, alcohol is a little easier to find than in some other parts of Indonesia. The local beer Bintang is between Rp 15,000 and 20,000 sold in resorts. Also worth trying is the local brews for something a little different.
[edit] Stay safe
The ethnic strife in central and south Sulawesi has not really affected the north. The Philippine rebel group Abu Sayyaf are said to operate in the northern islands near the Philippine border, but no attacks or kidnappings have been publicized.
[edit] Get out
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Australian Bureau of Statistics
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6202.0 - Labour Force, Australia, Preliminary, May 1999
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The Population Survey Monitor is an omnibus household survey vehicle which collects data on a wide and varied range of topics each quarter. Topics included in the August 1993 survey are Sport and Recreation Participation, Consumer Expectations, Women's Employment Patterns and Awareness of ABS Products and Services.
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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Manitoba PeriodicalsEdit This Page
From FamilySearch Wiki
Canada Manitoba Periodicals
Many local periodicals, including some for Manitoba, are indexed in:
The PERiodical Source Index is published by the Allen County (Indiana) Public Library Foundation in a joint effort with the Genealogy Department of the Allen County Public Library
PERiodical Source Index (PERSI). Ft. Wayne, Ind.: Allen County Public Library Foundation, 1987–. (Family History Library book 973 D25per; 1847–1985 on fiche 6016863 [set of 40]; 1986–1990 on fiche 6016864 [set of 15].) Indexes thousands of family history periodicals. Annual indexes have been published yearly since 1986.
• Indexes articles in over 2,000 periodicals.
• Provides subject access to about 500,000 articles.
• Includes nearly all English-language and French-Canadian genealogical periodicals.
• Indexes articles by locality, family (surname), and research methodology.
For further details, see the Periodical Source Index Resource Guide(34119).
Need additional research help? Contact our research help specialists.
Need wiki, indexing, or website help? Contact our product teams.
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• This page was last modified on 3 March 2013, at 05:22.
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Updated: 16 January 2004
Place Names Search: D'ENTRECASTEAUX REEF
STATE:SA
CUSTODIAN:SA
FEATURE CODE:REEF (Islands & Reefs)
STATUS:Official
LATITUDE: 31º 58' S [Decimal Degrees -31.974º]
LONGITUDE:131º 55' E [Decimal Degrees 131.931º]
EASTING:777000 [UTM zone 52, GDA 94]
NORTHING:6459000
FEATURE NUMBER:SA0017646
100K MAP No.:5234
NOTES: View this point in our products database.
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Light Poster
14Jan2011,19:02 #21
that's really a get article thanks for posting
Light Poster
17Jan2011,22:25 #22
yea really helpful stuff, an interesting insight.
Light Poster
7Mar2011,10:56 #23
Hello
Best tips for Link building.
Thank for sharing
Go4Expert Member
11Mar2011,17:57 #24
In my opinion the best way to getting more and more links is to do more and more forum posting.
Banned
12Mar2011,03:27 #25
Hello mate veru nice thread on link exchange. It is one ogf the good way to promote the website. Thanks for sharing such nice information. Take care.
Banned
15Mar2011,12:24 #26
Article Exchange is the most effective but most underused form of SEO today. It is ten times more effective than conventional link exchange.
Newbie Member
15Mar2011,15:38 #27
It can be done like this way. I totally agree with you. What is necessary is high quality content. Unless you get that, you won't get traffic. Yes, but your articles need some kind of marketing to attract visitors and make them know your good site. This can be achieved by submitting articles to forums and directories.
Banned
17Mar2011,02:43 #28
Hello mate your thread is really nice. Link Exchange is one of part of internet marketing or SEO. It increases PR of website by increasing back links.
Light Poster
18Mar2011,06:52 #29
Good information. Thanks.
Newbie Member
18May2011,16:56 #30
Thanks a lot for providing such a useful information.
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Bibliography: The Late Shift
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Title: The Late Shift
Author: Dennis Etchison
Year: 1980
Type: SHORTFICTION
Storylen: shortstory
ISFDB Record Number: 43741
User Rating: This title has fewer than 5 votes. VOTE
Current Tags: zombies (1) Add Tags
Awards:
Publications:
Copyright (c) 1995-2011 Al von Ruff.
ISFDB Engine - Version 4.00 (04/24/06)
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User:Marie-Eve Val
From OpenWetWare
Revision as of 11:29, 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
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[130] However, the tribe of Ephraim, when they besieged Bethel, made no advance, nor performed any thing worthy of the time they spent, and of the pains they took about that siege; yet did they persist in it, still sitting down before the city, though they endured great trouble thereby: but, after some time, they caught one of the citizens that came to them to get necessaries, and they gave him some assurances that, if he would deliver up the city to them, they would preserve him and his kindred; so he aware that, upon those terms, he would put the city into their hands. Accordingly, he that, thus betrayed the city was preserved with his family; and the Israelites slew all the inhabitants, and retained the city for themselves.
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Wolfram|Alpha Adds Pro Services For A Fee
Feb 8, 2012 • 8:25 am | (0) by | Filed Under Other Search Engines
Most people have no clue what Wolfram|Alpha is but it is one of the speciality search engines I use on a daily basis. I use it to look up data, facts and do some more advanced calculations.
The thing is - most people have no use for it. It is more for academics or power searchers.
Apple added it to Siri and it has accounted for 25% of Wolfram|Alpha's searches - so they are now getting on the map, thanks to Apple.
Wolfram|Alpha has announced they will be unveiling a "Pro" version of their search service for a $4.99/month fee. Yea, pay to use a search engine - but Wolfram|Alpha is no regular search engine.
What can you do in the paid Pro version of Wolfram|Alpha? Gary Price has those details:
(1) Analyze Your Own Datasets:
(2) 60 file formats can be uploaded from XLS, CSV all the way to images, audio files and more:
(3) Virtual extended keyboards.
(4) Visualized and interactive results using the CDF (computational data format).
"What's happening is you are giving freeform input, and Wolfram Alpha is creating a program on the fly to create the interactivity that you use," Chief executive Stephen Wolfram said.
Forum discussion at WebmasterWorld.
Previous story: Daily Search Forum Recap: February 7, 2012
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.
Irwin Gotlieb
From SourceWatch
Jump to: navigation, search
Irwin Gotlieb is the CEO of GroupM, a "media investment management" company and subsidiary of WPP, who has publicly opposed Google and eBay's entry into the business at the annual marketing conference of the Television Bureau of Advertising. [1] (Note the New York-based GroupM, the WPP subsidiary, is a different company from the New Jersey-based media and PR company Group M.)
Contact Information
GroupM Inc
498 Seventh Avenue,
New York, NY 10018
Website: http://www.groupm.com/output/Page7.asp
References
1. David Goetzl, "GroupM's Gotlieb Challenges Web Buying Schemes For Television", Media Daily News, April 13, 2007.
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Place:Cowlam, Yorkshire, England
Watchers
NameCowlam
Alt namesColetunsource: Domesday Book (1985) p 306
Colnunsource: Domesday Book (1985) p 306
Cowlam Villagesource: Gazetteer of Great Britain (1999) p 188
TypeInhabited place
Coordinates54.068°N 0.525°W
Located inYorkshire, England
Also located inEast Riding of Yorkshire, England
source: Getty Thesaurus of Geographic Names
source: Family History Library Catalog
Cowlam is an inhabited place.
Research Tips
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Wednesday, December 24, 2008
A Christmas Message
According to Bob Philips, there are three stages of man:-
• He believes in Santa Claus.
• He doesn't believe in Santa Claus .
• He is Santa Claus.
Festive greetings and a happy new year!
Tuesday, December 23, 2008
It's not who says it that matters ...
Though I've talked about commoditisation and worth in the IT industry for the best part of a decade, I consider myself a late arrival to the utility computing field (or what is now called cloud computing). I only actively became involved (as opposed to just talking about it and using virtualisation, large scale SANs etc) in 2005 when I directed my company towards building a utility computing service.
I was also a late arrival to the open source world, only becoming involved in 2000 when I ran Fotango. Furthermore, I was a late arrival to the field of 3D printing, only taking a real interest in the subject in the late 1990's.
I was late because lots of other people were involved much earlier, decades earlier in every single case.
However, some people are later than me. This doesn't mean that I'm right and they're wrong. This doesn't mean that I have some great insight and they have none. It doesn't even mean that I have some right of superiority. All it means is that I've been involved for longer and that act in itself is meaningless.
Good ideas come from any direction and unfortunately the field of cloud computing is just as awash with half-truths, thought leadership posturing and nonsense as it is with good ideas. There does appear to have been an unseemly scramble by some to set themselves up as the digerati of cloud computing, the purveyors of knowledge and the oracles of our time.
Don't let others decide for you what is right or good, decide yourself.
What I find uncomfortable are blog posts such as Daryl Plummer's and Reuven Cohen's follow on which could easily be taken as to mock the ideas of those who are late to a field (the instant experts, the pretenders vs contenders). Now, I've met Reuven and he seems a pleasant enough fellow but I don't agree with this approach of "I'm the expert" vs "Cloud posers".
As I've said before "in my simple world it's the idea that's important, not the source".
Monday, December 22, 2008
Congratulations
I read that Werner Vogels has been made InfoWorld's CTO of the year. Congratulations are much deserved.
Whilst Werner and the Amazon team might not have been the first to take utility computing from idea into practice, they have certainly been the most successful to date.
Their execution has been second to none and the award is justly deserved.
Maturity models for the cloud
A friend of mine in the cloud world, James Urquhart, who now blogs at CNET recently posted about cloud maturity models. It's worth a read.
I've added a comment, which I'll also leave here (a tidied up version and a mental reminder for myself to check that what I'm pressing is a preview and not a submit button.)
=== comment ===
Good post James,
I especially like "achieving an open marketplace is essentially cloud computing nirvana, and the ideal to which most enterprises should logically strive to achieve" but of course, I'll add onto this.
Such a nirvana will only be achievable (without the loss of strategic control and pricing competition to a technology vendor) if the standards which the marketplace is built upon are operational open sourced pieces of code rather than specifications (it's an old post from July'07 but it covers the basics).
Such open sourced standards (the equivalent of open design patterns, such as the open SDK for GAE) will allow competition and service innovation through implementation. The standards themselves will help encourage portability, the open marketplace you describe and hence consumer innovation through componentisation.
As for "I believe this open market is inevitable, as the economics are just too powerful" - well it's either going to be open or we will see government intervention in the field to force the market to behave in such a way.
You can create the illusion of open marketplaces with a proprietary stack but it is no more than an illusion.
Anyway, good post.
As far as maturity models go, well you've seen this before and though it's old and tongue in cheek, it does have some serious point to it.
Utility SaaS Maturity Model (USaaSMM)
(pronounced u'sass'em)
(click on image for larger size)
Congratulations on the new gig by the way. I'm looking forward to reading more and seeing how this develops.
Sunday, December 21, 2008
The cloud ... it's a triangle, damn it.
In 2006, I talked about the growth of utility computing and how distinct industries were being created. I used the ideas of componentisation to subdivide the computing stack into discrete layers.
In 2007, I formalised these three layers into hardware, framework and software. I used the following diagram at various conferences (from Web 2.0 to OSCON to FOWA) to describe utility computing as the transition of the computing stack from a product to a service based economy.
The shift of the computing stack
Then in early 2008, I added a bit more colour to my computing stack diagram to tart things up. But, alas the simple days of utility computing have been replaced by the cloud and its confusion of metaphors.
So, I was not that surprised to receive a very tongue in cheek email telling me that I was wrong about the cloud because it is a triangle (see diagram) .
How the cloud has changed ...
Apparently the source of this triangular insight is Michael Sheehan's post.
Oh no, did I got the colour, shape and names wrong? Who cares, it's not important unless of course the Appistry joke about Michael trademarking the triangle becomes true. In this case just use the rectangle (it's prior art and creative commons).
Alternatively, why not have a go and try experimenting with circles, dodecahedrons, the colour purple and paisley? Believe me you can't make any more of a mess than today's thought leaders.
As for my predictions for the future of cloud in 2009/10. Well, more and more analysts will start talking about the shift of IT from a product to a service based economy, there will be increasing user pressure for second sourcing options and growing demand for standards at various layers of the computing stack based upon operational open sourced code.
Don't ask me what name or shape it'll be, but as for the colour then judging by how much conflict there is in the cloud I'll take a stab at blood red.
Tuesday, December 16, 2008
Cloud, old idea but a new innovation.
There has been a lot of internet discussion recently over whether the cloud is anything new, if you're confused hopefully the following will help clarify the situation. Before getting into the nitty gritty, let's clear up some terms.
From Jan Fagerberg's work, Innovation is the first-ish attempt to carry out an idea into practice. It is the embodiment, combination, or synthesis of knowledge in original, relevant or new products, processes or services.
I say first-ish as it is notoriously difficult to determine who was the first person (or group) to put an idea into practice. As Eliot Sivowitch once postulated, in his Law of Firsts;
“Whenever you prove who was first, the harder you look you will find someone else who was more first. And if you persist in your efforts you find that the person whom you thought was first was third.”
An idea is an image or a concept or an abstraction. As John Locke said “it being that term which, I think, serves best to stand for whatsoever is the object of understanding when a man thinks”.
Discovery or invention are processes that result in the generation of new concepts or postulated entities or devices. Both of these processes involve serendipity, questioning and the use of analogy.
So how about the cloud then?
The cloud simply represents the shift of the computing stack (from the applications we write to the hardware we use) from a product to a service based economy. This shift is in a transitional stage at the moment, so you're equally likely to hear about product-like internal clouds as much as service-like external clouds. Consumers and vendors will take time to get used to this change.
However, the provision of this computing stack is not something new. Today, the use of computing hardware is not an innovation and the ideas of providing computing hardware as commodity-like products (standard servers) or as commodity-like services (through network connected virtualised machines) are several decades old. However, whilst the ideas are old, isn't the act of putting this into practice a relatively recent (the last decade or so)?
Well yes, it is and that's the point where confusion reigns because whilst computing infrastructure is not new nor is the provision of an activity as a service, isn't the combination of the two new?
In reality this is simply the natural development of an activity from a product to a service based economy. It doesn't repeat the original innovation of computing infrastructure, in much the same way that "car hire" doesn't recreate the original innovation of the motor car. It's less of an innovation and more of an expected evolution.
Unfortunately we use the term innovation everywhere and whilst you might think this doesn't matter, it does. The methods by which you manage an activity vary with whether it's an innovation or more commodity-like and not with whether it has this new feature (often called product innovation) or operational improvement (often called service innovation).
So is the cloud new? In practice it is, in concept it isn't. Is it an innovation, not really but lots of people will call it so.
I mention this also, because a friend recently described me as a thought leader on cloud computing. This is completely untrue and it would be fraudulent for me to even imply that this was the case. I might have been publicly speaking about commoditisation of IT over the past four years but as far as I'm aware, the real thought leadership in this field occurred decades ago.
Monday, December 15, 2008
A nice little earner ...
The U.K. government's use of a buy-out (re-capitalisation) strategy rather than a bail-out strategy has taken a lot of flak in the last month. I wholeheartedly support this Keynesian approach because it is a form of future wealth redistribution from the market to the state, assuming that we don't sell out too quickly when the market recovers (something which the laissez-faire vultures will obviously try hard to encourage).
Contrary to popular belief, most businesses are not the paradises of economic virtue and good management that they attempt to portray but are often haphazard structures prone to waste, incompetence, politics and simplified forms of management (often to ridiculous extremes). Dorian Gray would be proud.
It is the rare business that lasts fifty years without being seriously challenged by a couple of blokes in a garage start-up. If the military was run like most businesses, then we'd probably be on our twentieth regime change by now.
The government should be exploiting these weaknesses. The most obvious example of this, is the plans for more public building. Rather than making shareholders wealthy, we should be buying up the likes of Taylor Wimpey (on the cheap) and funnelling building projects through a part or wholly nationalised building company. Give people jobs rather than shareholders easy pickings.
It's worth remembering that money trickles up and not down, so if you want to get things going then start with those at the bottom of the social scale.
On the same note, the time has never been better to join the Euro. At such a low exchange rate, the potentials for investment and strengthening our manufacturing and export businesses are exceptional. Many pundits are asking the government to prop up the pound, however this form of interference is not only doomed to failure it also results in a transfer of wealth from state to market. Wrong way guys.
The debt burden maybe high but if we're buying out good future assets on the cheap then we're going to come out of this smelling like roses.
This is definitely not the continuing odour of the financial markets given the latest Ponzi scheme extravaganza. $50 billion in a pyramid scheme, talk about financial wizardry! You have to ask, who was auditing the books and signing off the accounts? Was it one of the big four again, the same gang who were also responsible for auditing many of the banks that have now collapsed.
We really should start asking ourselves whether we need a national owned auditing company and legislation that all company books have to be signed off by the government?
It'll be a nice little earner and we can always privatise it when the economy recovers.
Friday, December 12, 2008
For the people, by the people ...
The people of Sark have struck a blow for democracy. Not only did they decide to have elections but they also, rather peskily, voted for the people they wanted.
According to the BBC, this hasn't made the Barclay Brothers very happy and as advocate Gordon Dawes said:"Sark doesn't appear to want or appreciate the Barclays' investment and so it doesn't have it".
Hence 15% of the people of Sark are losing their jobs because the brothers didn't get the sort of democracy they wanted.
Naturally the brothers have the right to pull out of Sark, it's their choice. However, by doing so they throw down a gauntlet to free democracy. It is the right of every society to hold free elections without fear of recriminations or the economic equivalent of collective punishment. For us not to take up this challenge would only encourage other companies to bully governments and their people.
We too can exercise our own rights of choice. I will never knowingly buy any of the papers produced by the brothers companies including the spectator and the telegraph. I would ask you all to examine your conscience.
Tuesday, December 09, 2008
Why the cloud is unavoidable.
This is really old stuff, but I feel it's worth repeating.
The importance of "cloud" computing to business is far beyond simple cost savings, allocation of resources, capex to opex conversion and economies of scale. These are the obvious reasons for considering the cloud and they are little more than a follow my leader game caused by the commoditisation of IT. As more competitors adopt the cloud it will create cost competitive pressures for others to follow. Consumers of IT will need simply to adapt to this change in order to retain their relative competitive positions (this is known as the red queen effect).
It's a very old merry-go-round caused by the usual transition of the once novel and new field of IT infrastucture to more of a commodity. It will have all the trappings of past transitions from the cries of users for second sourcing options, the battles over standards and portability, the usual formation of exchanges, brokerages, marketplaces and the confusion created by vendors as they attempt to prevent their industry being commoditised.
However buried in all this is one truly interesting aspect known as componentisation. From the work of Herbert Simon's and his theory of hierarchy, we know that the speed of evolution of any system is directly related to the organisation of its subsystems. Take a moment to consider how fast it is to build an application today using a database and a development platform and then compare this to how slow it would be to build the same application if you had to first start designing the cpu, I/O and memory.
Componentisation can make an incredible difference and the more organised the subsystems are, the faster it is to build new and adapt old systems.
The computing stack, from the applications we write, to the platforms we build upon, to the operating systems we use are now moving from a product to a service based economy. This change can be clearly seen from a quick scan of what is hot today. Software as a Service, Web Services, Mashing up Data Services, Hardware as a Service, Service oriented architecture ... it's all the same thing.
The shift towards services will also lead to standardisation of lower orders of the computing stack to internet provided components. A consequence of this will be an acceleration in the speed at which new IT systems can be built and modified. The world of IT and business on the web is about to get a whole lot faster.
It should be remembered that the battle for survival of any company revolves around the non-trivial task of balancing the needs of adaptation (changes to the market, the red queen effect) and innovation (creative destruction). However, it is these two effects of adaptation (through maintaining cost competitiveness and matching increased competitor agility to adapt to changes) and innovation (an ability to bring new ideas to market more quickly) which will force any business to choose cloud.
You don't have a choice, you never did. The cat is well and truly out of the bag and the old way is in decline. If you think that "cloud" is simply about more efficient and lower cost provision of IT then prepare yourself for a rude awakening.
You might think that cloud computing won't effect you, but it will if you use any form of IT infrastructure. Unfortunately, at different layers of the computing stack, various companies are preparing a gilded cage for you to walk into.
You should already be thinking about the cloud and your first words to any vendor should be:-
• "Show me the alternative providers running a similar service not owned by you and how easy is it to switch between your service, their service and one I want to run myself?"
• "Am I dependent upon any particularly vendor with these services?"
Saturday, December 06, 2008
Promises, promises ...
In my quest to unfortunately come across the most hopeless companies in the world, I've found a new contender to the throne of the most disastrously hopeless. This is a company who's service or product is in my opinion more shoddy than Mercedes. Step forward ... Tiscali.
Ok, now I was asking for the impossible. I was asking for them to transfer my "superfast, reliable broadband" from one house to another. What I got was a superslow, unreliable service. If this broadband was a car it would be my old A-Class Mercedes.
So, here's the story:-
5th Nov : told by Tiscali that our broadband would be transferred in 10 working days.
12th Nov : phoned Tiscali, to check on progress. I was told that they had ordered the broadband for the old address. They apologised and said they would get it sorted.
19th Nov : no broadband, phoned Tiscali. I was told that they hadn't re-ordered the broadband as they had to wait for the old order to elapse. They said they would call back shortly and give me an update. They never called back. I phoned again and was told that the broadband was going to be connected on the 27th. I was assured that this was a confirmed date and this time it would happen.
27th Nov : no broadband, phoned Tiscali. I was told that there was a technical fault with BT and they were liaising with BT to get it sorted. The order was apparently placed yesterday but they said it would be completed on the 5th Dec. I corrected them on the date of order. I asked for the name of the person I was talking to which I received the immortal line "Sorry we're not allowed to give you our names because of the Data Protection Act". Wow, that's a new one.
... slowly, I'm started to get tired with this nonsense ...
27th Nov decided to double check the earlier story with Tiscali. New story found. Apparently the order hadn't gone through for 5th Dec. Talked to supervisor, apparently there was a problem with Tiscali's computer systems; it kept on putting orders into an error state. The system was telling him the order was only placed yesterday, however he fixed the problem and the order was now placed. He would call if there was any further problems and he said it wasn't BT's fault.
6th Dec : no broadband, phone Tiscali. Apparently there was a problem with BT and the order would be completed on the 19th December which seeing the order was placed only yesterday .... here we go again.
So from my view Tiscali blames other companies for its own faults, makes promises it doesn't keep, has problems it doesn't get sorted, completely fails to deliver its service and even its staff tell porkies - can't give a name indeed! Well, that's got to be more utterly hopeless than Mercedes.
Fortunately, I separately ordered cable broadband from Virgin which was done and installed in less than three days - thanks Virgin! The one last problem I have is to go through the task of cancelling my Tiscali account and getting them to refund the cash they owe me. I suspect that this is going to be painful.
Friday, December 05, 2008
Note for Self - that's a lot of talking.
For a number of years, I've been talking about how activities transition from innovation to commodity or more simply put how yesterday's hot stuff becomes today's boredom.
I undertook a piece of research into this field and found what appears to be an S-Curve relationship between the ubiquity (how common an activity is) and the certainty of an activity (approximated from the quantity of information published)
Now every presentation I give is slightly different. Each mashes up (thanks to Dennis for that) different parts from earlier presentations as well as new elements from my research. Well, I'm considering an entirely new style of presentation, so I've decided to write down the list of the themes I've covered and to use this as a basis for my new work. I thought, I'd keep a record of the list here (see below).
It's a lot, however there is a whole bunch of stuff that I've known about and barely touched upon. So next year, I'm going to provide a high speed, kitten based, mash-up of a presentation. It will contain an initial introduction and then fifty five themes, with the audience choosing which ones they want. I've got a nifty new way of doing this including bonus sections ... should be fun.
I've also been asked by numerous people whether I'm coming back to the U.S. to present again? I will probably do a presentation or two, on behalf of Canonical, for various cloud issues but regarding my management theory presentations that's strictly U.K / Europe based. The cost of travel and accommodation in the U.S. is simply too expensive.
Theme List
1. It's not just products that get commoditised but processes and all other forms of activities.
2. How an activity's characteristics change from innovation to commodity, no matter what it is.
3. Why management is complex and why there are no magic bullet solutions.
4. Why outsourcing often fails.
5. Why good management often leads to the death of a company.
6. How companies evolve between various stages from disorganisation to getting it together and finally "we need more innovation".
7. The inefficiency of organisational structure where similar types of activities are grouped together (such as marketing and IT) rather than the stages of an activity's lifecycle (transitional, commodity, first mover)
8. Why you need to constantly adapt to changes in the market place in order to just stand still and survive today (the business equivalent of the Red Queen Hypothesis)
9. The difference between commodification and commoditisation.
10. Why you need to constantly innovate in order to survive tomorrow (creative destruction)
11. Why commoditisation is both friend and foe.
12. Why change is the norm.
13. Why you need to constantly balance creative destruction and adaptation in an organisation and how this leads to a paradox of order and disorder. The innovation paradox.
14. Why Google's 20% rule was an efficient way of balancing this paradox and a continual source of competitive advantage.
15. Why marketing and branding for a vendor constantly creates a disadvantage for their consumers.
16. The shift of IT from a product to a service based economy (what we used to call utility computing many years ago, and now is unfortunately called cloud computing.)
17. Why open source standards are an essential part of our future.
18. Why organisations only exist in the intersection between people and activities and how traditional forms of management are inefficient.
19. The need for more dynamic methods of management.
20. The limits of ROI and why it is only suitable for certain stages of an activity's lifecycle.
21. Why you can't plan the future and why every organisation needs some chaos.
22. Why today's organisational structures often fail people and why innovation is not everyone's job.
23. How strategy varies with lifecycle.
24. Why innovation markets will only work for post-event inventions and discoveries.
25. The limits of open source and closed source technology and the domains where those techniques are particularly strong.
26. Why fortune favours the brave and how the future value of an activity is inversely proportional to the certainty we have about it.
27. Why transparency and portability matter in cloud computing.
28. Why you have no choice in the long run over whether you adopt cloud computing.
29. Why fuzziness in processes is valuable information.
30. Why single methods of project management (for example six sigma, prince 2 or agile) are inefficient and often harmful
31. Why getting it wrong doesn't matter as long as everyone else is getting it wrong.
32. Why web 2.0 is important and why now.
33. Why commoditisation leads to more innovation and a faster rate of evolution (extension from Herbert Simon's work on the Theory of Hierarchy)
34. The difference between innovation and product or service innovation (whether radical, incremental or disruptive)
35. Why KPI's and attempts to make management easy can seriously damage your wealth (extension from Ashby's law of Requisite Variety)
36. The three accelerators of innovation in web 2.0 - network effects, componentisation and bridging the divide between opportunity and ability.
37. How the growth of 3D printing and the commoditisation of manufacturing processes will create new languages.
38. Why IT organisations are under increasing organisational stress as they try to balance the needs of commoditisation and innovation.
39. Why competitive life just seems to get faster and faster.
40. Why the transition from one domain (such as products or services or bespoke) to another causes major disruption.
41. The difference between ideas, invention, discovery and innovation.
42. The effects and failure of organisations to deal with the commoditisation of human, physical and social capital.
43. How social networks allow us to challenge traditional views of management.
44. Why organisations need explorers, colonisers and town planners.
45. Why the role of the enterprise architecture is so important and never completed.
46. Why organisations should use both X & Y managers and something in between (the XY Manager).
47. The problem with patents and why the length of term of a patent should vary according to the innovation and how long society could be expected to independently discover it.
48. Why tailor made can be bad for the consumer.
49. Why failing and gambling are important management traits.
The other six ... well, I've got to have some surprises. However, just like the other stuff in this list, they are not new ideas just old ideas repackaged.
Thursday, December 04, 2008
Finally .... I have connection again!
After five weeks, I finally have connection again. There is lots I'd like to talk about but it's late, so I'll have to wait until this weekend.
However, I will note that there seems to be a growing argument that open standards will provide portability in the cloud world. This idea is seriously flawed and there is a far simpler way to ensure portability between one cloud environment and another. The solution is for both providers to offer an identical service.
The simplest way this can be achieved is if the standard for the service is not a written specification but an operational open sourced stack built with portability in mind. It doesn't matter what layer of the computing stack you're talking about.
I used identical because if the standard is an open sourced stack then there is nothing preventing a provider making operational improvements in the code whilst still maintaining exactly the same functionality. This is why GPLv3 and not AGPL is so important for the cloud world.
Back in 2006-7, I described this concept as an open sourced standard but you can think of it as an open pattern (thanks to Doug Neal) with competition around service provision. By providing the service as an open sourced standard, you can not only solve the issue of portability but also provide a faster means of implementing and hence achieving a defacto standard.
Of course a focus on service provision is in line with the shift of IT from a product to a service based economy, which is what cloud computing is really all about. I covered many of these subjects back at OSCON in 2007.
Whilst none of these ideas are new, the lack of portability is a result of the normal jostle of competitors in an emerging market. This will continue to provide a clear stumbling block for adoption and prevent the formation of functioning exchanges and brokerages.
I suspect that open standards will continue to be cited as a possible solution but the problem with these standards is that they define what can be done, not what can't be done. Product differentiation is the mortal enemy of portability.
Of course, you could achieve portability with a proprietary stack but only if consumers and providers are willing to sacrifice a major element of strategic control to a technology vendor. I wouldn't be surprised if Microsoft achieves this with Azure.
Of course, the simplest answer to all of these problems is open source. In less than a decade, I suspect you will find that the entire cloud world is either based upon open sourced stacks with provider competition around Price and QoS or we'll have ended up with government regulation.
Monday, December 01, 2008
Silence ...
A number of people have asked me why I'm being so quiet on Twitter and the Internet in general. Thank you for being concerned, however the simple reason is that I've moved home and my broadband provider (Tiscali) has taken almost four weeks to spectacularly fail in connecting my home to the internet.
As soon as I'm finally connected, I'll blog the whole sorry episode and play catch-up with the internet world.
For me, Tiscali is a name that does not conjure up the idea of "Superfast, reliable broadband" in the same way that Mercedes is a name that does not conjure up "trailblazing innovations".
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Welcome to the Kurobox Wiki
From NAS-Central Buffalo - The Linkstation Wiki
Revision as of 20:55, 9 July 2007 by Waite (Talk)
Jump to: navigation, search
Ku-ro-box(koo' ro boks), n. 1. a highly hackable headless PowerPC computer. It has Ethernet, USB, and an optional serial port. 2. Expert box.
wi-ki (wee' kee), n. a type of website that allows anyone visiting the site to add, remove, or otherwise edit all content, quickly and easily, often without the need for registration. This ease of interaction and operation makes a wiki an effective tool for collaborative writing.
News Flashes
Check out the News page for a list of all news.
Pricing Information Released
Revolution has confirmed pricing for the KuroBox Pro at $169.00 USD. Not a bad price whatsoever.
Sorry to all of you Europeans, but at the moment I do not have a pricing or release date for the Kurobox Pro. I will try to get one for you as soon as I can.
Hot off the presses
I Just received this email from Revolution
As I’m sure you know, Buffalo US is launching the Kurobox/Pro here in the US.
Well, after a spat with customs over our shipment, we finally got the first batch
in from our factories in Japan. KuroPro’s will be available for purchase this week.
KuroBox Pro documents pre-releaseed
Kurobox Pro US release delayed until July. But in the meantime......
Revolution has provided some documentation on the Kurobox Pro. This is preliminary documentation so translation errors may be fixed but the detail is good.
1. KuroboxPro User's Guide in English
2. Kurobox Pro specification document
3. Kurobox Pro microprocessor interface specifications
Getting Started
There are several applications and distros that can be used on the Kurobox. Check out the getting started page for a quick introduction on what can you do with your Kurobox.
Other areas of interest
How to get involved
Todo - Things that need to be done on this Wiki
HOWTO's
Please see documentation on customizing the interface and the User's Guide for usage and configuration help. <sp_ch>friend</sp_ch>
Personal tools
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TradeStrategyAnalyzer (1.0)
0 users
Trade Strategy Analyzer.
http://cran.r-project.org/web/packages/TradeStrategyAnalyzer
Simulates and visualizes different trading strategies on market data
Maintainer: Winnie Cheng
Author(s): Winnie Cheng, Tirto Adji
License: GPL (>= 2)
Uses: DBI, digest, ggplot2, googleVis, RJSONIO, RSQLite
Released almost 2 years ago.
Ratings
Overall:
(0 votes)
Documentation:
(0 votes)
Log in to vote.
Reviews
Related packages:(20 best matches, based on common tags.)
Search for TradeStrategyAnalyzer on google, google scholar, r-help, r-devel.
Visit TradeStrategyAnalyzer on R Graphical Manual.
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Do We Need Unit Testing?
0
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Do We Need Unit Testing? (Unpublished)
A recent poll examined how organizations perform unit testing. Despite the fact that the number of TDD adopters has grown nicely since the previous similar survey, unit testing is still widely conducted in a informal manner, when it is not simply ignored by developers.
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Generic Types and Inheritance (Unpublished)
Although I use Generics extensively, every once in a while it still throws me for a loop when dealing with complex generic parameters and inheritance. In this post I talk about a compilation error I ran into when trying to inherit a generic type including its generic parameters and a way to get around this particular issue.
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Scott County, IowaEdit This Page
From FamilySearch Wiki
United States Iowa Scott County
Guide to Scott County Iowa genealogy. Birth records, marriage records, death records, census records, family history, and military records.
Iowa
Online Records
Scott County, Iowa
Map
Location in the state of Iowa
Location of Iowa in the U.S.
Facts
Founded December 21, 1837
County Seat Davenport
Courthouse
Contents
County Courthouse
The Davenport Public Library has most of the courthouse records on microfilm. www.davenportlibrary.com/
The Davenport Iowa Family History Center has many local records on microfilm, also.
History
Parent County
1837--Scott County was created 21 December 1837 from Dubuque, Cook, and Muscatine Counties.
County seat: Davenport [1]
Boundary Changes
Record Loss
Places/Localities
Populated Places
Bettendorf
Blue Grass
Buffalo
Davenport
Dixon
Donahue
Durant
Eldridge
Le Claire
Long Grove
Maysville
McCausland
New Liberty
Panorama Park
Princeton
Riverdale
Walcott
Neighboring Counties
Cedar | Clinton | Muscatine | Rock Island County, Illinois
Resources
Cemeteries
Cemetery records can be found at the Davenport Public Library and at the Davenport Iowa Family History Center.
Census
Davenport Public Libary has put an index to the 1856, 1885, and 1925 Census for Scott County on the Internet. As of 29 April 2010, the 1925 index is still in data entry, and there are a stack of books several inches tall yet to be entered. If you'd like to help, contact Janet Greenlee of the the Scott County Iowa Genealogical Society (j dot .greenlee at hotmail dot com).
Church
Court
The Davenport Public Library has most of the local records on microfilm. www.davenportlibrary.com/
The Davenport Iowa Family History Center has many local records on microfilm, also.
Land
Local Histories
Maps
Military
Newspapers
The Davenport Public Library has the Davenport Daily Gazette on line, by clicking on Local databases.
Probate
The Davenport Public Library has most of the local records on microfilm. www.davenportlibrary.com/
Taxation
Vital Records
The Davenport Public Library has placed the Scott County Marriage Certificates: Index, pre 1836-c1925 on the internet.
Societies and Libraries
Family History Centers
Web Sites
References
1. The Handybook for Genealogists: United States of America,10th ed. (Draper, UT:Everton Publishers, 2002).
Need additional research help? Contact our research help specialists.
Need wiki, indexing, or website help? Contact our product teams.
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• This page was last modified on 23 April 2013, at 16:24.
• This page has been accessed 1,596 times.
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Research
Asymmetric directional mutation pressures in bacteria
Jean R Lobry1* and Noboru Sueoka2
Author Affiliations
1 Laboratoire BBE CNRS UMR 5558, Université Claude Bernard, 43 Bd du 11 Novembre 1918, F-69622 Villeurbanne cedex, France
2 Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309-0347, USA
For all author emails, please log on.
Genome Biology 2002, 3:research0058-research0058.14 doi:10.1186/gb-2002-3-10-research0058
The electronic version of this article is the complete one and can be found online at: http://genomebiology.com/2002/3/10/research/0058
Received:13 November 2001
Revisions received:18 June 2002
Accepted:15 August 2002
Published:26 September 2002
© 2002 Lobry and Sueoka, licensee BioMed Central Ltd
Abstract
Background
When there are no strand-specific biases in mutation and selection rates (that is, in the substitution rates) between the two strands of DNA, the average nucleotide composition is theoretically expected to be A = T and G = C within each strand. Deviations from these equalities are therefore evidence for an asymmetry in selection and/or mutation between the two strands. By focusing on weakly selected regions that could be oriented with respect to replication in 43 out of 51 completely sequenced bacterial chromosomes, we have been able to detect asymmetric directional mutation pressures.
Results
Most of the 43 chromosomes were found to be relatively enriched in G over C and T over A, and slightly depleted in G+C, in their weakly selected positions (intergenic regions and third codon positions) in the leading strand compared with the lagging strand. Deviations from A = T and G = C were highly correlated between third codon positions and intergenic regions, with a lower degree of deviation in intergenic regions, and were not correlated with overall genomic G+C content.
Conclusions
During the course of bacterial chromosome evolution, the effects of asymmetric directional mutation pressures are commonly observed in weakly selected positions. The degree of deviation from equality is highly variable among species, and within species is higher in third codon positions than in intergenic regions. The orientation of these effects is almost universal and is compatible in most cases with the hypothesis of an excess of cytosine deamination in the single-stranded state during DNA replication. However, the variation in G+C content between species is influenced by factors other than asymmetric mutation pressure.
Background
The G+C content of bacterial DNA ranges from around 25% to around 75% [1,2]. In contrast to the nuclear genomes of some vertebrates, the intragenomic heterogeneity of G+C content is generally small in bacteria [3,4], although there are some exceptions [5,6,7]. The wide interspecies variation and narrow intraspecies heterogeneity of the DNA G+C content was interpreted to be the result of differences in the bidirectional mutation rates between AT and GC pairs [8]. This kind of mutation pressure is said to be the G+C pressure. From Watson-Crick base-pairing rules [9], the G+C content is exactly the same for the two complementary strands in a DNA duplex, so the G+C pressure effects are symmetric with respect to the two strands. The effects of G+C pressure are dramatically increased in regions where selective pressure is weak: for instance, in the third codon positions in protein-coding sequences, where most substitutions do not alter the encoded amino acid, the average G+C content ranges from at least 7% to 95% between bacteria of different species [7,10,11]. It should be stressed that symmetric directional mutation effects are not restricted to purely neutral regions, and strongly influence amino-acid frequencies in proteins [12,13,14,15,16].
The two strands of a DNA duplex must have the same G+C content, but the different bases can still vary in frequency. For instance, one strand may have more G than C, say G/(G+C) = 0.8, and by complementarity the other one will have more C than G, G/(G+C) = 0.2 in this case. The strand-specific asymmetries in DNA have been the subject of considerable research [17,18,19,20,21,22,23]. Briefly, the theoretical predictions are as follows: when mutation and selection are assumed to be symmetric with respect to the two strands of DNA, parity rule 1 (PR1) holds where the following pairs of substitution rates are equal: rAT = rTA, rGC = rCG, rAG = rTC, rGA = rCT, rAC = rTG, rCA = rGT [20]. Here, rAT, and so on, are substitution rates of A → T, and so on, in a specific strand. Under the PR1 hypothesis, the intrastrand base composition at equilibrium is expected to be always in a particular state, the parity rule 2 (PR2) state, such that A = T and G = C within each strand [20,21,24]. This PR2 state is more than just an equilibrium point, because convergence towards PR2 continues even if the substitution rates are modified: there is no way to escape from the PR2 state under the PR1 hypothesis [25]. However, a bias in mutation or selection between the two strands of DNA can generate deviations from PR2 (that is, A ≠ T, or G ≠ C, or both). In this situation, the underlying cause, regardless of its mutational or selective nature, is asymmetric between the two strands.
Note that there is a serious confusion in the literature about substitution matrices that are 'symmetric' in the sense that the two strands evolve with the same pattern of substitutions (PR1 hypothesis), and 'symmetric' in the sense that the terms above and below the diagonal are the same (the SYM model, where rij = rji). The SYM model adopted previously by others, especially in the field of molecular phylogeny [26], assumes the equality of intrastrand mutation rates between any two bases: in contrast to the PR1 model, the SYM model does not incorporate DNA base-pairing rules. The SYM model has long been recognized as unrealistic because it predicts A = T = G = C at equilibrium without biases. The PR1 model is not a special case of the SYM model; rejection of the SYM model does not lead to rejection of the PR1 model.
The effect of asymmetric mutation pressure on the amino-acid content of proteins has been reported [27,28,29]. In terms of amino-acid composition, the diversifying selection on integral membrane proteins (enriched in hydrophobic amino acids) and on cytoplasmic proteins (enriched in hydrophilic amino acids) is generally the most important factor in within-proteome variability [30]. In Borrelia burgdorferi, however, the effects of this selective pressure are quantitatively less important than those resulting from asymmetric mutation pressure [31], stressing again that mutation pressure is far from being a negligible phenomenon.
Deviations from PR2 have been studied using many different approaches, including correspondence discriminant analysis [32], linear discriminant analysis with rotating windows [28], correspondence analysis applied to relative synonymous codon usage [27,33,34], analysis of variance [35], a comparative genomics approach [22,36,37,38], simple DNA walks [39], detrended DNA walks split by codon positions [40,41,42], skewed oligomer distributions [43], and moving windows plots with direct [44,45] or cumulated [46,47] or codon position-dependent [48] skew indices. Here we have used a simple graphical representation, very close to the raw data, that provides a straightforward visualization and interpretation of results.
Consider a complete annotated bacterial chromosome in which origin and terminus of replication have been located so that we know whether a subsequence is on the leading strand or the lagging strand at replication (Figure 1). Let A3, C3, G3, and T3 denote the base counts in the sense strand of a given coding sequence when only the weakly selected third codon positions are considered. Deviations from PR2 in third codon positions are characterized by G3/(G3+C3) and A3/(A3+T3) to draw PR2-plots [7].
Figure 1. Representation of the strands used for analysis in this paper. The leading strand for replication is black and the lagging one is shaded gray; note the switch at the origin of replication. The sense strand of coding sequences is represented by white arrows. The sense sequence of a coding region that is transcribed in the same direction as the motion of the replication fork is in the leading strand, whereas a sense sequence that is transcribed in the opposite direction is in the lagging strand. The strand used for large intergenic spaces, represented by large boxes, is always the published strand from 5' to 3'. The strand used for potentially transcribed untranslated spaces, that is, small intergenic regions among co-oriented genes, is represented by small boxes.
Figure 2a shows diagrammatically what would be expected under the null hypothesis PR1: the PR2 state should be observed. Although there will statistical fluctuations, spreading genes across the space indicated by each circle, the circles are centered at the midpoint of the plot (0.5, 0.5) which corresponds to the PR2 state. The range of dispersion is greater for the leading-strand group, because we have assumed here (for clarity, to avoid overlap in the figures), that there is an excess of coding sequences in the leading strand, as is usually observed in bacteria [48]. Figure 2b shows diagrammatically what would be expected when replication-associated mutation pressure enriches the leading strand in G and T. The leading-strand coding sequences, whose sense strand is, by definition, the leading strand for replication (Figure 1) are therefore also enriched in G and T. Thus, x1, their average G3/(G3+C3) value, is greater than 0.5, and y1, their average A3/(A3+T3) value, is less than 0.5. From DNA duplex base-pairing rules, if the leading strand for replication is enriched in G and T, its complementary lagging strand is conversely enriched in C and A. Therefore, we have a perfectly symmetric situation for the lagging-strand coding sequences, whose sense strand is, by definition, the lagging strand for replication (Figure 1), with x2 = 1 - x1 and y2 = 1 - y1. Note that the overall average is biased towards the leading-strand group because of the excess of leading-strand coding sequences, but that the midpoint (xc = (x1 + x2)/2, yc = (y1 + y2)/2) is not affected by this uneven distribution. Figure 2c shows diagrammatically what would be expected with asymmetric forces, such as codon usage that optimizes translation efficiency [49,50] or transcription-induced mutation pressure [51]. These affect the sense strand of both the leading and lagging coding sequences in the same direction, because the analyzed strand is always the sense strand. Note that the deviation from the null hypothesis could be higher [22] for the leading group because a greater number of highly expressed genes are found in this group [48], so that both transcription-induced mutation and translation-induced selection [52,53] could be higher in these genes. However, this effect was found to be negligible [35], and never produces a symmetric distribution around the center of the two groups, as in previous case (Figure 2b), because the two groups are expected to be moved in the same direction for transcription- and translation-induced biases, instead of in opposite directions for replication-induced biases. Figure 2d shows diagrammatically what would be expected when all phenomena are combined. The distance between the averages of the two groups,
Figure 2. Expected deviations in PR2 plots in coding sequences and small intergenic regions among co-oriented genes. (a) The null hypothesis: mutation and selection are symmetric with respect to the two DNA strands; (b) replication-induced mutation pressure is asymmetric; (c) transcription- or translation-associated mutation or selection pressures are asymmetric; (d) all forces in (b) and (c) combined are asymmetric.
is the contribution of replication-associated effects to PR2 deviations. The distance from the center of the plot to the midpoint of BI (xc; yc),
is the overall contribution of transcription- and translation-associated effects to PR2 deviations, where BI is the replication-associated bias.
Consider now a small transcribed untranslated intergenic region between two co-oriented coding sequences. Let A, C, G, T denote its base counts in the cis-sense, that is in the same strand as the sense strand of the two flanking coding sequences (Figure 1). As previously described, deviations from PR2 are characterized by using G/(G+C) and A/(A+T) values to draw PR2-plots. Expected effects in the cis-sense strand are the same as in the sense strand (Figure 2) except for translation-induced selection, which is absent in untranslated regions. Therefore, a difference in BII when compared with the analysis of coding sequences is evidence of translation-associated effects on PR2 deviations in coding sequences. Last, consider a large untranscribed intergenic region and note its base counts (A, C, G, T) in the published strand of the chromosome (Figure 1).
Figure 3a shows what would be expected in spacers under replication-induced effects alone when the leading strand is enriched in G and T. This is essentially the same as the situation for third codon position when there is only replication-induced mutation pressure (Figure 2b), because all bases are involved, not just those in protein-coding genes. The sole difference is that the leading and lagging group are now of similar size, because when working with the published strand, there are approximately the same number of intergenic regions in the two groups (Figure 1). Therefore, when BI is similarly oriented in the two analyses, this is an indication of a common underlying replication-induced mutation pressure, the difference in intensity being controlled by the difference in selective pressure between the two kinds of region.
Figure 3. Expected deviations in PR2 plots in large intergenic spaces (a) when replication-induced mutation pressure is asymmetric and (b) in an extreme case of asymmetric transcription-induced forces(see text for details).
In practice, however, it is impossible to verify from DNA database annotations whether large intergenic regions are completely free from transcription. Consider an extreme theoretical case in which all large intergenic regions are transcribed (Figure 3b). For simplicity, the whole intergenic region is assumed to be transcribed from the same strand: the whole intergenic region is either the template strand or the anti-template strand, but not a mixture of both. (The anti-template strand has the same nucleotide sequence as the transcribed RNA because the complementary strand is the template strand for transcription.) This simplification does not alter the reasoning, because a proper partition of intergenic regions would remove the mixed cases. In the leading-strand group, positioned to the right of the origin (Figure 1), there is an excess of anti-template strand for transcription because of the selection against head-on collisions between RNA and DNA polymerase complexes [54,55,56]. Therefore, the anti-template strand subgroup is bigger than the template one in the leading group, and by a symmetrical reasoning, on the left to the origin, the template strand subgroup is bigger than the anti-template one in the lagging-strand group. Figure 3b shows what is expected if transcription leads to an excess of G and T bases in the anti-template strand. Note that in this extreme case transcription effects yield BI ≠ 0, but the general pattern (Figure 3b) is completely different from replication-induced mutation pressure effects (Figure 2b), making it easy to discriminate between the two effects.
Results
Distribution of G+C content
Thanks to the availability of an increasing number of complete bacterial genomes with a high G+C content, there was a representative distribution of G+C content in the dataset (Table 1), and the values of G+C content in third codon positions (P3, as previously defined in [11]; see also Materials and methods), in first and second codon positions averaged (P12), and in intergenic spaces (GCIGR), were found to be consistent with previously known results [10,11] both in terms of their range of distribution and the correlation between them (Figure 4). Intragenomic P3 distributions of all species examined (all histograms are given in the tables in Additional data files under the 'GCorder' flag) are unimodal and narrow for a major class of genes comprising more than 90% of the total genes, although average P3 values differ widely between species. Some species show scattering of P3 distribution. In particular, a previous study of 254 genes in Pseudomonas [7] revealed a sizeable minor class of genes (28%) forming a trail toward lower G+C content (genes with P3 < 0.75). In our present study of 5,255 genes, the minor class of genes (with P3 < 0.75) is only 8% of the total, indicating that the previous sample was biased towards the minor class. Moreover, the width of the distribution (standard deviation) of the majority of genes is narrower in species with both extreme ranges of P3 than in those with middle ranges. These features of the P3 distribution are expected from the theory of bidirectional mutation rates and their equilibrium [8]. In this theory, mutation rates, u (GC → AT) and v (AT → GC), will lead to a G+C content (P3) at equilibrium of v/(u+v). The expected standard deviation is
Figure 4. Distribution of G+C content in the dataset. The G+C content of the 51 bacterial chromosomes under analysis was highly variable from 25.5% in the Ureaplasma urealyticum chromosome to 67.9% in Halobacterium sp., with a larger distribution in third codon positions (x-axis P3 from 11.2% to 88.0%) than in intergenic spaces (y-axis GCIGR from 15.5% to 63.4%) than in first and second position (y-axis P12 from 33.4% to 62.2%) as expected [10,11]. Regression slopes (or ε values) and their standard deviations for P12 and GCIGR were 0.343 ± 0.021 and 0.586 ± 0.024, respectively.
Table 1. List of 51 chromosomes under study
where b is an average of the number of third codon positions per gene [8].
Difference in G+C content between leading and lagging strands
Statistically highly significant differences (p < 0.01) in P3 between coding sequences located on the leading and lagging strands were found in 23 out of 43 chromosomes. In most cases (21 out of the 23) genes on the leading strand were found to have a lower P3 content than those on the lagging one. (Two exceptions were Mycoplasma genitalium, which is known to have a peculiar behavior with respect to G+C content [5,6], and Caulobacter crescentus.) As far as we know, this is the first time that such a systematic difference has been reported, but note that the differences were always very small. The maximum was only 0.035, for the difference in P3 content of leading and lagging strands of Vibrio cholerae chromosome 2, as compared to the 0.768 average P3 difference between Halobacterium sp. and Ureaplasma urealyticum, or the 0.050 accepted range of genomic G+C content polymorphism [57]. There was no significant correlation between the average P3 and the difference in P3 between the two groups of genes. A highly significant difference in G+C content between the leading and the lagging sequences was found in only five chromosomes for large intergenic regions, and three chromosomes for small intergenic spaces.
PR2-biases in coding sequences
Out of 43 chromosomes, the differences in PR2-biases between the leading and lagging groups were highly significant (p < 0.01) in 39 chromosomes for G3/(G3+C3) and in 34 for A3/(A3+T3) and in 32 chromosomes for simultaneously G3/(G3+C3) and A3/(A3+T3) (see Additional data files). In the PR2-bias-plot analysis, we found a general pattern of x1 >x2 and y1 <y2, as in Figure 2b, meaning that coding sequences in the leading strand had higher G3/(G3+C3) values and lower A3/(A3+T3) values than those on the lagging strand: leading coding sequences were enriched in keto-bases (G and T) in the third codon position compared to lagging coding sequences. There were, however, exceptions to this general trend: out of the 39 chromosomes that were highly significant for G3/(G3+C3), all had higher values in the leading strand, but out of the 34 chromosomes that were highly significant for A3/(A3+T3), three chromosomes did not follow the general trend (Lactococcus lactis and Staphylococcus aureus strains Mu50 and N315). Leading and lagging coding sequences are separated in PR2 plots as expected under replication-associated effects, and the leading group is almost always down right of the lagging group. However, the extent to which the groups are separated differs between species. The two most extreme species are B. burgdorferi, where the two groups of genes are completely resolved, and M. genitalium, where the two groups are almost completely overlapping (Figure 5). Other species with a spectacular difference in PR2 plots were Chlamydia muridarum, Chlamydia trachomatis and Treponema pallidum. Out of 43 chromosomes, the residual bias BII was in most cases oriented as in Figure 2c, with xc < 0.5 (all except Pyrococcus abyssi and T. pallidum) and yc < 0.5 (all except Thermotoga maritima). The relative contribution of replication-coupled bias (BI) to the total bias (BI plus BII) ranged from 6% (Mycoplasma pulmonis) to 86% (B. burgdorferi) with an average value of 52%.
Figure 5. Example of detailed results for two extreme cases with B. burgdorferi (left) and M. genitalium (right). (a)P3-P12 plot for coding sequences; (b) PR2-plot in third codon position; (c) PR2 plot in large intergenic spaces. Leading-group sequences are represented by black circles, and lagging ones by white circles.
PR2-biases in large intergenic regions
Out of 43 chromosomes, the differences in PR2-biases between the leading and lagging groups were highly significant (p < 0.01) in 36 chromosomes for G/(G+C) and in 34 for A/(A+T) and in 32 chromosomes for simultaneously G/(G+C) and A/(A+T) (see table in Additional data files). All the 36 chromosomes highly significant for G/(G+C) had higher values in the leading strand (that is, x1 >x2 as in coding sequences). Out of the 34 chromosomes highly significant for A/(A+T), 28 had lower values in the leading strand (that is, y1 <y2 as in coding sequences). Exceptions were Bacillus subtilis, Bacillus halodurans, L. lactis, S. aureus strains Mu50 and N315, and Streptococcus pyogenes. The distribution of intergenic regions in a PR2-plot was as expected under replication-associated effects (Figure 3a), and is particularly visible in the case of B. burgdorferi (Figure 5c). Unlike the third codon position, the leading and lagging groups clustered symmetrically around the center point of the PR2-bias plot. In intergenic regions, both xc and yc were always near 0.5, so that the residual bias BII was always close to zero. The relative contribution of replication-coupled bias (BI) to the total bias (BI plus BII) was therefore very high, on average 90%, and ranged from 88% (Helicobacter pylori) to 99.6% (B. subtilis) in the intergenic regions of species with significant BI values.
PR2-biases in potentially transcribed untranslated regions
Out of 43 chromosomes, the differences in PR2-biases between the leading and lagging small intergenic spaces among co-oriented genes were highly significant (p < 0.01) in 26 chromosomes for G/(G+C) and in 7 chromosomes for A/(A+T) and in 7 chromosomes for both G/(G+C) and A/(A+T) together (see table in Additional data files). All the 26 chromosomes with highly significant difference in G/(G+C) showed the same pattern as in third codon positions in coding sequences with x1 >x2. Of the seven chromosomes highly significant for A/(A+T), all showed the same pattern as in third codon positions in coding sequences with y1 <y2, except for B. subtilis and S. pyogenes. Out of 43 chromosomes, the orientation of the residual bias BII showed no clear tendency (only 31 chromosomes had xc > 0.5 and 23 yc > 0.5; the trend, if any, would be in the opposite direction, as in third codon positions). The relative contribution of replication-coupled bias (BI) to the total bias (BI plus BII) ranged from 10% (H. pylori strain 26695) to 93% (Thermoplasma acidophilum) with an average value of 58%.
Comparison of third codon positions and intergenic spaces
The differences between PR2-biases in intergenic regions between the leading and lagging strands (BI) were significantly and highly correlated with the PR2-biases in the third codon position as is evident from the regression coefficient of approximately 0.6 and correlation coefficient (r2 = 0.77) among 43 chromosomes (Figure 6). The correlation was still significant when the extreme B. burgdorferi was removed from analysis (r2 = 0.68). The 95% confidence interval for the value of the slope of the regression line [0.50-0.71] is less than 1, meaning that replication-associated biases were significantly smaller in intergenic regions than in third codon positions. This slope value was very close to the one obtained for the regression line between G+C content in intergenic regions versus third codon positions (Figure 4).
Figure 6. Comparison of the absolute contribution of replication-associated bias BI between intergenic and third codon positions.
Correlation between P3 and replication-associated biases
If differences in the G+C content between species were dictated by asymmetric replication-associated mutation pressure, one would expect a correlation between the extent of PR2-bias and G+C content; however, no significant correlation between BI in coding sequences and P3 were found (Figure 7).
Figure 7. Correlation between GC content and the extent of strand biases in third codon positions.
Discussion
Asymmetric mutation pressure
A general feature observed in the present study is that, whenever there is a difference in base composition between the leading and the lagging strand, the G and T bases are enriched in the leading strand, and the G+C content is somewhat lower in the leading strand (see Results). The direction of observed biases are universal in bacteria [28], although not every species is biased [58]. This pattern is not restricted to the bacterial world, as GT-enriched leading strands have been documented in mitochondria [59,60,61], in the chloroplast genome of Euglena gracilis [62], in viruses [45,46,47], and in the telomeric ends of the Saccharomyces cerevisiae genome [63]. Not all sequences are biased, as shown by the well-documented β-globin region in the Homo sapiens genome [37]. Remarkably, absolutely no exceptions to the relative enrichment in G of the leading strand were found here, either in third codon positions or intergenic positions. However, the sole general rule in biology is that there are no general rules, and during the time of revision of this manuscript the first exception was documented in the chromosome of Streptomyces coelicolor [64]. The relative enrichment in T of the leading strand suffers from some exceptions that, interestingly, are all found here in the low-G+C group of Gram-positive bacteria (namely B. subtilis, B. halodurans, L. lactis, S. aureus, and S. pyogenes).
Because of the strong correlation in direction and intensity of PR2 deviation between third codon positions and intergenic spaces (Figure 6), the most likely explanation for the GT enrichment of the leading strand is a replication-induced asymmetric mutation pressure between the leading and lagging strand.
Potential underlying causes
The universal excess of G and T in the leading strand is common to distantly related species, suggesting that asymmetric directional mutation pressure has a chemical basis. This does not mean that the mechanism is simple: there are 12 substitution rates under asymmetric molecular evolution, but only four base frequencies; many different substitution scenarios can explain the observed biases. Here we discuss only simple hypotheses in which only one of the 12 substitution rates is assumed to differ between the two strands: for example, only an excess of A → G or of C → T in the leading strand is able to produce a GT-rich leading strand. Because the leading strand spends more time in the single-stranded state than the lagging strand during DNA replication [65], it is natural to look for mutations that are increased in the single-stranded state as possible explanations.
Oxidations
We are not aware of any studies comparing the rate of base oxidation between the single-stranded and double-stranded state in DNA. However, in a study of peroxyl radicals [66], which have a longer biological half-life than other O2-derived oxidants, all products formed were from the major groove of the bases, implying that steric hindrance from Watson-Crick base pairing in double-stranded DNA is not a factor. Consequently, similar yields of products in both single- and double-stranded DNA were found. Additionally, 8-hydroxyguanine, a major product of oxidative damage in DNA, induces mainly G → T and A → C mutations [67,68]. In Escherichia coli, it has also been reported that 2-hydroxy-dATP induces G → T mutations [69]. These results do not explain GT excess in the leading strand and therefore are not good candidates for a single mechanism of asymmetric mutation pressures.
Deaminations
Within this group, only cytosine deamination to uracil (or 5-methylcytosine deamination directly to thymine) yields a C → T mutation, and only adenine deamination to hypoxanthine yields an A → G mutation. Interestingly, there is experimental evidence in vitro that the rate of these deaminations is increased in the single-stranded state. Deamination of cytosine occurs over 100 times faster in single-stranded than in double-stranded DNA [70,71]. This is also most likely true for adenine, but its deamination rate is one-fortieth of the rate of cytosine [72], so that it is not possible to determine its rate in double-stranded DNA. The rate-determining step in cytosine deamination involves attack by water at the C-4 of the cytosine to give a tetrahedral intermediate, difficult to obtain in the rigid structure of double-stranded DNA because of Watson-Crick base pairing with guanine [73]. Single-stranded-DNA-binding proteins do not offer specific protection from this type of mutation during DNA replication [74] but may differ between species in their ability to protect from solvent attack. The single-stranded state during transcription induces C → T mutations [75], and this effect increases with transcription level [76] or when the duration of the single-stranded state is increased using a slower, mutant, RNA polymerase [77]. Also consistent is the report [78] that GT enrichment increases with the time spent in the single-stranded state during mitochondrial DNA replication. In a study of the mutation pattern estimated from pseudogene data in B. burgdorferi, it was found that C → T mutation was the most frequent in the leading strand [79]. The small depletion in G+C content observed here in the leading strand is also consistent with an excess of C → T substitutions in the leading strand because C → T substitutions decrease the G+C content. This effect is also expected to be a second-order one because of the centripetal action of symmetric directional mutation pressure on the G+C content of both strands. Therefore, we found the cytosine deamination theory compatible in most cases with the data, but a more definitive answer may come from biochemical studies on an extreme case such as B. burgdorferi.
G+C content variation between species is not controlled by a unique asymmetric mutation pressure
From inspection of our data, we can reject the simple model in which a unique asymmetric mutation pressure causes variation in G+C content between species. For instance, if only C → T mutations were the underlying phenomenon, we would expect low G+C in species with the highest BI. Figure 7 shows that this is clearly not the case. Moreover, if asymmetric directional mutation pressures were the major origin of variation in G+C content between species, we would expect a much more important difference in term of G+C content between the genes on the leading strand and those on the lagging strand.
Intergenic regions could be under greater selective constraints than expected
If we exclude as an explanation that many unannotated genes remain to be discovered, or that the boundaries of annotated genes should be greatly extended, so that some intergenic regions under analysis are not actually intergenic, then, there are two non-exclusive interpretations of the fact that BI is smaller in intergenic regions than in third codon positions. On the one hand, one may postulate that intergenic regions are under weaker selection pressure against inversions, so that deviations from PR2 are cancelled. On the other hand, one may assume that some positions are not free to deviate from PR2 because of selective pressure for some function. For instance, there are 100 copies per enterobacterial genome of palindromic sequences in intergenic spaces [80], which may be under selective pressure to preserve their palindromic character and therefore follow PR2 (as pure palindromic sequences are effectively base-paired). This interpretation is compatible with the fact that interspecific G+C content variation is higher at the third codon position than in intergenic spaces [10,11], as shown here in Figure 4. Moreover, the surprisingly low level of polymorphism in large intergenic regions among natural strains of E. coli [81] is in favor of selective constraints.
Transcription-coupled PR2-biases
Francino and Ochman [22,81] pointed out that transcription is likely to cause more mutations in the sense strand than in the anti-sense strand because of its transient single-stranded state during transcription. We found no evidence for this in intergenic spaces (> 100 bp), which could be interpreted either as an absence of transcription-induced mutation pressure or by a low proportion of transcribed fragments in these regions. Third codon positions are known to be transcribed, so that we expect an effect of transcription-induced mutation pressure on the residual deviation from PR2 (BII). However, selection for translation optimization interferes, so that we cannot interpret unambiguously the almost universal orientation of BII (down left in PR2-plot, as in Figure 2c) as the result of transcription-induced mutation pressure. If we interpret results this way, we would have to postulate a different mechanism for replication-induced and transcription-induced mutation pressures, as BI and BII have different orientations. Moreover, in small intergenic spaces, which are potentially transcribed untranslated regions, no general pattern is evident for the residual deviation from PR2, so that no universal transcription-induced mutation pressure was found here as a strong contributor to the deviation from the PR2 state.
Asymmetric mutation pressure and chirochore structure
A chirochore is a contiguous segment of the chromosome homogeneous with respect to its deviation from PR2 [44]. A strong asymmetric mutation pressure induces a chirochore structure, as observed in B. burgdorferi [82], but the converse need not to be true: a weak asymmetric mutation pressure does not imply an absence of chirochore. For example in M. genitalium, replication-associated biases, BI/(BI + BII), are the weakest among species under study (BI = 12%), but there is still a strong chirochore structure [83] because of a large excess (80%) of coding sequences in the leading strand. The deviation from PR2 in the first and second codon positions, because of selection at the amino-acid level (for example [84]), is then a major factor. It is not known whether chirochores could be adaptative, but recent results suggest a functional polarization of the E. coli chromosome [85,86] and may be relevant to this problem.
PR2-plot analysis
A prerequisite for using the simple graphical representations and quantifications used here is that the coding sequences and intergenic spaces can be divided into two groups: the leading and the lagging group. This is not necessarily always possible when, for instance, all coding sequences are in the leading group (this situation has never been encountered in bacteria but could be problematic in small genomes such as those of mitochondria). Another limitation is encountered when there are genes in both groups but we are unable to assign sequences to the correct group because of limited information about the location of origin and terminus of replication used during the course of evolution. Although an estimation of BI is not possible in this latter case, an oblong distribution of points in PR2-plots may suggest a non-zero value for BI. When more than one strain was sequenced for a species (that is, Chlamydophila pneumoniae, E. coli, H. pylori, Mycobacterium tuberculosis, Neisseria meningitidis, and S. aureus) BI and BII values in third codon position are extremely stable within a species (see table in the Additional data files), but the maximum number of three strains available here for one species does not allow us to estimate their within-species variability, and therefore their taxonomic utility.
Materials and methods
Source of data
Data on 51 complete bacterial chromosomes were retrieved from the EMGLib server [87,88] and used to extract annotated coding sequences and intergenic spaces (Figure 1). These 51 chromosomes were from 49 different strains (there are two chromosomes in Deinococcus radiodurans and Vibrio cholerae), from 41 different species (there were three strains of C. pneumoniae, E. coli; two strains of H. pylori, M. tuberculosis, N. meningitidis, S. aureus) as detailed in Table 1.
Leading and lagging group assignment
To classify sequences into the leading and the lagging groups (Figure 1), we must be able to locate them relative to the origin and terminus of replication. Out of 51 bacterial chromosomes, the locations of the origin and the terminus were known from experimental evidence or were estimated from chirochore boundaries [44] in 43 chromosomes with the program Oriloc [89,90]. Details of assignments are given in EMGLib database under a '/strand=' qualifier. To discriminate between the origin and the terminus of replication, we used the assumption that organisms tend to avoid head-on collisions between the DNA replication apparatus and the RNA polymerase transcription complex [54,55,56]. We also assumed that coding sequences were more abundant on the leading than on the lagging strand. As far as we know, there is no exception to this rule, and the report that the trend is exacerbated in highly expressed genes supports this assumption [48]. Moreover, the comparison of the maps of closely related bacterial chromosomes shows that observed chromosome rearrangements tend to preserve an excess of genes in the leading strand [91,92,93,94,95,96,97,98]. Our figures show sequences on the leading strand as filled circles, and those on the lagging strand as open circles.
Coding-sequence analysis
The nucleotide composition of coding sequences was always calculated from the sense strand (Figure 1) for each codon position. The sense strand (or anti-template strand) is the DNA strand opposite to the template strand for transcription. The average G+C content of the third codon position (P3) and that of the first and second codon positions (P12) were computed to draw neutrality plots relative to P3 as previously described [11]: stop codons and codons from odd-numbered sets ATG (Met), TGG (Trp) and ATA (Ile) were excluded from the calculations of P-values below to avoid an extra cause of potential deviation from PR2. The coding sequences after position 1,950 kb on D. radiodurans chromosome 1 were discarded because of a frameshift error in the annotations. Some of the apparent coding sequences identified in genome sequences could be artifacts that do not correspond to actually expressible genes [99]. To overcome this problem, coding sequences of less than 300 bp were removed from the analysis (less than 10% of sequences were discarded). As the probability of obtaining an open reading frame with more than 300 bp by chance is low, most (> 99%) sequences analyzed should correspond to actual coding sequences [100].
Intergenic-sequence analysis
GCIGR denotes the G+C content, and deviations from PR2 were characterized by G/(G+C) and A/(A+T) to draw PR2-plots in a way similar to coding-sequence analyses. Intergenic sequences were split into two non-overlapping groups (Figure 1). The first group contained small intergenic sequences among co-oriented genes that are potentially transcribed untranslated spacers. The strand used to compute nucleotide composition - chosen to allow direct comparisons with coding-sequence analyses - is the same as the anti-template strand for transcription of the two flanking genes (CDS, tRNA, rRNA). Therefore, when the two flanking genes are coding sequences, the strand is the same as the strand used for the analysis of coding sequences, that is the sense strand (Figure 1). Their minimum size was set to 50 bp, a trade-off between the likelihood of being transcribed and the avoidance of too much scattering in PR2-plots. Their maximum size was set to 100 bp to avoid data overlap with large intergenic regions. The second group contained large intergenic regions that are potentially untranscribed untranslated regions. Their minimum size was set to 100 bp, which is an amount of information equivalent to the third codon position of 100 codons, the minium size required in coding-sequence analyses. The analyzed strand cannot be defined unambiguously with respect to the flanking genes when they are convergently or divergently transcribed. The nucleotide composition was therefore always calculated from the published strand (Figure 1).
Statistical tests and their interpretation
The significance of the analyses was assessed using unpaired t-test implemented in Statview 5.0 (SAS Institute Inc., North Carolina, USA) to compare the mean between two groups - here the leading and the lagging group. The null hypothesis is the equality of the mean value between the two groups. The critical value p is the probability of taking the wrong decision of rejecting the null hypothesis when the null hypothesis is true. Two notes of caution should be introduced about the interpretation of results in the present context. First, we made runs of 43 comparisons so that the odds of getting at least one wrong significant result, 1 - (1 - p)43, is 0.89, 0.35, 0.04 for p = 0.05, p = 0.01, p = 0.001 respectively. We selected the highly significant critical level (p < 0.01) so that odds of getting one, two, or three wrong decisions were 0.28, 0.06, and 0.01, respectively, for each run. Therefore, a simple figure to keep in mind when looking at the results is that the odds of getting by chance three or more highly significant differences in a run were less than 1 in 100. The second note of caution is that we were working with large data sets, typically one thousand values within each group, so that the power of the test, that is its ability to reject the null hypothesis, was high. As a matter of consequence, even a small difference between the mean of the two groups was considered, correctly from the statistical test point of view, as significant. However, statistically significant does not mean automatically biologically significant because a second-order or a side effect could easily be evidenced this way. To help interpretation, the simple graphical representations used here, very close to raw data, were connected through hyperlinks to the tabulated test results. By this means, readers can quickly form their own opinions by viewing the original data.
Additional data files
Tables of the intragenomic P3 distributions of all species examined, and the PR2-biases between leading and lagging groups for coding sequences, and small and large intergenic regions, together with associated histograms are available as additional data files in 1 format, with the tables also in text format (Tables 2,3,4,5).
Additional data file 1. Tables of the intragenomic P3 distributions of all species examined, and the PR2-biases between leading and lagging groups for coding sequences, and small and large intergenic regions, together with associated histograms
Format: PDF Size: 9.7MB Download file
This file can be viewed with: Adobe Acrobat Reader
Additional data file 2. Table 1 in text format
Format: TXT Size: 4KB Download file
Additional data file 3. Table 2 in text format
Format: TXT Size: 4KB Download file
Additional data file 4. Table 3 in text format
Format: TXT Size: 4KB Download file
Additional data file 5. Table 4 in text format
Format: TXT Size: 4KB Download file
Acknowledgements
We thank the anonymous referees for their helpful comments, and we thank Rob Knight for his kind help in improving this manuscript.
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Designing culture: The other community plumbing
Image credits: chubstock
(5 votes)
One of our frequent writers in the Business channel, Chris Grams, gave the keynote at DrupalCamp Boone today on "Designing culture: The other community plumbing." This post is based on that talk.
Drupal is great as a content management system. But as much as we like it, a community is not built by Drupal. It's built by people. Getting people to work together is not solved by a Drupal installation alone. You need culture--the other community plumbing.
Can culture be designed? Yes.
Great cultures activate great people.
Great people activate great communities.
How?
1. Give folks something to believe in.
How many times do you go into a meeting, and everyone's talking, but nobody is on the same page?
You need to create a core purpose, and to make sure you articulate the core purpose of the community in a way that has a common meaning.
"I believe that this nation should commit itself to achieving the goal, before this decade is out, of landing a man on the Moon and returning him safely to the Earth."
- John F. Kennedy, May 25, 1961
The amount of work that took, from people doing everything from building the rocket to the guy designing the space latrine, was done because they all came together under a common purpose.
There must be a shared mission. Everyone needs to know they're working towards accomplishing the same thing.
2. Default to open.
In Brand Communications + Design at Red Hat, we all sat together in the open. We built our environment around this idea of defaulting to open. I believe the best communities take this principle of defaulting to open and put it into every structure.
In this case, it was office design. If you have a phone call, you don't choose whether to open your door. You take your calls in public by default. If you actually have to take a private conversation, you can go to a private alcove. But the key is that you had to choose to have that conversation in private.
In that office design, team meetings are held in a large, open space. If there are people sitting there, those nearby can overhear and be a part of a meeting they weren't necessarily "in." They might learn something, or they might have a chance to contribute. And if they don't want to be involved, they can put on their headphones and close themselves off.
Most companies operate the opposite way. Usually the default is emails from one person to another. In the open source world, the default is to mail everything to the entire mailing list, which allows everyone to see what's going on and to make their choices about what they don't want to hear.
In an open environment, you can always "put the headphones on." But in a closed environment, you don't have the choice to opt for openness.
3. Give everyone the power to lead.
Great communities give everyone the opportunity to lead. Typical businesses operates with the "old kind" of management. A manager-leader has employee-followers. The "new kind" works by having everyone be both a leader and a follower.
You see this in good open source projects all the time. The project keeps rotating through leaders, and you create lots of future big leaders. One of the greatest things in the world is to be able to step aside because someone better than you is ready to step up.
Some people want to declare themselves dictators for life. But what they really do is starve the rest of the community by not allowing the ownership and accountability to come to the front. So should they get tired of the project or if something happens to them, the community and the project die. That's not how to cultivate a community.
In order to be a good community leader, you're making new leaders all the time.
4. Don't be Tom Sawyer.
Here stood the board fence which tom sawyer persuaded his gang to pay him for the privilege of whitewashing. Tom sat by and saw that it was well done.
Tom Sawyer is interesting because Tom, by being a smooth talker, convinced everyone to do his work for him. Many companies approach their community strategies as having other people painting their fences. The popular term now is crowdsourcing. In this model, a company says "I have a lot of problems. Maybe I can convince a bunch of people to do my work for me." Sometimes it works, like Dell's IdeaStorm. But it works only for big, powerful brands. It doesn't work when a company asks for help, and everyone ignores them. And it doesn't work because as a company, you can't build a community around yourself.
It rarely works to sit back and expect people to contribute and make your project great. It rarely works because a company doing this doesn't understand that it's better to ask if a community exists that they could go join. Rather than trying to create a community around your company, you could be a part of something greater. Then you become part of a network of contributors working towards a greater whole.
Here's the question to ask: How can we, as a company, use the resources we have to ensure everyone's fence gets painted? It's about being a humble contributor. Most companies aren't willing to do that.
5. Cultivate powerful stories and legends.
Storytelling is vital to any community, but it's often ignored when we're focused on things like building great technology and making it easier for people to contribute. But then people don't come because there's nothing to get them excited.
CEOs create a mission statement, a purpose. But the goal is to get people on board, and you don't do that by putting words on a board. You do it by telling stories.
One of Red Hat's stories is around the origins of its name. Bob Young has three versions of the story (ogg).
It doesn't matter which story is true. None of them are. Or all of them are. It's not important. Stories are about building mystery and excitement. Community members especially tend to like to retell the stories from the "early times" when the comm was forming. And those are the stories people want to hear because they want to be part of another story down the road.
As you think about the community you're building, think about what the stories are. And think about who your leaders are and will be. What your mission is. Overall, what will inspire people to put their time and energy into communities that aren't part of their jobs?
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You are here
Copyrights and patents not so important, economist says
Michele Boldrin of Washington University in St. Louis talks with EconTalk host Russ Roberts about intellectual property and Boldrin's book, co-written with David Levine, Against Intellectual Property. Boldrin argues that copyright and patent are used by the politically powerful to maintain monopoly profits. He argues that the incentive effects that have been used to justify copyright and patents are exaggerated--few examples from history suggest that the temporary and not-so-temporary monopoly power from copyright and patents were necessary to induce innovation. Boldrin reviews some of that evidence and talks about the nature of competition. Listen to the interview.
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BMCB625
From OpenWetWare
(Difference between revisions)
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(Extras)
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==Extras==
==Extras==
[http://openwetware.org/wiki/BE.109:Guidelines_for_oral_presentations Nice Hints on Talks]
[http://openwetware.org/wiki/BE.109:Guidelines_for_oral_presentations Nice Hints on Talks]
+
==Thanks==
+
Thanks to [http://www.ohsu.biz/pmcb/facultyresearch/ransom.shtml David Ransom, OHSU], [http://bmcb.biology.arizona.edu/weinert.html Ted Weinert, University of Arizona], [http://www.healthsystem.virginia.edu/internet/bims/mentors_atoz.cfm?uva_id=jdc4r& J. David Castle, U. Va], and many of our [http://www.openwetware.org/wiki/Main_Page OpenWetWare] colleagues who have helped inspire and inform development of this course. Special thanks to [http://openwetware.org/wiki/User:Rshetty Reshma Shetty] for creating a terrific course template.
==Recent updates to the course==
==Recent updates to the course==
Revision as of 16:19, 5 May 2007
BMCB625 Advanced Topics in Molecular Biology
Home People Materials Schedule Help Discussion
This week's tasks:
Attend Karlene Cimprich's talk (BMB seminar Tuesday)
Send out invitations to faculty for your individual talks and post acceptance so we can get a bigger room if needed
Post your slides after you give your presentation (see section on posting slides)
Don't forget the "Universal Slide Template" and the "BMB Seminar Series WIki Header" challenges
The Course Discussion Page is ready for you to populate. Your suggestions needed for future themes
Contents
Course overview
• Location: BRB 603. Wednesdays from 9:30 - 11:30 (practice and review session) and Thursdays (The Real Thang) from 10:30 - 12:30
• How the Class Works
Advanced Molecular Biology: Topics and Methods in Modern Molecular Biology. An advanced graduate course with an emphasis on the latest research from the primary literature along with in-depth presentation of the basic concepts of biochemistry and molecular biology. Topics will be chosen from areas of expertise in the Biochemistry and Molecular Biology faculty. Topics will include properties of nucleotides and nucleic acids, the composition and structure of eukaryotic chromatin, eukaryotic gene expression, DNA replication, RNA transcription, RNA splicing and metabolism, and protein translation.
This class is not a faculty-driven lecture class, but is based on student presentations of background material and research papers selected from the current literature. It is designed to maximize active roles for students in each class.
Goals of the Class
1. encourage students to sieze every available resource for sifting and apprehending scientific matter (e.g., Nature podcasts, RSS feeds, faculty, each other)
2. develop an appreciation for the molecular machines that duplicate nucleic acids
3. get familiar with collaborative web-based tools (OWW and wiki)
4. create ambassadors for open science
5. improve presentation skills, both in form and scientific content
6. engage in active group-based learning
7. gain leadership and organizational experience
Announcements
• A picture is needed for the BMB seminar series wiki banner jpg. A combo picture ala Jon Fay/Larry user page would be nice, except with a theme of molecular medicine (next year's theme) and maybe including some local color. If anyone is up to the challenge, please post an example link on your user page.
Extras
Nice Hints on Talks
Thanks
Thanks to David Ransom, OHSU, Ted Weinert, University of Arizona, J. David Castle, U. Va, and many of our OpenWetWare colleagues who have helped inspire and inform development of this course. Special thanks to Reshma Shetty for creating a terrific course template.
Recent updates to the course
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From OpenWetWare
(Difference between revisions)
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(Sponsor)
(Sponsor)
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The University of Tokyo
The University of Tokyo
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Molecular Robotics Research Group
Molecular Robotics Research Group
Revision as of 03:33, 28 October 2012
Contents
References
[1]. Paul W. K. Rothemund: Folding DNA to create nanoscale shapes and patterns (2006)
[2]. Shelley F. J. Wickham, Masayuki Endo, Yousuke Katsuda, Kumi Hidaka, Jonathan Bath, Hiroshi Sugiyama & Andrew J. Turberfield: Direct observation of stepwise movement of a synthetic molecular transporter (2011)
[3]. Kevin Montagne, Raphael Plasson, Yasuyuki Sakai, Teruo Fujii & Yannick Rondelez: Programming an in vitro DNA oscillator using a molecular networking strategy (2011)
[4]. Adrien Padirac, Teruo Fujii & Yannick Rondelez: Quencher-free multiplexed monitoring of DNA reaction circuits. (2012)
Design of the bistable system courtesy of Adrien Padirac (in publication process).
Sponsor
The University of Tokyo
Molecular Robotics Research Group
Twitter
Our account is @Biomod2012UTK.
Please follow us to get our newest information.
Extra
15×15 Origami Simulation
We did 15×15 origami simulation. You can see what is shown in each states, please guess what it is!!
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User:Allison K. Alix/Notebook/CHEM-581/2012/10/17
From OpenWetWare
< User:Allison K. Alix | Notebook | CHEM-581 | 2012 | 10(Difference between revisions)
Jump to: navigation, search
(Autocreate 2012/10/17 Entry for User:Allison_K._Alix/Notebook/CHEM-581)
Current revision (17:36, 6 November 2012) (view source)
(Objective)
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==Objective==
==Objective==
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* Finish AA/ISE/Conductivity
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* UV-Vis of Cu<sup>2+</sup> adsorption solutions
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* UV-Vis calibration curve for porphyrin solutions
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* Re-make films if necessary
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* Cross-Link porphyrin films
==Description==
==Description==
Current revision
Experimental Chemistry Main project page
Previous entry Next entry
Objective
• Finish AA/ISE/Conductivity
• UV-Vis of Cu2+ adsorption solutions
• UV-Vis calibration curve for porphyrin solutions
• Re-make films if necessary
• Cross-Link porphyrin films
Description
Data
• Add data and results here...
Notes
This area is for any observations or conclusions that you would like to note.
Use categories like tags. Change the "Course" category to the one corresponding to your course. The "Miscellaneous" tag can be used for particular experiments, as instructed by your professor. Please be sure to change or delete this tag as required so that the categories remain well organized.
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Quotation added by staff
Why not add this quote to your bookmarks?
The purpose of a man's heart are deep waters, but a man of understanding draws them out. [Proverbs 20:5] Bible
This quote is about purpose · Search on Google Books to find all references and sources for this quotation.
A bit about Bible ...
The Bible (sometimes The Holy Bible, The Book, Good Book, Word of God, The Word, or Scripture), from Greek, (ta) biblia, "(the) books", is the classical name for the Hebrew Bible of Judaism or the combination of the Old Testament and New Testament of Christianity ("The Bible" actually refers to at least two different Bibles). It is thus applied to sacred scriptures. Many Christian English speakers refer to the Christian Bible as "the good book" (Gospel means "good news"). For many people their Bible is the revealed word of God, or an authoritative record of the relationship between God, the world and humankind.
These people bookmarked this quote:
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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.
Make and then buy your OWN fantastic personalized gift from this quote
All concord's born of contraries. Jonson, Ben
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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°
Click here to buy this »
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Quotes by Shaw, George Bernard
George Bernard Shaw (July 26, 1856 November 2, 1950) was an Irish playwright and winner of the Nobel Prize for Literature in 1925..
"I'm not a teacher: only a fellow-traveler of whom you asked the way. I pointed ahead -- ahead of myself as well as you."
Shaw, George Bernard on advice
6 fans of this quote
"If you value a man's regard, strive with him. As to liking, you like your newspaper -- and despise it."
Shaw, George Bernard on affection
"Dying is a troublesome business: there is pain to be suffered, and it wrings one's heart; but death is a splendid thing --a warfare accomplished, a beginning all over again, a triumph. You can always see that in their faces."
Shaw, George Bernard on death
6 fans of this quote
"I want to be all used up when I die."
Shaw, George Bernard on death
15 fans of this quote
"Life levels all men. Death reveals the eminent."
Shaw, George Bernard on death
"The government who robs Peter to pay Paul can always depend on the support of Paul."
Shaw, George Bernard on debt
8 fans of this quote
"Democracy substitutes election by the incompetent many for appointment by the corrupt few."
Shaw, George Bernard on democracy
3 fans of this quote
"Our necessities are few, but our wants are endless."
Shaw, George Bernard on desire
3 fans of this quote
"As long as I have a want, I have a reason for living. Satisfaction is death."
Shaw, George Bernard on action
9 fans of this quote
"The doctor learns that if he gets ahead of the superstitions of his patients he is a ruined man; and the result is that he instinctively takes care not to get ahead of them."
Shaw, George Bernard on doctors
This quotation can be viewed in the context of a book
"Every doctor will allow a colleague to decimate a whole countryside sooner than violate the bond of professional etiquette by giving him away."
Shaw, George Bernard on doctors
"When a stupid man is doing something he is ashamed of, he always declares that it is his duty."
Shaw, George Bernard on duty
4 fans of this quote
This quotation can be viewed in the context of a book
"If all the economists were laid end to end, they would not reach a conclusion."
Shaw, George Bernard on economy and economics
7 fans of this quote
"What we call education and culture is for the most part nothing but the substitution of reading for experience, of literature for life, of the obsolete fictitious for the contemporary real."
Shaw, George Bernard on education
This quotation can be viewed in the context of a book
"An election is a moral horror, as bad as a battle except for the blood; a mud bath for every soul concerned in it."
Shaw, George Bernard on elections
This quotation can be viewed in the context of a book
"Clever and attractive women do not want to vote; they are willing to let men govern as long as they govern men."
Shaw, George Bernard on elections
"I can forgive Alfred Nobel for having invented dynamite, but only a fiend in human form could have invented the Nobel Prize."
Shaw, George Bernard on evil
"Love is a gross exaggeration of the difference between one person and everybody else."
Shaw, George Bernard on exaggeration
"If you must hold yourself up to your children as an object lesson, hold yourself up as a warning and not an example."
Shaw, George Bernard on example
"Men are wise in proportion, not to their experience, but to their capacity for experience."
Shaw, George Bernard on experience
9 fans of this quote
"If history repeats itself, and the unexpected always happens, how incapable must Man be of learning from experience!"
Shaw, George Bernard on experience
"Everything happens to everybody sooner or later if there is time enough."
Shaw, George Bernard on experience
This quotation can be viewed in the context of a book
"No man can be a pure specialist without being in the strict sense an idiot."
Shaw, George Bernard on experts
"We have not lost faith, but we have transferred it from God to the medical profession."
Shaw, George Bernard on faith
"He didn't dare to, because his father had a weak heart and habitually threatened to drop dead if anybody hurt his feelings. You may have noticed that people with weak hearts are the tyrants of English married life."
Shaw, George Bernard on family
"When our relatives are at home, we have to think of all their good points or it would be impossible to endure them. But when they are away, we console ourselves for their absence by dwelling on their vices."
Shaw, George Bernard on family
"Fashions, after all, are only induced epidemics."
Shaw, George Bernard on fashion
"My father must have had some elementary education for he could read and write and keep accounts inaccurately"
Shaw, George Bernard on fathers
"A gentleman is one who puts more into the world than he takes out."
Shaw, George Bernard on fellowship
3 fans of this quote
"That is the whole secret of successful fighting. Get your enemy at a disadvantage; and never, on any account, fight him on equal terms."
Shaw, George Bernard on fights and fighting
"What really flatters a man is that you think him worth flattering."
Shaw, George Bernard on flattery
This quotation can be viewed in the context of a book
"There is no love sincerer than the love of food."
Shaw, George Bernard on food and eating
10 fans of this quote
This quotation can be viewed in the context of a book
"Build a system that even a fool can use, and only a fool will want to use it."
Shaw, George Bernard on fools and foolishness
"The secret of forgiving everything is to understand nothing."
Shaw, George Bernard on forgiveness
5 fans of this quote
This quotation can be viewed in the context of a book
"Forgive him, for he believes that the customs of his tribe are the laws of nature!"
Shaw, George Bernard on forgiveness
4 fans of this quote
"The only service a friend can really render is to keep up your courage by holding up to you a mirror in which you can see a noble image of yourself."
Shaw, George Bernard on friends and friendship
6 fans of this quote
"But a lifetime of happiness! No man alive could bear it: it would be hell on earth."
Shaw, George Bernard on friends and friendship
This quotation can be viewed in the context of a book
"We are made wise not by the recollection of our past, but by the responsibility for our future."
Shaw, George Bernard on the future
But wait... There are more: 1, 2, 3, 4, 5, 6, 7 next
Take a look at recent activity on QB!
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Dancer audition photos
RedsArmyAdmin June 27, 2009 Uncategorized 4 Comments
A bunch of women showed up in Waltham and danced around in bras and short shorts.
That pretty much sums up how the Celtics Dancers auditions went. After the jump, more photographic proof of that… including the Red's Army favorite: Alison Preston
You can view the entire gallery at Celtics.com
Like this Article? Share it!
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Full Belly Deli
Info Map
Search:
Location
1225 Jefferson Road, Rochester NY, 14623 in Frontier Commons
(Wheelchair Accessible)
Hours (as of February 2011 per Website)
Monday - Friday: 7:30AM to 6:00PM
Phone/Fax
585 292-0210 Fax: 585 292-0220
Alcohol
No
Email
<customerservice AT fbdroch DOT com>
Website
http://www.thefullbellydeli.com/
Full Belly is a deli with ample seating-located off Jefferson Road in Frontier Commons in Henrietta. They also offer catering services.
Same proprietor as Grill & Greens
Comments:
Note: You must be logged in to add comments
2006-11-29 23:48:18 We *LOVE* this place....great food and the staff is terrific! Huge amounts of meat on their subs/sammys...Ed the owner is always up and walking around —PeteB
2008-03-12 16:18:35 Myself and 6 coworkers ordered from this place and we loved it!! They say bread makes sandwich but, I say so does the meat. This place has both! —JohnPirisino
2008-08-29 10:27:44 Best kept secret in Rochester sandwiches. This is the only place in town where I will order roast beef, and they don't look sideways at me when I ask for Thousand Island dressing. Great food and great service. —Petey
2008-08-29 12:47:48 Pretty good deli. With a wide selection of non deli items like cheese sticks and chicken fingers. I had a cheesesteak with fries and it was good. Not as good as the old Philly Steakout, but pretty decent. —MrRochester
2011-02-16 16:21:44 Checked out this place for the first time this week. The wraps were fantastic and so was the soup. I thought a $25 pice tag for soup and a sandwhich for 2 was slightly high, but for the quality of ingredients and the amount of meat on the sandwichs/wraps, the price was totally worth it. Will definately be going back!! —saraokirk
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Research article
Phylogenetic relationships among Staphylococcus species and refinement of cluster groups based on multilocus data
Ryan P Lamers1,5, Gowrishankar Muthukrishnan1, Todd A Castoe2, Sergio Tafur3, Alexander M Cole1* and Christopher L Parkinson4*
Author Affiliations
1 Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, 4000 Central Florida Boulevard, Orlando, FL, 32816, USA
2 Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, 12801 17th Avenue, Aurora, CO, 80045, USA
3 Stokes Advanced Research Computing Center, Institute for Simulation and Training, University of Central Florida, 3100 Technology Parkway, Orlando, FL, 32826, USA
4 Department of Biology, University of Central Florida, 4000 Central Florida Boulevard, Orlando, FL, 32816, USA
5 Current affiliation: Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada
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BMC Evolutionary Biology 2012, 12:171 doi:10.1186/1471-2148-12-171
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2148/12/171
Received:1 September 2011
Accepted:30 August 2012
Published:6 September 2012
© 2012 Lamers 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
Estimates of relationships among Staphylococcus species have been hampered by poor and inconsistent resolution of phylogenies based largely on single gene analyses incorporating only a limited taxon sample. As such, the evolutionary relationships and hierarchical classification schemes among species have not been confidently established. Here, we address these points through analyses of DNA sequence data from multiple loci (16S rRNA gene, dnaJ, rpoB, and tuf gene fragments) using multiple Bayesian and maximum likelihood phylogenetic approaches that incorporate nearly all recognized Staphylococcus taxa.
Results
We estimated the phylogeny of fifty-seven Staphylococcus taxa using partitioned-model Bayesian and maximum likelihood analysis, as well as Bayesian gene-tree species-tree methods. Regardless of methodology, we found broad agreement among methods that the current cluster groups require revision, although there was some disagreement among methods in resolution of higher order relationships. Based on our phylogenetic estimates, we propose a refined classification for Staphylococcus with species being classified into 15 cluster groups (based on molecular data) that adhere to six species groups (based on phenotypic properties).
Conclusions
Our findings are in general agreement with gene tree-based reports of the staphylococcal phylogeny, although we identify multiple previously unreported relationships among species. Our results support the general importance of such multilocus assessments as a standard in microbial studies to more robustly infer relationships among recognized and newly discovered lineages.
Background
The genus Staphylococcus currently contains more than 60 species and subspecies. Many are of clinical, agricultural, and economic interest because they lead to high levels of infection among human populations or agricultural loss within the dairy, swine, and poultry industries. Moreover, multiple species within this genus are common pathogens in non-human animals and thus should be monitored with concern as these animals provide reservoirs for pathogenic bacteria [1-3]. Although seemingly uncommon, host switching is an important mechanism in the evolution of Staphylococcus. For example, in S. aureus, human-to-poultry [4] and bovine-to-human [3] host switches have been observed. As such, a thorough understanding of species relatedness is a necessity for understanding host-pathogen interactions within this genus [5-7].
Many previous estimates of the staphylococcal phylogeny have been based on single locus gene trees, which in many cases exhibit differing topologies. As such, robust species tree estimations have proved to be difficult. Historically, staphylococcal species identification has been a laborious task, requiring multiple biochemical and genotypic methodologies [6,8]. Fortunately, more efficient and reliable assays based on PCR and DNA sequencing have become commonplace as part of the identification process of novel species (and differentiating closely related species). As with most bacterial systems, the 16S rRNA gene continues to be the most common method for staphylococcal species identification, although its utility is limited due to high sequence similarity among different staphylococcal species [9,10]. For this reason, increased emphasis has recently been devoted towards identifying additional genes for use in species identification that offer greater taxonomic resolution between closely related species, while also limiting the incidence of misidentification. Such genes as rpoB (β-subunit of RNA polymerase), tuf (elongation factor Tu), and dnaJ (heat shock protein 40), have been found useful for the identification of staphylococcal species. With the exception of one study where dnaJ and rpoB were concatenated and assessed under a single evolutionary model [11], each has only been analyzed singularly in a phylogenetic context.
We targeted two related primary goals in this study. First, we aimed to utilize a multilocus phylogenetic dataset to critically evaluate the proposed cluster groupings of species of Staphylococcus, and to amend these groupings to reflect estimates of phylogeny. Second, on a broader scale, we aimed to infer the deeper phylogenetic relationships among cluster groups of all Staphylococcus species using multilocus data analyzed under different strategies including concatenated and species-tree methods. We analyzed a large multilocus Staphylococcus dataset in multiple ways to thoroughly explore the phylogenetic signal in the data, and provide robust confirmatory evidence for the relationships among species. We first analyzed the combined four-gene dataset using partitioned Bayesian and maximum likelihood analyses, in which a single species tree was inferred. Such probabilistic methods of phylogeny are particularly powerful as they incorporate alternative models of character evolution into the analysis and search for a tree that ultimately maximizes the probability of data given the tree [12,13]. Their accuracy, however, can be dependent on the complexity and biological realism of the models of sequence evolution used.
There is a tradeoff between having enough parameters to accurately capture the complexity of sequence evolution in a multilocus dataset, while not having more parameters than can be accurately estimated from the data [14-17]. We therefore tested multiple differently partitioned model schemes to identify which best fit the multilocus dataset. Generally, we expect such partitioned model analysis of the combined (concatenated) dataset will have the best power for inferring the phylogeny of Staphylococcus, as long as basic assumptions of the approach are met. The most important of these assumptions is that all the underlying gene trees are the same as the species tree. There are, however, situations where gene trees and species tree are not the same [18,19], or where systematic error in gene-tree estimation may lead to overconfidence in an incorrect species tree [20]. There is some indication, however, that in such cases, maximum likelihood bootstrap support values may be more sensitive to conflicting phylogenetic signals in the data than Bayesian posterior probability support for nodes, although both concatenated data analysis approaches are likely to experience some error [21-23].
Therefore, we also used an alternative approach to estimate relationships among species of Staphylococcus in which gene trees are estimated separately, and jointly considered to estimate an underlying species tree. This approach, called Bayesian Estimation of Species Trees analysis [24], thereby avoids concatenation of multiple loci, and estimates a species tree based on a model that accounts for deep coalescence of gene trees. Although this approach does not specifically model all possible scenarios that may violate the assumptions of the concatenated analysis, comparisons of results between this approach and concatenated analyses provides added perspective on the relative robustness of species-level phylogenetic inferences.
Methods
DNA sequence acquisition and alignment
DNA sequences for a total of four genes from 57 staphylococcal species, and two outgroup species (Macrococcus caseolyticus - strain JCSJ5402, and Bacillus subtilis - strain 168) were downloaded from NCBI's GenBank. For each species included in the analysis, sequences were specifically downloaded from the type strain. The four loci collected included the non-coding 16S rRNA gene, and the three protein coding genes: dnaJ, rpoB, and tuf. The list of all species analyzed in this study with the accession numbers for each of the four gene fragments is given in Additional file 1: Table S1.
Additional file 1: Table S1. GenBank accession numbers for 16S rRNA gene fragments,dnaJ, rpoB, andtufgene fragments analyzed in this study.
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Nucleotide sequences were aligned using ClustalW in MEGA 4.1 [25], with manual adjustment to ensure that complete codons remained in tact for downstream analyses. Regions of high variability were omitted from the alignments because assessment of homology was questionable [15]. This was only observed to be the case for dnaJ in which nucleotide positions 63–93 in the original sequence was omitted. Additional manual codon adjustment of this region did not improve the alignment and thus, was omitted. Secondary structure predictions (i.e. stem and loop regions) for 16S rRNA gene fragments were estimated using the RNAalifold approach [26,27]. The data matrix and trees have been deposited in TreeBase ([28]; http://purl.org/phylo/treebase/phylows/study/TB2:S12505 webcite). Analyses of incongruence length differences (ILD; [29]) among partitions of the dataset were performed using PAUP* 4.0 [30]. Nucleotide diversities and species divergence calculations were performed using MEGA 4.1 [25] and DnaSP v5 [31].
Nucleotide model selection
Models of nucleotide evolution for each gene and nominal partition of the data were estimated using jModelTest v0.1.1 [32,33] based on Akaike Information Criterion (AIC). For the purpose of model testing (and later partitioned Bayesian analyses) we divided the dataset by gene, and into biologically relevant subsets: coding versus non-coding gene fragments, codon position, and stem versus loop secondary structures (for the 16S rRNA gene fragment). These individual partitions, and the best-fit evolutionary model selected for each partition, are shown in Additional file 2: Table S2.
Additional file 2: Table S2. Evolutionary models for each partition were chosen based on AIC using jModelTest.
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For analyses of the combined data with partitioned models, we formulated nine different partitioning schemes. These were designed to provide a hierarchical spectrum of model complexity, and parameter richness, with increasing partitioning of biologically reasonable sets of the data (Table 1). The simplest model (MB1) was a single evolutionary model (GTR + ΓI) fit to the entire dataset followed by additional models (MB2-MB9) that were created by the addition of dataset partitions among and within non-coding and coding gene fragments (Table 1).
Table 1. Description of alternative model partitioning strategies tested for fit to the combined nucleotide data
Bayesian phylogenetic analysis
Bayesian inference (BI) was carried out using the Metropolis-Hastings coupled Markov chain Monte Carlo method in MrBayes v3.1.2 [34,35] and BEST v2.3.1 [36]. All Bayesian phylogenetic analyses performed in this study were carried out using the STOKES IBM High Performance Computing Cluster at the University of Central Florida. MPI-enabled versions of MrBayes v3.1.2 and BEST v2.3.1 were compiled and run in parallel [37]. For each BI run, gaps in alignments were treated as missing data. For each MrBayes analysis, two independent BI runs were carried out using random starting trees with one cold chain and three heated chains (following program defaults). Each model was assessed in triplicate with summary statistics being estimated from all runs.
In addition to performing BI runs in MrBayes on the unpartitioned multilocus dataset (using the evolutionary model specified by AIC), eight additional models were assessed where independent models of evolution were applied to different nucleotide regions within the combined dataset (refer to nucleotide model selection section). This was achieved by using the “unlink” command in MrBayes v3.1.2. Each BI run consisted of 4 million generations with every 100 steps being sampled. As verified using Tracer v1.5 [38], stationarity was reached in all BI runs prior to 500 000 generations and a conservative burn-in of 1 million (25%) generations was performed. To verify that additional sampling (i.e., increasing the number of generations) for MrBayes runs would not affect the outcome of the data, a final run of 20 million generations with sampling every 1 000 steps and a burn-in of 4 million generations was performed.
In addition to reconstructing phylogenies using MrBayes v3.1.2, Bayesian phylogenetic reconstruction was also performed using BEST v2.3.1, which is a modified version of MrBayes. BEST was implemented by setting the prior for BEST = 1, and unlinking topologies, branch lengths, and mutation rates across loci. For each independent BEST analysis, four simultaneous runs consisting of 16 chains each were performed for 20 million generations with sampling every 1 000 generations. A prior for theta was set at 0.04, based on the mean estimates of theta for the dataset calculated in DnaSP and MEGA 4.1. Consistent with previous reports [39,40], run convergence was only achieved by setting a uniform prior for branch lengths (prset brlenspr = clock:uniform). As with all BI runs, nucleotide regions were assigned nucleotide substitution models based on AIC, estimated in jModelTest.
Assessment of BI runs
All partitioning strategies employed using MrBayes were run in triplicate to verify reproducibility while BEST analyses were run two separate times. Subsequently, MrBayes and BEST runs, under each model, were assessed using multiple criteria to determine the success of each model and the overall best-fit model. Bayes factors (BF; 2ΔlnB10) were calculated from estimates of the harmonic mean of the posterior distribution of cold chain likelihoods. Consistent with previous reports [14,16,41], we set a cutoff of BF > 10 to support one model over another. Recently, multiple studies have suggested that biases introduced by using the harmonic mean estimator may practically affect model selection using BF [42-45]. Based on our results however, we discuss why such biases are practically tolerable in this study (i.e., model choice has little effect on topology and nodal support).
Akaike weights (Aw) [46] were also used to identify best-fit partitioned models [17]. Initially AIC values were calculated by the equation AIC = −2lnL + 2 k where k equals the total number of free parameters within the model. For small samples sets, where the sample size (n) to free parameter (k) ratio is <40, it has been suggested that a small-sample bias adjustment be applied to the AIC calculation, thus calculating AICc instead [47,48]. The sample size of the staphylococcal dataset (with outgroups) is 59 and the minimum number of free parameters was 10 for model MB1. As such, the n/k ratio was always <40, so we calculated the AICc instead. The equation for . The ΔAICc was then calculated by subtracting the model with the minimum AICc (AICcmin) (i.e. highest lnL) from the ith model using the equation . Following calculations of the ΔAICc for each model, Aw were calculated using the equation . By this equation, the relative likelihood of a model given the data is normalized over all models and thus, the greater the Aw for a given model, the greater the relative support for that model [14].
Further assessment of model performance was based on examining the output of model parameters and carried out by analyses of multiple additional features. Posterior distributions of parameters and analysis of trace plots were assessed for failed convergence and stationarity using Tracer v1.5 [38]. Also, because model overparameterization has been linked to estimates of tree length in partitioned Bayesian analyses [49], we also compared tree length estimates among runs.
Maximum likelihood analysis
Phylogenetic reconstruction using maximum likelihood (ML) analysis was carried out using the program GARLI v.2.0 [50], using default parameters except where specified. Phylogenetic estimates using ML were performed using both the combined, unpartitioned dataset as well as the combined dataset partitioned by locus (Additional file 2: Table S2). Five ML search replicates were run for each dataset using random starting trees, and up to five million generations were employed for each run unless the scoring topology lnL did not improve by ≥ 0.01 for 20 000 generations, in which case the run was terminated prematurely and the next bootstrap replicate was begun. Two hundred bootstrap replicates were conducted for each run and consensus trees were generated using the SumTrees v.3.0 software which is part of the DendroPy v.3.7 phylogenetic computing library [51]. Likelihood ratio tests (LRTs) [13,52] were performed to compare competing model partitioning schemes, M0 and M1. Statistical support for model M0 over M1 (or vice versa) was assessed using the Chi-square distribution for q degrees of freedom (df) where q equals the difference in the number of free parameters between model M0 and M1 (df = 19 in this study) [52].
Results
Gene fragments used for analyses contain differing degrees of variability
Among the four gene fragments analyzed in this study, 3 521 nucleotides were included (1 481 from the 16S rRNA gene fragment, 816 from dnaJ, 474 from rpoB, and 750 from tuf) for 59 different taxa. The dataset contained 1 016 parsimony-informative sites and 2 142 conserved sites. The nucleotide diversity of the 16S rRNA gene fragment was 0.029 substitutions (subs.) per site, while that for dnaJ, rpoB, and tuf was 0.241, 0.147, and 0.097 subs. per site, respectively. The average theta per site for the combined dataset was 0.04. The lowest interspecies divergence was between S. pseudintermedius and S. delphini (0.014 subs. per site). The highest estimated evolutionary divergence within the complete dataset was between S. piscifermentans and the outgroup species, B. subtilis (0.266 subs. per site), while the highest level among staphylococcal taxa was between S. piscifermentans and S. vitulinus (0.182 subs. per site).
Individual gene tree analyses
Phylogenetic analysis of individual genes revealed that 16S rRNA and dnaJ fragments resolved similar major clades but different branching orders of these clades (Additional file 3: Figure S1). Similarly, most relationships and clusters of species within rpoB and tuf gene trees were in general agreement with the 16S and dnaJ gene trees, but multiple higher-level clades were present in these that were unique (Additional file 3: Figure S1). Thus, individual gene tree analyses supported similar clusters of species, but varying arrangements of these clusters relative to one another. As expected, nodal support values for individual gene trees were relatively low, particularly for nodes more deeply nested in the tree. Formal partition homogeneity (or incongruence length difference test [29]) tests indicated that there were significant differences between all partitions except for 16S rRNA gene and dnaJ. This test, however, is based on parsimony criteria and known to have highly variant type-1 and type-2 error rates depending on different tree structures, rates across sites, and informative site contents among datasets [53,54]. We therefore interpret these results cautiously, as the potential for there to exist some conflicting phylogenetic signal among genes, and incorporate this caution in later interpretations of the combined data analyses. Such conflicting signal might result from multiple sources, including phylogenetic estimation error leading to different inferences from individual gene trees, and/or different underlying evolutionary histories among genes due to lateral gene transfer or lineage sorting effects.
Additional file 3: Figure S1. Gene trees for individual loci assessed in this study. Shown are Bayesian 50% majority rule phylograms for A) the 16S rRNA, B) dnaJ, C) rpoB, and D) tuf gene fragments. MrBayes was run under the same conditions as those used for concatenated analyses with evolutionary model specified for whole gene fragments in Additional file 2: Table S2. Numbers represent posterior probabilities with grey-filled circles representing a posterior support of 1.00.
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Dataset partitioning improves likelihood estimates of Bayesian phylogenetic analyses
Regardless of partitioning strategy employed, all Bayesian inference (BI) runs yielded highly reproducible phylogenetic inferences (Additional file 4: Figure S2). Within MrBayes BI runs, log-likelihood (lnL) estimates rapidly reached stationarity and convergence. Log-likelihoods ranged from −38830.66 (MB1) to −37421.36 (MB7) with intermediate lnL generally increasing with partition complexity (Figure 1). Dataset partitioning for concatenated BI runs (i.e., MrBayes) ranged from the most simple (unpartitioned) to highly complex (11 partitions; Table 1). Initial assessments of Bayes factors (BF; 2ΔlnB10) were used to compare topological likelihoods across each different model. As shown in Table 2, a large disparity between the lnL from various partitioning strategies was observed. Partitioning strategy MB7 yielded the highest lnL (Figure 1) with a BF > 230 that of the next best model (MB5) and >2800 compared to the unpartitioned model (MB1). Model MB7 was the most complex strategy (11 different partitions) with a separate model for each codon position of each protein-coding gene, as well as stem versus loop regions of the 16S rRNA gene fragment (Table 1). The model with the second highest likelihood was MB5 whereby the 16S rRNA gene fragment was again partitioned by stem and loop position, however, only two independent partitions were applied to each individual protein coding gene fragment (codon positions 1 & 2; and codon position 3). Using AICc for the Aw calculation identified model MB5 as the best-fit model (Aw = 1.000; Table 2). Thus, based on lnL-centric criteria, models MB5 and MB7 are the preferred models for the concatenated data analysis.
Additional file 4: Figure S2. Bayesian inferences of phylogeny are highly reproducible, regardless of model employed. Shown are plots of post-burnin generational log likelihoods (lnL) from five representative partitioning strategies across triplicate concatenated BI runs (A); and duplicate BEST runs (B). All runs were highly reproducible regardless of methodology and partitioning strategy.
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Figure 1. Dataset partitioning improves model fit. Shown are log-likelihood plots comparing partitioning strategies used for concatenated BI runs. Error bars represent the mean ± 95% confidence interval.
Table 2. Bayes factors and Akaike weights reveal differences in model fitness for the different partitioning strategies applied to the concatenated, multilocus dataset
Inspection of TL identified that the more highly partitioned models (MB4-MB7) yielded TLs between two and four times longer than less partitioned models (MB1-3; MB8-9; refer to Additional file 5: Figures S3 and Additional file 6: Figure S4). The more highly-partitioned model runs with high TLs also tended to show very high TL variance among generations, resulting in quite broad TL posteriors (Additional file 5: Figures S3 and Additional file 6: Figure S4). Considering this evidence for unreliability in the more highly partitioned model runs, we tempered our choice of partitioning scheme. A combination of lnL (BF and Aw) and TL reliability criteria suggest that MB8 is the preferred partitioned model, since it had better lnL than other models (e.g., MB1-2) while resulting TL estimates were apparently uninflated and of low variance (Additional file 5: Figures S3 and Additional file 6: Figure S4). Hereafter, we discuss results based on the BI runs from model MB8, and identify any notable differences between this model and others (particularly MB5 and MB7). It is important to note however that while lnL and TLs differed between partitioning scheme models, tree topologies remained nearly identical (discussed below). It is possible that the inconsistency between the BF-based support for more highly partitioned models versus evidence for model overparameterization that we observed may be related to calculation of BFs based on harmonic mean approximations of marginal likelihoods, which has been shown previously [42,43,45]. Thus, while no substantial topology or support value differences were observed between results from different models, we have taken a conservative approach and chosen to use MB8 as the preferred model because more complex models exhibited excessive TL indicative of overparameterization.
Additional file 5: Figure S3. Tree length (TL) analysis indicates that overparameterization may be occurring within more highly partitioned datasets. Shown are post-burnin generational TL estimates for partitioning strategies assessed in this study. Note that as the complexity of partitioning increases evidence of increased TL and failed convergence is observed.
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Additional file 6: Figure S4. Model partitioning increases the mean tree length (TL) and run variance. Shown is a box plot indicating the mean TL and 95% confidence interval among partitioning strategies.
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Bayesian and maximum likelihood analyses of concatenated data
Regardless of the model under which the concatenated staphylococcal dataset was analyzed using BI, high overall nodal support was observed for nearly all nodes in the tree. Tree topologies were highly concordant between different partitioned model schemes, with only a single topological inconsistency between models. In addition to the placement of S. devriesei shown in Figure 2, this species was also estimated to form a clade with S. lugdunensis under four models (MB2-4, and MB6). Additionally, under models MB5 and MB7, S. devriesei was estimated to diverge after S. lugdunensis, forming the sister lineage to a clade containing S. haemolyticus and S. hominis (data not shown). Nodal support for these alternative relationships was quite low (avg. Pp = ~0.64), however, in comparison to the support of S. devriesei forming a clade with S. haemolyticus (Pp = 0.85; Figure 2). Beside this single topological difference, nodal support differed by very little among models (Pp ≤ 0.02), with only two cases (MB1 and MB6) in which a single node differed by a Pp = 0.05.
Figure 2. Bayesian MCMC analysis of the concatenated dataset. Shown is a 50% majority rule phylogram from BI runs under the combined, partitioned dataset in MrBayes. Numbers represent posterior probabilities with grey-filled circles representing a posterior probability of 1.00.
Bayesian concatenated phylogenetic estimates supported strongly (Pp = 1.00) the separation of staphylococcal species into two deeply-diverging major clades (Figure 2). One of the two clades contained all of the oxidase positive staphylococcal species (frequently referred to as the Sciuri group), with the second group containing all other oxidase negative staphylococcal species (Figure 2). The single lineage S. auricularis formed the sister group to all other members of this second group, with the next most basally-diverging lineage in this clade including the following species: S. simulans, S. condimenti, S. carnosus (both subspecies), and S. piscifermentans (Pp = 1.00). The subspecies of S. carnosus proved to cluster tightly together, as expected, and formed the sister group to S. condimenti.
The next major divergence within the staphylococcal tree was that of a strongly supported clade (Pp = 1.00) containing the pathogenic species S. saprophyticus (Figure 2). This clade contained many members of the polyphyletic group of coagulase negative, novobiocin resistant species, and included the recently described species S. massiliensis[55] and S. pettenkoferi[56]. Following this divergence, species of heightened clinical significance diverged, including S. aureus, S. epidermidis, S. warneri, S. haemolyticus and S. lugdunensis, which formed a well-supported clade (Pp = 1.00) (Figure 2). We also found that the most recently discovered Staphylococcus species, S. agnetis[57] formed a strongly supported clade (Pp = 1.00) with S. hyicus, for which S. chromogenes was the sister lineage.
The concatenated ML estimation of the staphylococcal phylogeny was consistent with reconstructions from the concatenated BI method (Figure 3). Log-likelihoods under a single evolutionary model were −39186.39 while partitioning the concatenated dataset by individual gene yielded a lnL = −36632.34. The likelihood-ratio test supported the partitioned dataset as the best-fit model (p < 0.0001; likelihood-ratio (−2ΔlnL) = 5 108; degrees of freedom (df) = 19). Topologies estimated under both models were identical except for a single discordant node: S. devriesei formed a single-species sister taxon to S. haemolyticus and S. hominis in the unpartitioned dataset (bootstrap support (BS) = 59%), while in the dataset partitioned by individual gene, S. devriesei shared a clade with S. haemolyticus (BS = 72%). Aside from minor discrepancies between the concatenated ML and BI topologies (Figure 3), high topological agreement was observed. Although weakly supported (BS < 50%), S. felis diverged more deeply under ML than BI, forming a single species sister lineage to the larger clade containing S. hyicus, S. intermedius, and S. schleiferi in the ML tree (Figure 3). Among the oxidase containing species clade, ML estimated a more basal divergence of S. lentus and S. stepanovicii than was estimated under the concatenated BI approach (Figure 3). Comparisons between BI and ML nodal support values indicated that support values at discordant nodes between BI and ML methods ranged from Pp = 0.75-0.98 for BI and BS = 30-98% for ML (Figure 4). Thus, differences in the tree and support values between methods included both weakly and strongly supported nodes.
Figure 3. Maximum likelihood phylogram of staphylococcal species. Shown is a ML phylogram obtained from the assessment of the locus-partitioned dataset (similar to MB3) using GARLI v.2.0 [50]. The consensus phylogram was generated from 200 bootstrap replicates with five ML search replicates per bootstrap. Nodes receiving Pp = 1.00 and/or BS = 100% are indicated by grey-filled circles; otherwise, MrBayes posterior probability is shown in red text, and ML bootstrap support is shown in black text. Clades that were not present in MrBayes are indicated by a red §.
Figure 4. Comparison of nodal support between MrBayes and maximum likelihood methodologies. Shown is a scatter plot comparing the differences in MrBayes posterior probabilities (Pp) and maximum likelihood (ML) bootstrap support (BS) for identical nodes (Figure 3). Open circles represent Pp support for discordant nodes present in MrBayes and absent in ML. Open triangles represent BS values for discordant nodes present in ML and absent in MrBayes. Note that MrBayes exhibits heightened overall node support as compared to ML.
Concatenated and unconcatenated phylogenetic methods broadly agree on clustering of staphylococcal species
Estimation of staphylococcal phylogeny was also performed on the unconcatenated dataset using Bayesian Estimation of Species Trees (BEST) analysis [36]. BEST analyses treated each locus as an independent gene, thereby inferring the likely species tree given four independent gene trees. Trees inferred from duplicate BEST runs were identical in topology with no nodes differing by Pp > 0.05, indicating that multiple runs converged on nearly the same posterior tree space. With three exceptions, the BEST tree resolved the same major clades as the concatenated BI and ML trees, although in some cases the relative branching order of major clades differed (Additional file 7: Figure S5). BEST estimated that S. auricularis formed a clade with S. sciuri (Pp = 0.99) as opposed to the later (less basal) divergence of S. auricularis observed in concatenated BI and ML estimates (Pp = 1.00 and BS = 100%, respectively; Additional file 7: Figure S5). BEST also estimated a more divergent relationship between S. kloosii and S. arlettae, whereas these two species formed an exclusive clade in concatenated data analyses. The concatenated BI and ML analyses estimated S. felis to diverge more basally than was inferred by BEST analyses, although support for the placement of S. felis was generally low among all methods (BEST, Pp < 0.50; concatenated BI, Pp = 0.75; concatenated ML, BS < 50%).
Additional file 7: Figure S5. Inference of phylogeny using Bayesian estimation of species trees (BEST). Shown is a consensus phylogram of the staphylococcal species tree generated using all four gene fragments under the BEST methodology. Each gene fragment was treated as an individual locus for which individual gene trees were estimated (similar to MB3). Numbers represent posterior probabilities with grey-filled circles representing a posterior probability of 1.00.
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In order to achieve convergence using BEST method, we chose to enforce a molecular clock to reduce the number of parameters in the analysis. To evaluate the impact of this parametric restriction on the resulting inferences, we also conducted BEST analyses without enforcing a molecular clock. Only minor differences in cluster groupings between analyses were observed where S. agnetis and S. hyicus formed a clade with S. chromogenes as the sister taxon in Additional file 7: Figure S5, while the alternate (non-clock BEST) analysis estimated S. agnetis and S. chromogenes to form a clade, sister to S. hyicus (data not shown). However, because convergence was not achievable without application of a strict molecular clock, overall node supports for this tree tended to be lower than the clock-constrained BEST analysis. These results also suggest that differences in tree topology between concatenated methods and BEST analyses are not necessarily the result of applying a molecular clock to the dataset.
To obtain a more robust estimate of the staphylococcal phylogeny using BEST, additional datasets were assessed in which suspected conflicting loci and taxa were omitted. Omission of the tuf and rpoB loci, as well as taxa for which data were missing (i.e., S. agnetis, S. stepanovicii, and S. devriesei), substantially altered the branching order of major clades (as compared to original BEST methodologies incorporating all gene fragments and taxa), resulting in higher agreement with the concatenated BI and ML analyses (Figure 5). These data also support our previous ILD tests that suggested a significant difference between all loci except 16S rRNA and dnaJ (above). With the exception of a few notable differences, the modified BEST analysis was similar to the concatenated BI and ML analyses (Figure 5). The modified BEST analysis estimated, with weak support, the later divergence of S. auricularis as compared to BI and ML runs. This analysis also estimated a more basal divergence of the clades containing S. muscae, S. hyicus, and S. intermedius with a later divergence of clades containing S. pettenkoferi, S. arlettae, S. saprophyticus, and S. lugdunensis as compared to concatenated analyses (Figure 5). S. felis and S. lutrae shared a weakly supported clade (Pp = 0.44) within this BEST analysis as compared to belonging to different clades (described above) in concatenated BI and ML data analyses. S. gallinarum formed a clade (Pp = 1.00) in the modified BEST analysis with S. arlettae, and S. kloosii while concatenated analyses estimated S. arlettae to form an exclusive clade with S. kloosii and S. gallinarum belonging to a more distant clade (compare Figures 3 and 5).
Figure 5. Inference of the staphylococcal phylogeny using Bayesian estimation of species trees (BEST) methodology on 16S rRNA anddnaJgene fragments. Shown is a consensus phylogram of the staphylococcal species tree generated under the BEST methodology incorporating only 16S rRNA and dnaJ gene fragments. Each of the two gene fragments were treated as an individual locus for which individual gene trees were estimated. Numbers represent posterior probabilities with grey-filled circles representing a posterior probability of 1.00. Refer to Additional file 7: Figure S5 for the BEST analysis incorporating all four gene fragments.
Discussion
Using multilocus data to infer the Staphylococcus phylogeny
Staphylococcus is a species-rich genus of importance from both a human health and economic perspective. Relevant to the first goal of this study, our results provide strong evidence that the current groupings of Staphylococcus species require revision, and provide a clear consensus across analyses on how this could be done to reflect inferred evolutionary relationships among species groups. The second goal of the study was to infer higher-level relationships among species and cluster groups, and our results provide good evidence for much consensus across methods although there remains some alternative hypotheses for such higher-level relationships that differed between methods. To infer phylogenies relevant to both species-grouping and higher-level relationships, we used a combination of Bayesian and maximum likelihood analyses of multilocus data. We found that both Bayesian and maximum likelihood analysis of multilocus data yielded high-resolution species trees with overall high nodal support values for relationships among Staphylococcus species. We also found that partitioned-model analysis of the combined dataset, versus the concatenation-free analysis using BEST, produced near-identical estimates of the species composition of major clades and putative revised cluster groupings (i.e., more recent relationships).
In contrast to broad consensus across methods for resolution of relationships among more recent groupings of species, concatenated and gene-tree-based methods (BEST) inferred several alternative relationships among more ancient lineages of staphylococcal species. It is not entirely clear, however, what the source of these differences are (e.g., different evolutionary histories among genes being differentially resolved between methods, difference in how methods extracted signal from the multilocus data, etc.). It is notable that our finding that the BEST method inferred similar major clades as the concatenated methods, but inferred a different branching order among these major clades, has also been observed in other studies [40]. Such an observation may be indicative that although the phylogenetic signal contained within gene trees affords robust estimates of membership of particular species to major clades, conflicting signal or simply very little signal for deeper relationships among major lineages is available from single gene tree inferences (as in BEST). Our analysis of individual gene trees further supports this hypothesis whereby there appears to be substantial disagreement about higher-level relationships, but individual gene trees are consistent with one another regarding the placement of species within clusters towards the tips of the tree. It is notable that the modified BEST analysis, in which only two gene fragments were incorporated, more consistently resolved higher order relationships with the concatenated BI and ML methodologies. This suggests further that conflicting signal within the other two gene fragments was contributing to the discord among the original BEST analysis, incorporating all four loci.
It has been shown that staphylococcal species routinely laterally transfer genes [58], and it is therefore reasonable to consider that lateral gene transfer might complicate inference of phylogeny in this study. For example, lateral transfer (potentially combined with phylogenetic inference error) may explain instances of disagreement between gene trees and multi-locus inferences. Particularly in the case of inferring bacterial phylogeny, generally high instances of gene transfer inherently complicate inference of species-level trees, and even raise philosophical questions about the meaning of such species-level inferences [59]. Our results do, however, provide good evidence that there is indeed phylogenetic signal of an underlying species-level tree with many shared relationships across analytical methods, and this tree contrasts strongly with the existing higher-level classification scheme of the group that was based on less robust inferences methods. Our results largely agree across methods about the membership of species and subspecies to major clades, and thus provide new important confirmatory information sufficient for refining the nomenclature of the group.
Historically, staphylococcal species have been clustered into between four and eleven species groups [6,60-64]. Most of these groupings, however, were inferred based on a single locus with a small number of staphylococcal taxa. Phylogenetic estimates from this study suggest the separation of staphylococcal species into six major staphylococcal species groups comprised of 15 refined cluster groups (Figure 6). We have used our Bayesian, partitioned-model concatenated data estimate (i.e., Figure 2) as the focal phylogeny for illustrating evolutionary groupings of Staphylococcus since this phylogeny was also supported by our ML analysis, and previous reports on phylogenetic estimates of the staphylococcal phylogeny. Additionally, this phylogeny was essentially the same regarding these cluster groups based on the BEST tree. Current knowledge of phenotypic properties and relationships among staphylococci are also in agreement with the staphylococcal phylogeny estimated from concatenated analyses. For example, concatenated analyses resolved the oxidase positive species as being the sister to the remaining species, which is sensible given that outgroups of staphylococcal species are also oxidase positive; this relationship was also observed in the modified BEST analyses. For the purposes of reference, we indicate on the concatenated BI tree (Figure 6) where ML concatenated and BEST inferences differed. Wherever possible, we have attempted to name cluster groups and species groups following the original nomenclature put forth by Takahashi et al. [64], while recognizing only evolutionarily distinct, monophyletic groupings based on our estimates of phylogeny. As with previous analyses, cluster groups represent a single monophyletic clade of species, based on branching pattern [64], while species groups follow those previously described by Kloos et al.[65] and present cluster groups sharing similar phenotypic properties [64,66].
Figure 6. Staphylococcal species can be combined into six species groups and 15 cluster groups. Shown is a summary phylogram adapted from Figure 2 with clades collapsed to represent staphylococcal groupings. Whenever possible, cluster and species group names were kept consistent with [64]. Cluster groups have been color-coded to represent: blue, species that are novobiocin resistant, coagulase negative, and oxidase positive; green, species that are novobiocin susceptible, coagulase negative, and oxidase negative; orange, species that are novobiocin resistant, coagulase negative, and oxidase negative; purple, species that are novobiocin susceptible, coagulase positive, and oxidase negative; and red, species that are novobiocin susceptible, coagulase variable, and oxidase negative. Color scheme exceptions are: #S. schleiferi schleiferi is coagulase negative; *S. simiae is coagulase negative; S. hominis novobiosepticus is novobiocin resistant; and S. equorum linens is novobiocin susceptible. Members of each cluster group are listed below the cluster group name. Nodes receiving Pp = 1.00 or BS = 100% are indicated by grey-filled circles; otherwise, MrBayes posterior probability is shown in red text, BEST posterior probability is shown in blue text, and ML bootstrap support is shown in black text. Clades that were not present in BEST or ML are indicated by a blue or black §, respectively.
Refined phylogeny and classification of Staphylococcus spp
Consistent with previous studies [55,63,64,67,68], our analyses identified the monophyletic group containing the novobiocin-resistant, oxidase positive species (Sciuri group; Figure 6, blue cluster group) as the sister group to all other Staphylococcus. This cluster group also contains the recently discovered species, S. stepanovicii[11]. Within this group, we inferred a close relationship, with little sequence divergence, between S. vitulinus and S. pulvereri (BI and BEST Pp = 1.00; BS = 100%), potentially supporting the reclassification of S. pulvereri as a later synonym of S. vitulinus[67]. After the basal divergence of the Sciuri group, the second lineage to diverge from the remaining staphylococcal lineages was the oxidase negative Auricularis group, containing only S. auricularis (Figure 6). Our phylogeny therefore suggests that cytochrome C oxidase was lost in Staphylococcus sometime in the common ancestor of S. auricularis and the remaining Staphylococcus species, after their divergence from the Sciuri group (Figure 6, red star).
Our phylogenetic placement of S. auricularis as the sister lineage to all non-Sciuri group staphylococci is unique to our study, and we find strong support for this inference (MrBayes Pp = 1.00 and ML BS = 99%). Based on the 16S rRNA gene alone, Takahashi et al.[64] estimated that S. auricularis shared a common ancestor with the S. saprophyticus, S. lugdunensis, S. haemolyticus, S. warneri, S. epidermidis and S. aureus cluster groups. More recently, Ghebremedhin et al.[6] estimated a similar relationship to that of Takahashi et al. based on 16S rRNA gene alone. Analyses of subsequent gene fragments, however, yielded varying relationship estimates for S. auricularis, and no previous studies have found particularly strong support for the placement of this lineage. For example, Ghebremedhin et al.[6] recovered bootstrap support of 31% for a clade containing S. auricularis and S. kloosii based on the 16S rRNA gene, although average BS support across their tree was particularly low, at BS = 52%. Similarly, S. auricularis was placed as the sister lineage to S. kloosii plus the S. saprophyticus group, with BS = 25% based on analysis of the 16S rRNA gene by Takahashi et al.[64].
We inferred that the next lineage of Staphylococcus to diverge was the Simulans species group (Figure 6), which contains four species that are all novobiocin susceptible and coagulase negative. For consistency with previous nomenclature [6,64], we refer to this clade as the Simulans-Carnosus cluster group and the species group as the Simulans group (Figure 6). Our estimate of relationships among species of this group agree with previous studies, although the inclusion of S. condimenti in our trees is novel [6,64]. We inferred a single clade (Simulans-Carnosus cluster) containing the novobiocin susceptible, coagulase negative species, S. simulans, S. condimenti, S. carnosus and S. piscifermentans.
Following the split of these three early-diverging lineages, the remaining Staphylococcus species diverged into three large species groups. The first of these to diverge from the remaining was the Saprophyticus species group (Figure 6), which we inferred consists of four cluster groups. Within this species group, the Pettenkoferi-Massiliensis cluster group contains novobiocin susceptible species while all of the remaining members of the Saprophyticus group are novobiocin resistant. Thus, it seems that an alternative gyrase B gene conferring novobiocin resistance may have been acquired in this clade sometime after the Pettenkoferi-Massiliensis cluster group diverged from the rest of the Saprophyticus species group. Based on analysis of the 16S rRNA gene, Al Masalma et al.[55] reported the newly discovered species S. massiliensis to be a member of the Simulans group, although they failed to recover this relationship in analyses of the dnaJ, rpoB, and tuf genes, where they instead placed it with S. pettenkoferi as we have here. It is also notable that the close relationship between these coagulase-negative species was also suggested based on their phenotypic similarities across a range of biochemical tests [55]. Additionally, in the Saprophyticus cluster group, we inferred a close relationship between S. equorum, S. succinus, S. saprophyticus, and S. xylosus with S. gallinarum as the sister lineage to these four species. The placement of S. gallinarum in other studies is variable, but on multiple occasions has clustered with the Arlettae-Kloosii group [6,57,60,63,64]. This alternative placement of S. gallinarum seems reasonable as we find the Arlettae-Kloosii cluster group to be closely related to the Saprophyticus cluster group (Figure 6).
The Epidermidis-Aureus species group contained five cluster groups, including the most common taxa of heightened clinical significance [6]. In general, our estimates of relationships among these species are consistent with previous reconstructions [57,64]. Relationships within the Haemolyticus cluster group also agree with previous estimates [64], with the placement of the recently discovered coagulase-negative bovine strain, S. devriesei, forming a clade with S. haemolyticus[69]. Lastly, the Hyicus-Intermedius species group contained species of the "S. hyicus-S. intermedius cluster group" originally proposed by Takahashi et al. [64] based on a 16S rRNA gene dataset, and additional studies have found similar estimates of relationships based on analyses of other loci [1,6,60,61,63,70]. The limited number of taxa assessed in these studies has, however, prevented a more detailed understanding of species relationships within this species group prior to our analysis here. Moreover, recent novel species discovery (in particular S. rostri[70], S. microti[1], and S. agnetis[57]) has also contributed to the enhanced diversity of the Hyicus-Intermedius group. We have divided this species group into three cluster groups based on their phylogenetic relationships, which is also supported by their phenotypic diversities (Figure 6). Species among the Intermedius cluster group are all coagulase positive, excepting S. schleiferi schleiferi. Interestingly, S. schleiferi coagulans is coagulase positive, consistent with the other members of this cluster group, implying a recent loss in S. schleiferi schleiferi. In contrast, the Muscae cluster group contains only coagulase negative species (S. muscae, S. rostri, and S. microti). Within the last two years, both S. rostri[70] and S. microti[1] were discovered and found to cluster with S. muscae, thus altering previously known relationships within this species group. The Hyicus cluster group is coagulase-variable, including coagulase positive (S. hyicus), negative (S. chromogenes, S. felis), and variable (S. agnetis) species (Figure 6, red cluster group).
Conclusions
Through the analysis of multiple loci under a variety of phylogenetic methods, we achieved one of our main goals of inferring a robust estimate of the cluster groupings among staphylococcal species. We have used this estimate of cluster groupings to refine the current knowledge of the systematics and nomenclature for this important genus. Our results also contribute to a presumably more accurate understanding of the higher-level relationships among Staphylococcus species, although we do note that there are several outstanding questions left by the alternative resolutions of our concatenated versus species-tree-based inferences. We have attempted to present these yet unresolved inferences in a transparent fashion such that future work might directly test remaining alternative hypotheses and add further clarity to the relatively small number of remaining questions about relationships among staphylococcal species. The availability of such a comprehensive estimate of the evolutionary origins of, and relationships among, staphylococci provides an important context for understanding patterns of gain and loss of genetic and physiological attributes, and the potential role of lateral gene transfer in both pathologically-relevant phenotypes and in estimation of phylogenetic relationships among species. Such questions are of particular relevance considering the clinical and economical significance of some Staphylococcus species. Approaches such as this will provide a more natural classification of species based on phylogenetic inferences and lend support to future evolutionarily-informed studies of microbial diversity and physiology.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
RPL participated in study conception and design, data acquisition, genetic analyses, and manuscript preparation. GM participated in data acquisition, maximum likelihood analyses, and manuscript preparation. TAC contributed to conceptualization, data interpretation, and preparation of the manuscript. ST participated in data acquisition, and manuscript revision. AMC provided analytical software and hardware, participated in study design, data analysis, and manuscript preparation. CLP provided analytical software, participated in study design, data analysis, and manuscript preparation. All authors read and approved the final manuscript.
Acknowledgements
Funding for this study (including that for Open Access, stipend support, computational software/hardware, and usage of the STOKES IBM High Performance Computer Cluster) was provided in part by a doctoral postgraduate scholarship (PGS-D) from the Natural Sciences and Engineering Research Council of Canada (to R.P.L.), a National Institutes of Health grant AI060753 (to A.M.C.), and a National Science Foundation grant 0525429 (to C.L.P.). The authors would also like to thank Matthew P. Wood for assistance in editing the manuscript and the University of Central Florida STOKES Advanced Research Computing Center for providing computational resources and support that have contributed to results reported herein.
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Research article
Comparative analyses imply that the enigmatic sigma factor 54 is a central controller of the bacterial exterior
Christof Francke1,2,4,6*, Tom Groot Kormelink1,2,3,6, Yanick Hagemeijer6, Lex Overmars1,3,6, Vincent Sluijter6, Roy Moezelaar1,5 and Roland J Siezen1,2,4,6
Author affiliations
1 TI Food and Nutrition, P.O.Box 557, 6700AN Wageningen, The Netherlands
2 Kluyver Centre for Genomics of Industrial Fermentation, Julianalaan 67 2628 BC Delft, The Netherlands
3 Wageningen University and Research Center, Laboratory of Microbiology, Dreijenplein 10, 6703 HB Wageningen, the Netherlands
4 Netherlands Bioinformatics Centre, Geert Grooteplein 28 6525 GA Nijmegen, The Netherlands
5 Wageningen University and Research Center, Food and Biobased Research, PO Box 17, 6700 AA The Netherlands
6 Center for Molecular and Biomolecular Informatics (260), NCMLS, Radboud University Nijmegen Medical Center, P.O.Box 9101, 6500HB Nijmegen, The Netherlands
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Citation and License
BMC Genomics 2011, 12:385 doi:10.1186/1471-2164-12-385
Published: 1 August 2011
Abstract
Background
Sigma-54 is a central regulator in many pathogenic bacteria and has been linked to a multitude of cellular processes like nitrogen assimilation and important functional traits such as motility, virulence, and biofilm formation. Until now it has remained obscure whether these phenomena and the control by Sigma-54 share an underlying theme.
Results
We have uncovered the commonality by performing a range of comparative genome analyses. A) The presence of Sigma-54 and its associated activators was determined for all sequenced prokaryotes. We observed a phylum-dependent distribution that is suggestive of an evolutionary relationship between Sigma-54 and lipopolysaccharide and flagellar biosynthesis. B) All Sigma-54 activators were identified and annotated. The relation with phosphotransfer-mediated signaling (TCS and PTS) and the transport and assimilation of carboxylates and nitrogen containing metabolites was substantiated. C) The function annotations, that were represented within the genomic context of all genes encoding Sigma-54, its activators and its promoters, were analyzed for intra-phylum representation and inter-phylum conservation. Promoters were localized using a straightforward scoring strategy that was formulated to identify similar motifs. We found clear highly-represented and conserved genetic associations with genes that concern the transport and biosynthesis of the metabolic intermediates of exopolysaccharides, flagella, lipids, lipopolysaccharides, lipoproteins and peptidoglycan.
Conclusion
Our analyses directly implicate Sigma-54 as a central player in the control over the processes that involve the physical interaction of an organism with its environment like in the colonization of a host (virulence) or the formation of biofilm.
Keywords:
biofilm; enhancer binding protein; exopolysaccharide; lipopolysaccharide; nitrogen assimilation; motility; peptidoglycan
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Research article
Effects of chronic carbon monoxide exposure on fetal growth and development in mice
Carolina C Venditti1, Richard Casselman1 and Graeme N Smith1,2*
Author affiliations
1 Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada
2 Obstetrics and Gynecology, Kingston General Hospital, Kingston, ON, Canada
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Citation and License
BMC Pregnancy and Childbirth 2011, 11:101 doi:10.1186/1471-2393-11-101
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2393/11/101
Received:3 October 2011
Accepted:14 December 2011
Published:14 December 2011
© 2011 Venditti 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
Carbon monoxide (CO) is produced endogenously, and can also be acquired from many exogenous sources: ie. cigarette smoking, automobile exhaust. Although toxic at high levels, low level production or exposure lends to normal physiologic functions: smooth muscle cell relaxation, control of vascular tone, platelet aggregation, anti- inflammatory and anti-apoptotic events. In pregnancy, it is unclear at what level maternal CO exposure becomes toxic to the fetus. In this study, we hypothesized that CO would be embryotoxic, and we sought to determine at what level of chronic CO exposure in pregnancy embryo/fetotoxic effects are observed.
Methods
Pregnant CD1 mice were exposed to continuous levels of CO (0 to 400 ppm) from conception to gestation day 17. The effect on fetal/placental growth and development, and fetal/maternal CO concentrations were determined.
Results
Maternal and fetal CO blood concentrations ranged from 1.12- 15.6 percent carboxyhemoglobin (%COHb) and 1.0- 28.6%COHb, respectively. No significant difference was observed in placental histological morphology or in placental mass with any CO exposure. At 400 ppm CO vs. control, decreased litter size and fetal mass (p < 0.05), increased fetal early/late gestational deaths (p < 0.05), and increased CO content in the placenta and the maternal spleen, heart, liver, kidney and lung (p < 0.05) were observed.
Conclusions
Exposure to levels at or below 300 ppm CO throughout pregnancy has little demonstrable effect on fetal growth and development in the mouse.
Background
At very high levels, carbon monoxide (CO) is a toxic gas; exogenous inhalation of CO levels higher than 3% (30 000 ppm) leads to lethal outcomes [1], but this is usually through accidental inhalation of smoke or exhaust in enclosed spaces [2]. Interestingly, CO is produced endogenously at low concentrations with normal physiologic functions: smooth muscle cell relaxation, control of vascular tone [3], platelet aggregation [4], anti-inflammatory and anti-apoptotic events [5].
Endogenously, the oxidization of heme by the enzyme heme oxygenase (HO) produces equimolar amounts of CO, iron and biliverdin [6]. Heme is a major structural component of hemoglobin (Hb), and the abundance of this molecule in red blood cells allows for the largest amount of heme for degradation. Additionally, CO has been measured in a number of tissues; most abundantly in muscle, heart, liver, spleen, and kidney [7]; although both endogenous levels and functionality are not well understood.
Exogenous inhalation of CO leads to its preferential binding with Hb, producing carboxyhemoglobin (COHb). This binding is in direct competition with molecular oxygen (O2), and binds to Hb with 250 times greater affinity than O2 [8]. This effect shifts the O2 dissociation curve to the left [9], limiting the release of O2 to the tissues, and can lead to hypoxia, or further, the asphyxiating effects of CO poisoning. Measurable CO levels in non- smoking adults are 0 to 1.5% COHb [10], whereas people who smoke may increase their %COHb levels to 14% [11,12]. Refer to Table 1 for a comparison of reference CO levels.
Table 1. Reference Carbon Monoxide levels in humans and various environmental sources
Although many negative effects are associated with cigarette smoking in pregnancy, 17% of Canadian women smoked cigarettes in their pregnancy between 1995 and 2001 [13]. Of the greater than 4800 toxic chemicals identified within cigarette smoke [14], a major combustible product is CO. It readily crosses the placenta and can combine with fetal Hb and tissue heme moieties [15]. When pregnant sheep were exposed to CO, a lag period was found before fetal CO levels began to rise, but shortly afterwards, they matched and even surpassed those of their mother. Fetal hypoxia may result at high levels of maternal CO exposure, however, the level at which maternal CO exposure becomes a fetal threat is unknown.
In vitro, researchers have isolated HO in human placental and umbilical cord tissues [16], suggesting that CO is produced in this tissue. We have shown that CO, at levels similar to those found in umbilical cord blood at delivery, is capable of placental vasorelaxation [17]. As the levels of CO in pregnant women who smoke are increased, this suggests an exacerbation of placental vasorelaxation, while we have shown that nicotine has no effect on the basal feto/placental perfusion pressure [18]. These results suggest that CO may play a role in placental development and/or its regulation of placental hemodynamics [19].
A few studies have examined the effects of CO exposure in pregnancy, but they yield conflicting results in different animal species [20-23]. Studies conducted in pregnant wister rats exposed dams to one CO dose above 1000 ppm for varying lengths of time throughout pregnancy, observing decreased fetal weights and litter size [20,21]. It is likely at such high exposures that CO poisoning occurred, however venous CO levels (57% COHb recorded) were measured only in one of the studies, with no mention of the method by which this number was obtained [21]. Studies conducted at 500 ppm CO and below [22-24] yield maternal %COHb levels of roughly 28 [7], approximating more closely %COHb of adults smoking roughly two packs of cigarettes/day (up to 14%) [25]. The results from each of these studies are difficult to compare, as dosing mechanisms, lengths and amounts of CO concentrations given to the animals vary between groups.
In the present study, we hypothesized that CO would be embryotoxic. We investigated the effect of chronic CO exposure to mice in pregnancy, and sought the level at which no maternal or feto/embryotoxic effects were demonstrable.
Methods
Ethics Statement
Experimental procedures were carried out according to the University Animal Care Committee of Queen's University and was approved by the Queen's University Ethics Committee (REB no. Smith 2007-052- Or).
Animals and Husbandry
Timed matings of CD1 mice (Charles River, USA), female (6-8 weeks old) and males (5-7 weeks old), were performed overnight. Females were weighed and placed into a regulated CO-dosing chamber on GD1 (morning detection of a vaginal plug). Food and water were provided ad libitum.
Carbon Monoxide Concentrations
Concentrations of CO administered were 0, 25, 60, 100, 150, 200 250, 300 and 400 ppm in ambient air. At each concentration a minimum of six pregnant female mice were utilized. Room air was collected using a compressor (Panther Compact 106, Silent Air Compressor, Texas, USA) and passed through a Norgren air dryer (Littleton, CO USA). The dry air was mixed with 10%CO gas (Praxair, Kingston, ON) using flow meters (Alicat Scientific, Tucson, AZ USA), and adjusted to the specific CO concentration required, using a Gas Mixing software Program (Qubit Systems Inc, Kingston, ON). The air was bubbled through distilled water, reintroducing humidity levels of 40-50% (animal care regulations), and monitored using a Humidity Sensor (Vernier relative humidity sensor, Mississauga, ON, CAN) and its software (Vernier Logger Lite Software, Mississauga, ON, CAN). This sensor also ensured the cage temperature was maintained at 25°C. The air mixture was vented into a tightly- sealed plastic aquarium, in which the mouse cage was placed, and exhausted out of the chamber into the room's air filter system. The chamber air was changed a minimum of 10 times per hour (flow rate 7000 ml/min). The cage was changed twice weekly by research personnel, at which time the CO administration was stopped (20 minute maximum). Air samples were collected at least twice weekly from the aquarium air- port, and measured using a gas-solid chromatography machine (GC) (Peak Performer 1, Palo Alto, San Francisco, USA), as previously described[26], ensuring CO levels matched the desired concentrations.
Experimental Procedure
Female mice were anesthetised on GD17 by intraperitoneal injection of 10 mg/g of 2-2-2-Tribromoethanol (T48402, Sigma Aldrich, Canada). Upon reaching a surgical plane of anaesthesia, maternal blood was drawn by retro-orbital blood collection using a glass pipette, transferred to a microcentrifuge tube containing 10 microliter (μl) of 1430 U/ml sodium heparin (Sigma Aldrich, H0777), and placed immediately on ice. Mice were then perfused (gravity perfusion) through the left ventricle for 15 minutes with either phosphate buffered saline (PBS) (minimum of four mice/experiment) or 4% paraformaldehyde (PFA) (minimum two mice/experiment).
Blood CO measurement
Hemoglobin was measured within 5 minutes of blood collection using a Hemocue Hb 201 (Hemocue, Sweden). Amber vials (2 ml) (Sigma- Aldrich Ltd) capped (Chromatographic Specialties C223710C) with 8 mm silica septa (Chromatographic Specialties, C13302) and containing 20 μl of 2% sulfosalycylic acid (Sigma Aldrich, Cat no. 86193) were purged with 21%O2/5%CO2/balance N2 (Praxair, Kingston, ON) sent through a catalytic converter (to reduce any CO present). Between 0.1 μl and 1 μl of blood (depending on the level of CO administration) was added using a gas tight Hamilton syringe and repeater system (Hamilton, USA). Triplicate vials per blood sample were prepared and set on ice for 60-120 minutes. Carbon monoxide levels were read using a GC and expressed as a percentage of total Hb using the following equation:
(1)
where "vol CO" is milliliters of CO bound to 1L of blood, Hb is total Hb concentration in the blood (g/L) and 1.368 is the CO-binding capacity of Hb in millilitres per gram.
PBS perfused mice
Following a 15 minute perfusion, the uterus was dissected out, and all fetuses and their respective placentas (excluding gestational losses) were removed and weighed. Litter size was noted for each mouse. All fetuses and placentas were examined for gross morphological abnormalities. Fetal mortality was classified as early gestational demise (EGD), or as a late gestational death (LGD) (Figure 1). We classified EGD as a resorbed fetus, where no separate distinction existed between placenta and fetus (Figure 1A), while LGD was determined by a discernible fetus and placenta (Figure 1B). A normal fetus at gestation day 17 is shown in Figure 1C.
Figure 1. Representation of fetal early/late gestational death. A typical fetal early gestational demise is shown in A, a fetal late gestational death is shown in B, a normal fetus at GD17 is shown in C.
Fetal Blood Collection
Three random fetuses were decapitated and blood was collected using a heparin-coated capillary tube (Fisher brand, Cat no. 22-260-950). The blood from the fetuses was pooled into a microcentrifuge tube and blood processing was completed as previously described for the dams.
Tissue CO Levels
Sections of maternal organs (brain, liver, lung, kidney, spleen, heart) and placenta were collected and placed on ice immediately. Tissue CO measurement was performed as per Vreman et al.[7].
4% PFA perfused mice
A minimum of 2 mice per experiment were perfused with PFA. Following perfusion with 4% PFA, the uterus was removed. Dissecting between implantation sites, three embryos were removed from each mouse's uterus, stored in 4% PFA for 24 hours, and transferred to 70% ethanol until processing. Embryos were embedded in paraffin according to standard procedures.
Each embryo (six per CO concentration) was sectioned (0.4 μm thickness) a minimum of 10 times in a saggital plane and placed on slides. Of the 10 slides, a random selection of 5 slides were chosen and stained with hematoxylin and eosin. Placentas were analyzed for histological morphometric changes compared to control. Three pictures were taken using Nikon Eclipse E800 Light Microscope and Q capture software of the whole placenta (10X and 40X magnification) as well as the placenta labyrinth (200X magnification). The placentas were analyzed for relative proportions of labyrinth versus junctional zone and alterations in cell shape and size. A third party anatomist was consulted on all histological slides analyses.
Statistical Analysis
Dose response curves for maternal/fetal %COHb and Hb concentration were analyzed using linear regression analysis. The EGD and LGD data was analyzed with a chi squared test using the fisher exact method. EGD were compared to total implantation sites subtract EGD and LGD, while LGD were compared to live implantation sites subtract LGD. For this test, OpenEpi.com version 2.3.1 was used to analyze data. All other analyses were completed using a one way analysis of variance with a post-hoc Dunnett's multiple comparison test, using Graphpad prism version 6. A p-value less than 0.05 was deemed significant for all tests. All statistical results are reported with standard deviation.
Results
All of the required CO levels for this study were achieved using the computerized software and were confirmed using GC to be between 0.5 and 5.0 ppm (up to 1.6%) of the desired CO levels.
For each CO exposure, a minimum of four mice were perfused with PBS and two mice with PFA. The amount of litters per experimental group for the exposures of 0, 25 and 60 ppm CO are larger than the remaining exposures. This was due to a slight change in protocol following the beginning of the study, where we developed a method to measure fetal blood CO levels. Therefore, we repeated the first three experiments at 0, 25 and 60 ppm CO, in order to acquire this data.
The blood %COHb levels were positively correlated with increasing CO concentration exposure, for both maternal (p < 0.01) and fetal (p < 0.01) measurements (Figure 2A). The ratio of fetal/maternal %COHb was a mean (SD) of 1.74X (0.12), beyond 25 ppm. Additionally, Hb followed the same trend as %COHb levels, and was positively correlated with increasing CO concentrations for both maternal (p < 0.01) and fetal (p < 0.01) levels (Figure 2B).
Figure 2. Dose responses of maternal/fetal Hb and CO levels to increasing maternal exogenous CO exposure. A positive trend was observed with both maternal and fetal blood %COHb vs. CO concentration exposure (A). A positive trend was observed with both maternal and fetal Hb vs. CO concentration exposure (B).The slope of the line significantly deviated from zero in both cases, A and B (p < 0.05).
Mean fetal mass did not differ compared to control with CO concentrations of 25 ppm to 300 ppm (Figure 3A). At 400 ppm CO, fetal mass was significantly lower than that of the control (p < 0.05). Placental mass was not found to be significantly different than the control with any of the CO doses (p > 0.05) (Figure 3B). Litter size was significantly reduced only at 400 ppm compared to control (p < 0.05) (Table 2).
Table 2. The effect of maternal CO exposure on total number of early gestational demise/late gestational death
Figure 3. Comparison of mean fetal and placental mass to maternal exogenous CO exposure. Mean fetal mass for each CO exposure level is displayed in figure A, with a significant decrease in mass observed only at 400 ppm (* p < 0.05). Mean placental mass for each CO exposure level is displayed in figure B; no significance at any of the CO exposures was observed (p > 0.05).
In Table 2, total implantation sites/litter did not differ between experimental CO exposures. The number of EGD and LGD increased with maternal CO exposure. EGD is presented as EGD/(total implantation sites- EGD) *100% and LGD is presented as LGD/[total implantation sites- (LGD + EGD)]*100%. A significant increase in number of fetal EGD was observed at 300 and 400 ppm, while LGD were found to be significant compared to control at 400 ppm (p < 0.05). Relative risk data and confidence intervals are listed in Table 2.
Figure 4 displays the tissue CO concentration in the maternal heart, liver, lung, kidney and brain, for each CO exposure. An elevation in tissue CO concentration is observed for most tissues, as maternal CO exposure increases. Figure 5 displays the CO levels in the placenta and maternal spleen for each CO exposure. These organs are shown separately as they contained at least four times the CO level as the other tissues examined. At 60 ppm CO exposure, significant differences (p < 0.05) are observed in both tissue samples, compared to control tissue.
Figure 4. Maternal tissue CO levels in heart, liver, lungs, kidney and brain for each CO exposure. Significance was found in the heart tissue at CO levels ≥100 ppm, in the liver at CO levels ≥ 200 ppm, in both the lung and kidney at the CO level of 400 ppm only and finally in the brain at CO levels of 250 and 300 ppm only (* p < 0.05).
Figure 5. Placenta and maternal spleen tissue CO levels with increasing CO exposure. Compared to control, significance was observed in both placenta and spleen at CO levels ≥ 60 ppm exposure (* p < 0.05).
Blinded histological analysis of placental tissue did not show any gross morphological differences between those exposed to CO and controls (data not shown). All parties analyzing histological slides noted no differences in relative amounts of labyrinth versus junctional zone. Additionally, no alterations in cell shape and size were observed.
Discussion
A number of studies have evaluated the effects of CO exposure on pregnancy; however a direct comparison of these studies is difficult because of significant methodologic differences. For example, the method of CO delivery varied from whole body[20-22] to nose-only inhalation [27], time exposure (acute vs. chronic) differed; daily time intervals or specific days of gestation. The dosing concentrations differed, with some studies evaluating CO levels of 1000 ppm to 10 000 ppm [20,28], well above the toxic range. No previous study has correlated maternal/fetal CO levels with maternal/fetal outcomes. Our study's aim was to use a highly regulated CO chamber system to expose pregnant mice to chronic CO concentrations throughout gestation, that would mimic those of smoking adults (2-14%COHb)[25].
Maternal cigarette smoking is perhaps one of the most common chronic methods by which CO levels are increased, thereby exposing the fetus to greater than normal CO levels. Our laboratory has measured a range of COHb in maternal smokers of 1.5-9.85%COHb (unpublished), while a level of 14%COHb has been determined previously by other researchers [11,12]. Cigarette smoke contains an average of 4% or 40 000 ppm CO by volume [29], and during the smoking process it becomes diluted in air, leaving the alveoli to see roughly 400-500 ppm [15]. It is known that CO can cross the placenta, therefore CO can affect the fetal partial pressure of O2 (pO2) [15].
In the present study, the highest dose of CO yielded a mean maternal %COHb level of 15.6, while women who smoke heavily during pregnancy have a calculated CO level of up to 14%COHb [11,12]. It is important to note that in comparison with women who intermittently smoke, and thus are affected by peaks and troughs of high CO exposure, these mice were subjected to elevated CO concentrations on a constant basis. The half- life of CO is 2-3 hours when breathing room air [15], therefore a smoker would have peak CO levels directly following their smoking a cigarette, which would slowly dissipate until the next cigarette. Also of importance are the elevated ventilation and elimination rates, along with increased CO uptake, present in smaller mammals compared to humans [30]. As explained by Klimisch et al.[30], the higher ventilation rates by smaller mammals allow for a faster rate of Hb saturation by CO. Therefore, the %COHb results observed in this study are presumably higher than those that would be seen in women under similar exposure. The %COHb values cannot be evaluated directly, but can be used as representative values to compare the mouse model with the potential effects in pregnant women.
As an adaptation response to increased CO levels, likely in part due to hypoxia, it is documented that mammals will increase Hb concentration [31] in order to increase the O2 carrying capacity of the blood. A significant dose- response was observed with both the maternal and fetal Hb to increasing CO exposure levels, and one would expect a similar response in pregnant women.
The ratio between maternal and fetal %COHb concentrations (1.74) is in agreement with a study conducted by Longo and Hill [32], and similar to results recorded by Bureau et al.[33]who showed that the ratio of fetal/maternal COHb was 2.5 (using umbilical blood as a fetal representative value). The Hb levels of both maternal and fetal systems differ and the affinity of fetal Hb for CO is established to be higher than that of the maternal system [12]. This, coupled with the lower pO2 in capillary blood of the fetus versus maternal system [12], would add to the effect of increased fetal %COHb compared to maternal %COHb.
There is considerable variability in the effects of CO exposure on fetal birth weight in the published literature. It is well established that pregnant women who smoke cigarettes will give birth to a neonate roughly 200 g lighter (per pack per day smoked) than a fetus born to a non- smoking mother [34]. However, given that there are thousands of toxic substances in cigarette smoke, the specific role of CO in these situations cannot be determined. Wouters et al [28] and Soothill et al.[35] studied the human effects of increased fetal COHb on fetal weight, with conclusions in both cases that data was not convincing for a simple cause-effect relationship. Our study found a significant decrease in birth weight compared to control only at our highest CO dose. Other studies have also found a decrease in birth weight with increasing CO exposure [20-23]. Singh and Scott found that subjecting pregnant CD-1 mice (on GD 8 to GD 18) to CO exposures of 0 to 500 ppm (controlling chamber levels using a CO monitor), lead to a significant decrease in fetal weight as early as 125 ppm, but not in a dose dependent manner [24]. This study did not measure CO levels in either maternal or fetal mice. Given the toxic effects demonstrated by Singh and Scott as early as 125 ppm, which conflicts with our data, this presents a possibility of fetal adaptation to CO exposures when subjected from conception, rather than mid- way through pregnancy. Future studies would be necessary to further examine this hypothesis.
Interestingly, placental weight was not significantly different than the control at any of the CO doses. Bissonnette and Wickham [36] reported that placental CO diffusing capacity increased significantly with greater gestational age, and correlated with fetal weight but not placental weight. Thus, as CO levels increased across our experiment, no correlation was expected with placental weight. Litter size (number of healthy fetuses) however, was significantly decreased at 400 ppm CO exposure compared to control. In previous studies, litter size in rats was not shown to be affected when dams were chronically exposed to 150 ppm CO throughout gestation [37], but was decreased when dams were exposed to acute doses of 1000 to 1600 ppm twice daily throughout pregnancy [20]. An increase in EGD and LGD above 180 ppm maternal CO exposure has been reported previously in varying animal models [23,24], although CO exposure levels and dosing schedules were different amongst them. In our study, while EGD proved significant compared to control at 300 ppm, at 400 ppm, more fetuses appeared to have died in late gestation. As the placenta's diffusing capacity increases with gestational age [38], perhaps fetal health was more greatly compromised later in pregnancy with higher CO doses, as more potent CO was able to diffuse to the fetal circulation.
Maternal tissue CO levels proved that aside from Hb, the gas was also accumulating in the heme- containing molecules found throughout tissue. At 0 ppm CO, tissue CO levels closely approximated those previously reported [7]. Both the spleen and the placenta were the most difficult tissues to perfuse, as their open circulation proved difficult for the complete removal of blood. This would explain the much higher CO levels compared to the other tissues sampled. A dose response was observed in both tissues. Of the remaining tissues measured, the heart expressed the highest CO concentration, possibly due to high myoglobin content, a heme containing protein with an affinity for CO second only to Hb [39].
In this study, at 400 ppm maternal CO exposure, a number of toxic results were noted. Compared to control, both maternal and fetal %COHb and Hb values were significantly increased, fetal birth weight and litter size were significantly decreased, and EGD/LGD were significantly increased. Maternal tissue CO levels increased as CO doses were raised, lending to the highest measurable CO amounts at 400 ppm. These results indicate that the chronic CO exposure to pregnant mice, at levels above 300 ppm, results in a feto-toxic effect.
Recently, CO has come into light as a possible therapeutic, due to its many beneficial effects: endogenous and exogenous CO can promote angiogenesis[40], suppress the release of anti-angiogenic markers[41], decrease inflammation and apoptotic events[5], and vasodilate blood vessels[16]. These beneficial properties of CO may be helpful in the treatment of disorders concerning angiogenesis and vascularity, including those in pregnancy. This study is of great importance as we have identified a fetal toxic threshold of CO in pregnancy above 300 ppm maternal exposure. This information can be used in future experimental designs, when examining the potential beneficial properties of CO exposure to treat disorders of pregnancy.
Conclusions
Our study indicates that exposure to levels at or below 300 ppm CO throughout pregnancy has little demonstrable effect on fetal growth and development in the mouse.
Abbreviations
CO: carbon monoxide; %COHb: percent carboxyhemoglobin; HO: heme oxygenase; Hb: haemoglobin; O2: oxygen; GC: gas chromatography; μl: microliter; EGD: early gestational demise; LGD: late gestational death; PBS: phosphate buffered saline; PFA: paraformaldehyde.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
CCV, RC and GNS participated in the design of the study. CV and RC carried out all mouse procedures. CCV carried out all analysis and preparation of histology, blood and tissue samples. The manuscript was drafted by CCV and reviewed and edited by GNS. Statistical analysis was performed by CCV, and reviewed by GNS. All authors read and approved the manuscript.
Acknowledgements
This study was supported by the Physicians' Services Incorporated Foundation http://www.psifoundation.org/ (Grant number 09-37 - "Effect of Carbon Monoxide on Placental Function and Development") (to G.N.S.); a Queen's Graduate Award and a McLaughlin Fellowship Award (to C.C.V)
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Findings presented in part at the 56th SGI Annual meeting, Glasgow, Scotland March 2009 and the 57th SGI Annual Scientific Meeting, Orlando, USA, March 26, 2010
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Technical advance
A Wireless Health Outcomes Monitoring System (WHOMS): development and field testing with cancer patients using mobile phones
Emilia Bielli1*, Fabio Carminati1, Stella La Capra1, Micaela Lina2, Cinzia Brunelli2 and Marcello Tamburini2
Author Affiliations
1 Reply-PlaneT, Via Ripamonti 89, 20139 Milan, Italy
2 Unit of Psychology, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy
For all author emails, please log on.
BMC Medical Informatics and Decision Making 2004, 4:7 doi:10.1186/1472-6947-4-7
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1472-6947/4/7
Received:1 March 2004
Accepted:15 June 2004
Published:15 June 2004
© 2004 Bielli et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.
Abstract
Background
Health-Related Quality of Life assessment is widely used in clinical research, but rarely in clinical practice. Barriers including practical difficulties administering printed questionnaires have limited their use. Telehealth technology could reduce these barriers and encourage better doctor-patient interaction regarding patient symptoms and quality-of-life monitoring. The aim of this study was to develop a new system for transmitting patients' self-reported outcomes using mobile phones or the internet, and to test whether patients can and will use the system via a mobile phone.
Methods
We have developed a prototype of a Wireless Health Outcomes Monitoring System, which allows structured questionnaires to be sent to the patient by their medical management team. The patients' answers are directly sent to an authorised website immediately accessible by the medical team, and are displayed in a graphic format that highlights the patient's state of health. In the present study, 97 cancer inpatients were asked to complete a ten-item questionnaire. The questionnaire was delivered by display on a mobile phone, and was answered by the patients using the mobile phone keypad.
Results
Of the 97 patients, 56 (58%) attempted the questionnaire, and all of these 56 completed it. Only 6% of the total number of questions were left unanswered by patients. Forty-one (42%) patients refused to participate, mostly due to their lack of familiarity with mobile phone use. Compared with those who completed the questionnaire, patients who refused to participate were older, had fewer years of education and were less familiar with new communications technology (mobile phone calls, mobile phone SMS, internet, email).
Conclusion
More than half of the patients self-completed the questionnaire using the mobile phone. This proportion may increase with the use of multichannel communications which can be incorporated into the system. The proportion may also increase if the patient's partner and/or family were able to assist the patient with using the technology. These preliminary results encourage further studies to identify specific diseases or circumstances where this system could be useful in patients' distance monitoring. Such a system is likely to detect patient suffering earlier, and to activate a well-timed intervention.
Background
Health-Related Quality of Life (HRQOL) measures simultaneously capture both past and current concepts of health. In 1948 the World Health Organisation identified health as "a state of complete physical, mental, and social well-being – not merely the absence of disease or infirmity" [1].
HRQOL measures can potentially aid routine clinical practice in the following eight ways: 1. prioritising problems; 2. facilitating communication; 3. screening for potential problems; 4. identifying preferences; 5. monitoring change or response to treatment; 6. training new staff; 7. clinical auditing; and 8. clinical governance [2].
HRQOL assessment is widely used in clinical research, yet rarely in clinical practice [3]. It appears barriers include lack of knowledge surrounding questionnaires, methods and terminology, and too little attention to subjective information [4,5]. Evaluation is generally carried out by giving patients printed questionnaires, which have proven difficult to administer in daily clinical practice.
Quality of life instruments
Over a thousand generic or specific questionnaires are used world-wide for HRQOL assessment of people with chronic diseases [6]. Other questionnaires have been developed to evaluate needs, satisfaction or treatment compliance. In the majority of cases the questionnaires are 'self-reported' and contain a list of questions (from 10 to over 100) requiring structured responses chosen by the patient between 4/7 possible options using a Likert scale (e.g. from "not at all" to "very much so").
Questionnaires are developed using a procedure that must demonstrate their psychometric properties, which include validity, reliability, responsiveness and interpretability. Questions usually refer to the physical, psychological, and social domains of health, and ask patients to recall their experiences during a fixed time frame, generally a week. A new generation of succinct instruments has proven to be potentially useful in clinical practice. Some of these have been developed for patients suffering from ageing [7], chronic respiratory diseases such as asthma [8], chronic obstructive pulmonary disease (COPD) [9], neurological diseases such as stroke [10] or headache [11], rheumatological diseases such as osteoporosis [12], nutritional and metabolic diseases such as obesity and weight loss [13], cardiovascular diseases such as arterial hypertension [14] and neoplastic diseases such as prostate cancer [15] or cancer in advanced or terminal phases [16,17], to cite but a few.
Quality of life monitoring
It has been observed that health care providers tend to underestimate the functional status and intensity of some physical symptoms like pain, and overestimate patients' feelings of anxiety, depression and distress [18-22]. The consequence of such errors in evaluation is inadequate treatment [23,24].
It is usually difficult for medical staff to obtain up-to-date information when patients return home. HRQOL monitoring by means of a questionnaire completed by the patient may assist in determining the problems of the patient to the same degree as standard biological assessments. This may provide an easy way to monitor a patient and prevent major problems developing. The function of a questionnaire could be considered similar to that of a thermometer, which detects fever without revealing its cause, leaving it to the physician to determine the nature of the problem. Such monitoring should not be considered as a bureaucratic tool or a way to reduce communication with the patient, but as a way to detect patient suffering earlier, and to activate a well-timed intervention.
New communication technologies can be used to reduce certain barriers, thereby encouraging better doctor-patient interactions through periodical monitoring of health status and physical symptoms in particular. The wide and growing use of mobile phones and the internet by the general population provides important new methods for communication between doctor and patient. The aim of the present study was to develop a new system for transmission of patients' reported outcomes using mobile phones or internet and to test the acceptability and the ability of patients using this system through mobile phones.
Methods
Development of the system
A Wireless Health Outcomes Monitoring System (WHOMS) prototype was designed and developed in order to satisfy two main objectives:
1. To allow patients to receive and self-report structured questionnaires via either WAP [25,26] or the Web [27];
2. To allow the physician to examine data reported on questionnaires through a graphical and chromatic interface.
These objectives can be met in the following ways (Figure 1):
Figure 1. Scenarios representation.
• (Scenario 1) Periodical sending of questionnaires to patients with mobile handsets. The questionnaire shipment uses a WAP/GPRS connection to send a "WAP Push Service Indication" message to the patient's mobile phone. The patient can see the questionnaire on the phone display via the GPRS connection.
• (Scenario 2) Questionnaire (10 symptoms questions in the prototype) completed by the patient. Using their mobile phone, the patient completes the questionnaire following the directions presented on the display. Questions are displayed one at a time and a set of answers is presented in a menu (Figure 2). The patient chooses the most appropriate answer according to their symptoms. Alternatively, for patients who prefer to use personal computers, a reserved online area can be accessed, where questionnaires can be compiled or overall reports containing previous answers can be displayed (note this internet option for patients was not trialled in the present study).
Figure 2. Questionnaire compilation. Questionnaire compilation using a mobile phone. The question is displayed on the left, and the answer set associated with each question is displayed on the right.
• (Scenario 3) Answer management. Using a reserved online area, the physician can examine patient's symptoms according to their questionnaire answers. The graphical and chromatic representation allows the doctor a quick and clear vision of how the patient's symptoms are evolving. A light flashes by the names of those patients that present seriously modified symptoms, so that the physician can identify the most significant changes at once and immediately take the necessary action. The parameters that determine the type of change that will cause a flashing signal can be customised by the physician and are specific for each questionnaire (Figures 3 and 4).
Figure 3. Patients' list. Patients' list display example. The physician can monitor all patients in a schematic way. A flashing light allows the physician to identify patients in which there has been significant change.
Figure 4. Patients' graph simulation. Example display of a patient's answers to the questionnaire.
Functional architecture
The functional requirements have been translated into a system architecture made up of the following modules (Figure 5):
Figure 5. Functional architecture.
Identification system: this component manages accounts, profiles assigned to system users and related identification. Once identified, the user is authenticated and authorised to use certain functions based on their profile and role recognised by the system. The authentication process is based on the user's MSISDN (mobile number) if connected through WAP, or on the user's account (login and password) if connected through the internet. The users' authentication guarantees both transmitted and accessed data privacy.
Questionnaire management system: this represents the heart of the system, and allows us to manage questionnaires (i.e. create, modify and delete). Through this module, it is possible to assign a questionnaire to one or more patients by specifying the examination elapse and the delivery recurrence. Questionnaire results are processed using the analysis function of this module.
Messaging system: this supplies the interface for sending SMS and MMS messages in order to solicit patients for recurrent compilation of questionnaires.
Rendering system: this module controls the questionnaire display based on user's type of handset. As far as possible, it aims to make the display not dependent on the type of device used.
Technological infrastructure
The prototype has been developed through use of open source software. The data structure was implemented through the MySql database [28], while the application logic was based on PHP language [29] and the Apache Web Server [30]. A Nokia emulator [31] was employed to develop and run preliminary tests on the WAP component of the system. The WHOMS was designed to offer a tool that can comprehensively enter each user's home. The channels used at present are WAP and WEB (Figure 6).
Figure 6. Operational workflow. The physician accesses the system through the internet and assigns a questionnaire to one or more patients by specifying the examination elapse as well as the delivery recurrence. The web server, through the use of a scheduler and interfacing the MMSC and SMSC modules, forwards a message to patients, inviting them to compile the questionnaire. Once compiled, the patient forwards their answers to the server which then stores the data using another module. A physician can then monitor the patient's health by connecting to the internet and viewing a graphical representation of the patient's answers.
For most patients, mobile phones are easily available at reasonable prices, which is why we have recruited GPRS technology for questionnaires. In contrast, the use of ad hoc media requires a bigger investment in terms of time and cost, and would have brought about many organisational issues linked to its propagation and maintenance, in addition to user training.
In order to limit problems linked to the display of questionnaires on handsets, only one mobile phone model was used in the present study. This allowed prompt implementation of a prototype and rapid feedback from pilot users. The mobile phone selected can display questionnaires with a very simple, immediate and appealing graphical interface.
A demonstration has been developed on the internet that allows us to test some of the functions offered by the system. It is possible to simulate a questionnaire completed by a patient, and then see the monitoring report for the physician updated with this new information transmitted by the patient http://www.qlmed.org/whoms/ webcite.
While the ultimate aim is for patients to also use this system via the internet, the current study focussed on patients accessing the system by mobile phone.
Patients
In the present study, the WHOMS was tested using a sample of 97 cancer inpatients. The patients were asked to complete a ten-item questionnaire using a mobile phone.
The survey was conducted in 12 sample days during two months (January–February 2004) in 5 Hospital's Units at the Istituto Nazionale Tumori of Milan. All inpatients (with the exception of those in the immediate post-surgery period or with visible physical impairments or slipping) were invited to use the system after receiving a ten minute explanation and demonstration of how the questionnaire was to be completed. The aim of this pilot study was to determine whether this mobile phone-based WHOMS questionnaire method would be successfully used by patients. Thus, patients would not directly benefit medically from this particular questionnaire compilation as their doctors would not be invited to see the answers or make clinical decisions based upon them. For this reason patients were volunteers rather than compulsory recruits. All patients used the same model of mobile phone – a Nokia 6600 – and the GPRS connection was via Vodafone.
Data regarding gender, age, years of education, primary tumor site, surgical unit, use of communication technologies (calls or SMS from mobile phone, internet or email use by personal computer), time to compile the questionnaire and the number of items missing were also collected. Patient's free observations after compilation were also documented.
The questionnaire
For this pilot study we used an easy questionnaire regarding 10 symptoms (pain, lack of energy, worry, weight loss, cough, difficulty sleeping, shortness of breath, problems urinating, lack of appetite, difficulty concentrating) extracted from the MSAS-SF [17]. Patients were requested to select the response that best described the extent to which the symptoms distressed or bothered them during the past week. They were asked to select from one of the following responses: Not at all / A little bit / Somewhat / Quite a bit / Very much.
Statistical analysis
The association between the outcome variables (ability to compile and acceptability of WHOMS) and patients' characteristics was examined firstly at univariate and then multivariate level using logistic regression models. Regression diagnostics and indices of model fit were applied to evaluate how well the models fitted to the data. Results are presented in terms of odds ratios and their 95% confidence intervals (CIs).
In order to reduce the dimensionality in the set of predictors, and to avoid sparseness of data, the four variables dealing with use of communication technology (mobile phone calls, mobile phone SMS, internet, email) were collapsed into a single score representing the number of communication tools they declared to have used in the week prior to hospital admission. Using this approach, the Familiarity with Communication Technology (FCT) score obtained ranged from 0 (no familiarity – no tool used in the week before) to 4 (high familiarity – all the tools used in the week before).
Results
The data in Table 1 shows patient profiles and indicates the number that either accepted or rejected the offer to complete the questionnaire. Patients had a mean age of 52 years, a mean of 10 years education, and the majority were women. In terms of use of communication tools, twice as many used mobile phones compared to the internet, and in the week prior to hospital admission, the most used communication type was mobile phone calls, and the least was email (Table 1).
Table 1. Acceptance or refusal by 97 cancer inpatients to compile the questionnaire using a mobile phone as related to patient characteristics
Of the 97 patients approached, 56 (58%) agreed to attempt the mobile phone-based questionnaire, and all of these completed the questionnaire. Forty-one (42%) patients refused to use the mobile phone. Of the 560 expected answers, only 6% were missing. The last item of the questionnaire had the highest number of missing answers (27%; Table 2). Patient profiling showed that compared those who attempted the questionnaire, those who refused were older, had fewer years of education and were less familiar with communication technology (mobile phones, internet, email). No differences emerged with respect to other factors such as gender, type of tumor or the hospital department to which patients were admitted.
Table 2. Mobile phone-based compilation of the questionnaire by 56 patients
One study aim was to determine the main reasons for inability to complete the questionnaire (i.e. visual or manual problems). However, this aim became redundant since all patients who attempted the questionnaire completed it satisfactorily.
Multivariate analysis for the "WHOMS acceptability" outcome confirmed the pattern of association that emerged in univariate analysis. Variables most strongly associated with acceptability were: FCT score, age and number of education years (Table 3). The model showed a good fit with the data (Hosmer-Lemeshow chisquare = 3.55, p = 0.89), and a high proportion of correctly classified observations (83.5%, sensitivity 87.5% specificity 78.1%). In particular, the odds ratios reported in Table 3 indicate that for a unit increase in the FCT score, holding all other variables constant, the odds of accepting WHOMS increased by 173%, indicating a very strong relationship. Both age and education years still maintain an independent, although weaker, association with acceptability (results indicate a reduction by 9% and an increase by 32% in the odds of accepting WHOMS for a unit increase, respectively).
Table 3. Association between WHOMS acceptability and patients' characteristics
Of the 41 patients that declined to answer the questionnaire, 37 refused due to inexperience, incapacity or idiosyncrasies regarding mobile phones. Examples of comments were: "I don't know how to use them", "I can't understand these things", "I don't like using this equipment", "I'm afraid I'll break it", "I wouldn't know where to put my hands","If it were necessary I would ask my son, who's good with that sort of thing, for help", "I'd tell my husband what to answer on his mobile phone", "I don't want a mobile phone, the computer's at home but it's my son's and I don't want him to read about my illness", "It would be too tiring for me if they sent me a questionnaire everyday." The other four patients refused on physical and psychological grounds. Examples of comments from these patients were: "I'm in too much pain at the moment", "I don't feel well", "I'm too worried about my test results", "I'm too worried, tomorrow I have to be operated."
Of the 56 patients that attempted the questionnaire, some spontaneous comments were: "It's really easy!", "In the 16 months that I've been going back and forth from hospital the only flaw I have had has been trying to contact the doctors from home. I believe it's extremely useful!", "I don't think I'll have any problem filling it out at home. Let's hope that the doctors go to see how the patients are doing!". One lady, after completing the questionnaire, decided to try a second time using the symptoms of her husband who was suffering from benign prostatic hyperplasia. In another case, after completing the questionnaire, the patient commented he was a doctor and that he would be interested in using WHOMS at his own specialist clinic. Only three patients owned the same model mobile phone as that used in this study. All three of them were immediately successful and it took them much less time to compile the questionnaire compared to other patients.
Discussion
In this field test study, the number of patients who refused to use a mobile phone to complete the questionnaire proved to be higher than expected. The reasons for refusal were usually related to the patient's unfamiliarity with this form of communication technology. Preoccupation due to an imminent operation and physical pain were also given as explanations for refusal.
The sample population comprised cancer patients with a mean age of 52 years. The number of patients who used mobile phones (82%) was unexpectedly high and was more than twice the number of internet users (37%). The latter are included (with the exception of one patient) among those who used a mobile phone, therefore the complimentary quota of around 20% use a fixed line only.
As expected, older age, lower number of education years, and in particular, lack of familiarity with new communication technologies were the most predictive factors for test refusal.
The absence of compilation problems for those who accepted to fill in the questionnaire confirmed the user-friendliness of the system for people familiar with modern communication technologies. The last question was associated with the highest amount of missing data (27%). This was probably due to the selection field being too close to, and indistinguishable from, the button used to confirm results.
The data generated in the present pilot study must be viewed cautiously in terms of the use of this WHOMS for communicating with patients at home. Firstly, the responses were from patients staying in the hospital, not from patients who had returned home. Furthermore, the questionnaire was designed to be particularly brief and easy. However, it was promising that there was a high percentage of successfully completed questionnaires given that all but three patients were completely unfamiliar with the mobile phone model used.
On the basis of the results obtained from this first study, we are currently introducing modifications aimed at improving the system. In particular, we are investigating multichannel approaches so as to offer WHOMS functions through palm computers, speech recognition and interactive voice responder (IVR) to provide a better interface and wider choice.
The WHOMS described in this study is being developed for monitoring patients at home and in clinical practice. It is likely to be more readily applied in hospitals, because it is easier to oversee questionnaire compilation by patients while they are in hospital. It is also likely to be more readily applied in HRQOL research, as only a part of the system is used since no medical intervention is requested on the basis of the data collected. HRQOL research with repeated measures can be completed with a very small amount of missing data. The system allows automatic inclusion of data in the electronic database, avoiding possible errors in data entry.
Conclusions
It is difficult to monitor patient symptoms and quality of life at home with paper-pencil questionnaires. This difficulty can be largely overcome through developments in telemedicine, telehealth (or e-health) and home telecare [32]. Numerous computer-based approaches have been useful in reporting patient conditions [33-36]. Although use of the Internet is one of the best ways to carry out distance health monitoring, it is still used only infrequently. For people over sixty, amongst whom chronic illnesses are more common [37,38], WHOMS has the advantage of offering both internet and mobile phone options to patients.
Medical and nursing staff are increasing their use of mobile phones during home visits in order to provide a smooth and speedy connection with care centres. Increasingly, programs are being established where telephones are used directly by the patient to monitor and pass on vital information concerning blood pressure, cardiac pulsation or ECG, so that any anomalies can result in fast medical intervention [39,40]. Furthermore, monitoring of the patient's quality of life/satisfaction/needs/treatments compliance can be achieved using standardised questionnaires created for patient use. Patients recently discharged following surgery, the elderly, those suffering chronic/evolving pathologies and terminally ill patients can communicate from a distance with their medical team, including the family doctor. In many cases the compilation of these questionnaires through video communication will provide for doctors a more up-to-date picture of the patient's state of health, and may allow the solving of problems without requiring the patient or carer to move locations. Any problems coping with the new communications technology are likely to be even less frequent when working with children and adolescents patients.
The present study demonstrated the majority of patients agreed to use a mobile phone-based wireless health outcomes monitoring system. Furthermore, 100% of these patients successfully completed the questionnaire. These are the first steps required in the process of seeking to apply this system to standard clinical practice. The next steps are to demonstrate the system's usefulness for patients and/or providers, and demonstrate provider acceptance and use of the system.
List of abbreviations
FCT score Familiarity with Communication Technology score
GPRS General Packet Radio Service
HRQOL Health-Related Quality of Life
IVR Interactive Voice Responder
MMS Multimedia Messaging Service
MMSC Multimedia Messaging Service Centre
PHP Hypertext Preprocessor
SMS Short Message Service
SMSC Short Messaging Service Centre
WAP Wireless Application Protocol
WHOMS Wireless Health Outcomes Monitoring System
XHTML eXtended HTML
Competing interests
Reply always keeps the focus on innovation and know-how: wireless technology and programming devices are key drivers of Reply business development in order to build advanced and effective mobile solutions. Company's investments have always been done according to this point of view, like in WHOMS, where Reply joined together technological experience and scientific knowledge to help people. Up to now, everything's been done thanks to the enthusiasm of Marcello Tamburini, his staff and Reply people. We didn't get any revenues, just costs, but we strongly believe it can be a big sales opportunity for the future, apart from being a way to improve patients quality of life, using a common device as mobile phones.
Authors' contributions
EB directed the project and provided critical revision of the manuscript, including important intellectual input. FC developed the WHOMS in collaboration with SLC and wrote the original draft of the manuscript. MT suggested the original system, reviewed the literature and wrote the sections dealing with HRQOL assessment. ML and MT tested the system with patients. CB performed the statistical analyses. All authors approved the final paper.
Acknowledgements
The authors are grateful to James T. Fitzgerald and Mark J. Atkinson for reviewing the manuscript and providing invaluable suggestions.
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Pre-publication history
The pre-publication history for this paper can be accessed here:
http://www.biomedcentral.com/1472-6947/4/7/prepub
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Inhibitory Effects of Commercial and Enriched Green Tea Extracts on the Growth of Brochothrix thermosphacta, Pseudomonas putida and Escherichia coli
Elodie Rozoy, Laurent Bazinet, Monica Araya-Farias, Anthony Guernec, Linda Saucier
Abstract
The major catechin found in green tea, called epigallocatechin gallate (EGCG), have been reported to have antimicrobial properties. In this study, we examined in vitro the antimicrobial effects of a commercial green tea extract sold in a capsule form, and two prepared green tea extracts enriched in catechins against Brochothrix thermosphacta, Pseudomonsas putida and Escherichia coli which have been associated with meat spoilage. The antimicrobial activity of the different tea extracts was evaluated by Spot-On-Lawn and Well Diffusion assays and the Minimum Inhibitory Concentration (MIC) was also determined in Brain Heart Infusion broth. The three methods used showed an inhibition of Brochothrix thermosphacta, whereas the inhibition of Pseudomonas putida and Escherichia coli was only detected with the MIC assay. The determination of the MIC in broth culture appeared to be the most reliable method to determine the inhibitory activity of catechin compounds.
Full Text: PDF DOI: 10.5539/jfr.v2n1p1
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Peter Pan, 1974 Series
Published in English (United States)
Publication Date:
1974
Number of Issues Published:
1
Format:
Color; 7" x 10"; Saddle-Stitiched; Heavy Stock Paper; One-Shot
Series Details:
Publisher's Brands:
Indicia Publishers:
• without indicia publisher information (1 issue)
Tracking
Numbering continues from Curse of the Werewolf!, The [Book and Record Set] (Peter Pan, 1974 series); numbering continues in Escape from the Planet of the Apes [Book and Record Set] (Peter Pan, 1974 series).
Notes
Includes 45 RPM record.
Editing
Index Status
Indexed Partially Indexed Pending Approval Reserved Skeleton Data Only
PR18
Cover Status
Scan available Needs Replacement No Scan available
PR18
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< Terror of Fox Terrier
Next >
: Just now I learned how to not have your multiple bash shells overwrite each other's history. And I realized that that was the first time in a long time that I expanded my knowledge of living in a Unix environment (as opposed to programming in one). I guess this big list of other things you can change in bash is a good start.
[Main] [Edit]
Unless otherwise noted, all content licensed by Leonard Richardson
under a Creative Commons License.
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Walden: Chapter 07 (historical)
Walden: Chapter 07 (historical)
This article has been reviewed by the following Topic Editor: Cutler J. Cleveland
Historical E-Book: Walden
Author: Henry David Thoreau
Edition Used: Boston: Ticknor & Fields, 1854.
First published: 1854
Chapter 07: The Bean-Field
Meanwhile my beans, the length of whose rows, added together, was seven miles already planted, were impatient to be hoed, for the earliest had grown considerably before the latest were in the ground; indeed they were not easily to be put off. What was the meaning of this so steady and self-respecting, this small Herculean labor, I knew not. I came to love my rows, my beans, though so many more than I wanted. They attached me to the earth, and so I got strength like Antaeus. But why should I raise them? Only Heaven knows. This was my curious labor all summer — to make this portion of the earth's surface, which had yielded only cinquefoil, blackberries, johnswort, and the like, before, sweet wild fruits and pleasant flowers, produce instead this pulse. What shall I learn of beans or beans of me? I cherish them, I hoe them, early and late I have an eye to them; and this is my day's work. It is a fine broad leaf to look on. My auxiliaries are the dews and rains which water this dry soil, and what fertility is in the soil itself, which for the most part is lean and effete. My enemies are worms, cool days, and most of all woodchucks. The last have nibbled for me a quarter of an acre clean. But what right had I to oust johnswort and the rest, and break up their ancient herb garden? Soon, however, the remaining beans will be too tough for them, and go forward to meet new foes.
When I was four years old, as I well remember, I was brought from Boston to this my native town, through these very woods and this field, to the pond. It is one of the oldest scenes stamped on my memory. And now to-night my flute has waked the echoes over that very water. The pines still stand here older than I; or, if some have fallen, I have cooked my supper with their stumps, and a new growth is rising all around, preparing another aspect for new infant eyes. Almost the same johnswort springs from the same perennial root in this pasture, and even I have at length helped to clothe that fabulous landscape of my infant dreams, and one of the results of my presence and influence is seen in these bean leaves, corn blades, and potato vines.
I planted about two acres and a half of upland; and as it was only about fifteen years since the land was cleared, and I myself had got out two or three cords of stumps, I did not give it any manure; but in the course of the summer it appeared by the arrowheads which I turned up in hoeing, that an extinct nation had anciently dwelt here and planted corn and beans ere white men came to clear the land, and so, to some extent, had exhausted the soil for this very crop.
Before yet any woodchuck or squirrel had run across the road, or the sun had got above the shrub oaks, while all the dew was on, though the farmers warned me against it — I would advise you to do all your work if possible while the dew is on — I began to level the ranks of haughty weeds in my bean-field and throw dust upon their heads. Early in the morning I worked barefooted, dabbling like a plastic artist in the dewy and crumbling sand, but later in the day the sun blistered my feet. There the sun lighted me to hoe beans, pacing slowly backward and forward over that yellow gravelly upland, between the long green rows, fifteen rods, the one end terminating in a shrub oak copse where I could rest in the shade, the other in a blackberry field where the green berries deepened their tints by the time I had made another bout. Removing the weeds, putting fresh soil about the bean stems, and encouraging this weed which I had sown, making the yellow soil express its summer thought in bean leaves and blossoms rather than in wormwood and piper and millet grass, making the earth say beans instead of grass — this was my daily work. As I had little aid from horses or cattle, or hired men or boys, or improved implements of husbandry, I was much slower, and became much more intimate with my beans than usual. But labor of the hands, even when pursued to the verge of drudgery, is perhaps never the worst form of idleness. It has a constant and imperishable moral, and to the scholar it yields a classic result. A very agricola laboriosus was I to travellers bound westward through Lincoln and Wayland to nobody knows where; they sitting at their ease in gigs, with elbows on knees, and reins loosely hanging in festoons; I the home-staying, laborious native of the soil. But soon my homestead was out of their sight and thought. It was the only open and cultivated field for a great distance on either side of the road, so they made the most of it; and sometimes the man in the field heard more of travellers' gossip and comment than was meant for his ear: "Beans so late! peas so late!" — for I continued to plant when others had begun to hoe — the ministerial husbandman had not suspected it. "Corn, my boy, for fodder; corn for fodder." "Does he live there?" asks the black bonnet of the gray coat; and the hard-featured farmer reins up his grateful dobbin to inquire what you are doing where he sees no manure in the furrow, and recommends a little chip dirt, or any little waste stuff, or it may be ashes or plaster. But here were two acres and a half of furrows, and only a hoe for cart and two hands to draw it — there being an aversion to other carts and horses — and chip dirt far away. Fellow-travellers as they rattled by compared it aloud with the fields which they had passed, so that I came to know how I stood in the agricultural world. This was one field not in Mr. Coleman's report. And, by the way, who estimates the value of the crop which nature yields in the still wilder fields unimproved by man? The crop of English hay is carefully weighed, the moisture calculated, the silicates and the potash; but in all dells and pond-holes in the woods and pastures and swamps grows a rich and various crop only unreaped by man. Mine was, as it were, the connecting link between wild and cultivated fields; as some states are civilized, and others half-civilized, and others savage or barbarous, so my field was, though not in a bad sense, a half-cultivated field. They were beans cheerfully returning to their wild and primitive state that I cultivated, and my hoe played the Rans des Vaches for them.
Near at hand, upon the topmost spray of a birch, sings the brown thrasher — or red mavis, as some love to call him — all the morning, glad of your society, that would find out another farmer's field if yours were not here. While you are planting the seed, he cries — "Drop it, drop it — cover it up, cover it up — pull it up, pull it up, pull it up." But this was not corn, and so it was safe from such enemies as he. You may wonder what his rigmarole, his amateur Paganini performances on one string or on twenty, have to do with your planting, and yet prefer it to leached ashes or plaster. It was a cheap sort of top dressing in which I had entire faith.
As I drew a still fresher soil about the rows with my hoe, I disturbed the ashes of unchronicled nations who in primeval years lived under these heavens, and their small implements of war and hunting were brought to the light of this modern day. They lay mingled with other natural stones, some of which bore the marks of having been burned by Indian fires, and some by the sun, and also bits of pottery and glass brought hither by the recent cultivators of the soil. When my hoe tinkled against the stones, that music echoed to the woods and the sky, and was an accompaniment to my labor which yielded an instant and immeasurable crop. It was no longer beans that I hoed, nor I that hoed beans; and I remembered with as much pity as pride, if I remembered at all, my acquaintances who had gone to the city to attend the oratorios. The nighthawk circled overhead in the sunny afternoons — for I sometimes made a day of it — like a mote in the eye, or in heaven's eye, falling from time to time with a swoop and a sound as if the heavens were rent, torn at last to very rags and tatters, and yet a seamless cope remained; small imps that fill the air and lay their eggs on the ground on bare sand or rocks on the tops of hills, where few have found them; graceful and slender like ripples caught up from the pond, as leaves are raised by the wind to float in the heavens; such kindredship is in nature. The hawk is aerial brother of the wave which he sails over and surveys, those his perfect air-inflated wings answering to the elemental unfledged pinions of the sea. Or sometimes I watched a pair of hen-hawks circling high in the sky, alternately soaring and descending, approaching, and leaving one another, as if they were the embodiment of my own thoughts. Or I was attracted by the passage of wild pigeons from this wood to that, with a slight quivering winnowing sound and carrier haste; or from under a rotten stump my hoe turned up a sluggish portentous and outlandish spotted salamander, a trace of Egypt and the Nile, yet our contemporary. When I paused to lean on my hoe, these sounds and sights I heard and saw anywhere in the row, a part of the inexhaustible entertainment which the country offers.
On gala days the town fires its great guns, which echo like popguns to these woods, and some waifs of martial music occasionally penetrate thus far. To me, away there in my bean-field at the other end of the town, the big guns sounded as if a puffball had burst; and when there was a military turnout of which I was ignorant, I have sometimes had a vague sense all the day of some sort of itching and disease in the horizon, as if some eruption would break out there soon, either scarlatina or canker-rash, until at length some more favorable puff of wind, making haste over the fields and up the Wayland road, brought me information of the "trainers." It seemed by the distant hum as if somebody's bees had swarmed, and that the neighbors, according to Virgil's advice, by a faint tintinnabulum upon the most sonorous of their domestic utensils, were endeavoring to call them down into the hive again. And when the sound died quite away, and the hum had ceased, and the most favorable breezes told no tale, I knew that they had got the last drone of them all safely into the Middlesex hive, and that now their minds were bent on the honey with which it was smeared.
I felt proud to know that the liberties of Massachusetts and of our fatherland were in such safe keeping; and as I turned to my hoeing again I was filled with an inexpressible confidence, and pursued my labor cheerfully with a calm trust in the future.
When there were several bands of musicians, it sounded as if all the village was a vast bellows and all the buildings expanded and collapsed alternately with a din. But sometimes it was a really noble and inspiring strain that reached these woods, and the trumpet that sings of fame, and I felt as if I could spit a Mexican with a good relish — for why should we always stand for trifles? — and looked round for a woodchuck or a skunk to exercise my chivalry upon. These martial strains seemed as far away as Palestine, and reminded me of a march of crusaders in the horizon, with a slight tantivy and tremulous motion of the elm tree tops which overhang the village. This was one of the great days; though the sky had from my clearing only the same everlastingly great look that it wears daily, and I saw no difference in it.
It was a singular experience that long acquaintance which I cultivated with beans, what with planting, and hoeing, and harvesting, and threshing, and picking over and selling them — the last was the hardest of all — I might add eating, for I did taste. I was determined to know beans. When they were growing, I used to hoe from five o'clock in the morning till noon, and commonly spent the rest of the day about other affairs. Consider the intimate and curious acquaintance one makes with various kinds of weeds — it will bear some iteration in the account, for there was no little iteration in the labor — disturbing their delicate organizations so ruthlessly, and making such invidious distinctions with his hoe, levelling whole ranks of one species, and sedulously cultivating another. That's Roman wormwood — that's pigweed — that's sorrel — that's piper-grass — have at him, chop him up, turn his roots upward to the sun, don't let him have a fibre in the shade, if you do he'll turn himself t' other side up and be as green as a leek in two days. A long war, not with cranes, but with weeds, those Trojans who had sun and rain and dews on their side. Daily the beans saw me come to their rescue armed with a hoe, and thin the ranks of their enemies, filling up the trenches with weedy dead. Many a lusty crest — waving Hector, that towered a whole foot above his crowding comrades, fell before my weapon and rolled in the dust.
Those summer days which some of my contemporaries devoted to the fine arts in Boston or Rome, and others to contemplation in India, and others to trade in London or New York, I thus, with the other farmers of New England, devoted to husbandry. Not that I wanted beans to eat, for I am by nature a Pythagorean, so far as beans are concerned, whether they mean porridge or voting, and exchanged them for rice; but, perchance, as some must work in fields if only for the sake of tropes and expression, to serve a parable-maker one day. It was on the whole a rare amusement, which, continued too long, might have become a dissipation. Though I gave them no manure, and did not hoe them all once, I hoed them unusualy well as far as I went, and was paid for it in the end, "there being in truth," as Evelyn says, "no compost or laetation whatsoever comparable to this continual motion, repastination, and turning of the mould with the spade." "The earth," he adds elsewhere, "especially if fresh, has a certain magnetism in it, by which it attracts the salt, power, or virtue (call it either) which gives it life, and is the logic of all the labor and stir we keep about it, to sustain us; all dungings and other sordid temperings being but the vicars succedaneous to this improvement." Moreover, this being one of those "worn-out and exhausted lay fields which enjoy their sabbath," had perchance, as Sir Kenelm Digby thinks likely, attracted "vital spirits" from the air. I harvested twelve bushels of beans.
But to be more particular, for it is complained that Mr. Coleman has reported chiefly the expensive experiments of gentlemen farmers, my outgoes were,—
For a hoe $ 0.54
Plowing, harrowing, and furrowing 7.50 Too much.
Beans for seed 3.12+
Potatoes for seed 1.33
Peas for seed 0.40
Turnip seed 0.06
White line for crow fence 0.02
Horse cultivator and boy three hours 1.00
Horse and cart to get crop 0.75
--------
In all $14.72+
My income was (patrem familias vendacem, non emacem esse oportet), from
Nine bushels and twelve quarts of beans sold $16.94
Five " large potatoes 2.50
Nine " small 2.25
Grass 1.00
Stalks 0.75
-------
In all $23.44
Leaving a pecuniary profit, as I have elsewhere said, of $ 8.71+
This is the result of my experience in raising beans: Plant the common small white bush bean about the first of June, in rows three feet by eighteen inches apart, being careful to select fresh round and unmixed seed. First look out for worms, and supply vacancies by planting anew. Then look out for woodchucks, if it is an exposed place, for they will nibble off the earliest tender leaves almost clean as they go; and again, when the young tendrils make their appearance, they have notice of it, and will shear them off with both buds and young pods, sitting erect like a squirrel. But above all harvest as early as possible, if you would escape frosts and have a fair and salable crop; you may save much loss by this means.
This further experience also I gained: I said to myself, I will not plant beans and corn with so much industry another summer, but such seeds, if the seed is not lost, as sincerity, truth, simplicity, faith, innocence, and the like, and see if they will not grow in this soil, even with less toil and manurance, and sustain me, for surely it has not been exhausted for these crops. Alas! I said this to myself; but now another summer is gone, and another, and another, and I am obliged to say to you, Reader, that the seeds which I planted, if indeed they were the seeds of those virtues, were wormeaten or had lost their vitality, and so did not come up. Commonly men will only be brave as their fathers were brave, or timid. This generation is very sure to plant corn and beans each new year precisely as the Indians did centuries ago and taught the first settlers to do, as if there were a fate in it. I saw an old man the other day, to my astonishment, making the holes with a hoe for the seventieth time at least, and not for himself to lie down in! But why should not the New Englander try new adventures, and not lay so much stress on his grain, his potato and grass crop, and his orchards — raise other crops than these? Why concern ourselves so much about our beans for seed, and not be concerned at all about a new generation of men? We should really be fed and cheered if when we met a man we were sure to see that some of the qualities which I have named, which we all prize more than those other productions, but which are for the most part broadcast and floating in the air, had taken root and grown in him. Here comes such a subtile and ineffable quality, for instance, as truth or justice, though the slightest amount or new variety of it, along the road. Our ambassadors should be instructed to send home such seeds as these, and Congress help to distribute them over all the land. We should never stand upon ceremony with sincerity. We should never cheat and insult and banish one another by our meanness, if there were present the kernel of worth and friendliness. We should not meet thus in haste. Most men I do not meet at all, for they seem not to have time; they are busy about their beans. We would not deal with a man thus plodding ever, leaning on a hoe or a spade as a staff between his work, not as a mushroom, but partially risen out of the earth, something more than erect, like swallows alighted and walking on the ground:—
"And as he spake, his wings would now and then </dd>
Spread, as he meant to fly, then close again —" </dd>
so that we should suspect that we might be conversing with an angel. Bread may not always nourish us; but it always does us good, it even takes stiffness out of our joints, and makes us supple and buoyant, when we knew not what ailed us, to recognize any generosity in man or Nature, to share any unmixed and heroic joy.
Ancient poetry and mythology suggest, at least, that husbandry was once a sacred art; but it is pursued with irreverent haste and heedlessness by us, our object being to have large farms and large crops merely. We have no festival, nor procession, nor ceremony, not excepting our cattle-shows and so-called Thanksgivings, by which the farmer expresses a sense of the sacredness of his calling, or is reminded of its sacred origin. It is the premium and the feast which tempt him. He sacrifices not to Ceres and the Terrestrial Jove, but to the infernal Plutus rather. By avarice and selfishness, and a grovelling habit, from which none of us is free, of regarding the soil as property, or the means of acquiring property chiefly, the landscape is deformed, husbandry is degraded with us, and the farmer leads the meanest of lives. He knows Nature but as a robber. Cato says that the profits of agriculture are particularly pious or just (maximeque pius quaestus), and according to Varro the old Romans "called the same earth Mother and Ceres, and thought that they who cultivated it led a pious and useful life, and that they alone were left of the race of King Saturn."
We are wont to forget that the sun looks on our cultivated fields and on the prairies and forests without distinction. They all reflect and absorb his rays alike, and the former make but a small part of the glorious picture which he beholds in his daily course. In his view the earth is all equally cultivated like a garden. Therefore we should receive the benefit of his light and heat with a corresponding trust and magnanimity. What though I value the seed of these beans, and harvest that in the fall of the year? This broad field which I have looked at so long looks not to me as the principal cultivator, but away from me to influences more genial to it, which water and make it green. These beans have results which are not harvested by me. Do they not grow for woodchucks partly? The ear of wheat (in Latin spica, obsoletely speca, from spe, hope) should not be the only hope of the husbandman; its kernel or grain (granum from gerendo, bearing) is not all that it bears. How, then, can our harvest fail? Shall I not rejoice also at the abundance of the weeds whose seeds are the granary of the birds? It matters little comparatively whether the fields fill the farmer's barns. The true husbandman will cease from anxiety, as the squirrels manifest no concern whether the woods will bear chestnuts this year or not, and finish his labor with every day, relinquishing all claim to the produce of his fields, and sacrificing in his mind not only his first but his last fruits also.
This is a chapter from Walden (historical e-book).
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Citation
Cutler J. Cleveland (Lead Author);Cutler J. Cleveland (Topic Editor) "Walden: Chapter 07 (historical)". 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 August 17, 2008; Last revised Date August 17, 2008; Retrieved May 18, 2013 <http://www.eoearth.org/article/Walden:_Chapter_07_(historical)>
The Author
Cutler J. Cleveland is Professor of Earth and Environment at Boston University, where he also is on the faculty of the Center for Energy and Environmental Studies. Professor Cleveland is Editor-in-Chief of the Encyclopedia of Energy (Elsevier, 2004), winner of an American Library Association award, the Dictionary of Energy (Elsevier, 2005), Handbook of Energy (Elsevier, forthcoming), and is the Founding Editor-in-Chief of the Encyclopedia of Earth. He is the recipient of the Adelma ... (Full Bio)
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Apple iOS
From Grand Theft Wiki
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The first generation iPad.
The iOS mobile operating system powers a series of multimedia devices created by Apple, including the iPhone, iPad and iPod Touch. Three Grand Theft Auto games have been released for iOS devices: GTA Chinatown Wars, Grand Theft Auto III and Grand Theft Auto: Vice City.
As the devices run the same operating system and applications, they are quite similar in functionality. The iPod Touch is essentially an iPhone minus the telephone functionality, and any other functionality which requires a SIM Card - whilst the iPad can be described as a larger tablet version of the iPod Touch. More expensive versions of the iPad, however, have 3G mobile Internet functionality. Apple has also released a smaller 'iPad Mini'.
While all applications designed for iOS run on all devices, many applications are released in an 'HD version' optimised for the iPad. These iPad versions of applications are often more expensive than the iPhone and iPod Touch version. Recently, however, many developers are moving to developing 'universal apps', which use hardware detection to determine which device to optimise for.
Applications developed for iOS must be approved by Apple, and released via the 'App Store'; An online store which can be accessed via an application on the device or through Apple's iTunes software.
GTA Chinatown Wars
GTA Chinatown Wars was quietly released onto the App Store at midnight on January 18th, 2010. The game features the same missions available for the PSP version. One difference is the lack of Rockstar Games Social Club - the bonus Xin missions, which were previously only available after completing the main story line, locating the two Lions of Fo and syncing the device to Social Club, are now available without the use of Social Club. A new radio station allows players to use a custom radio tracklist from their iTunes library. This version features the enhanced graphics of the PSP version released after the DS iteration, but re-introduces the touch screen functionality of the DS, replacing the quicktime events supplemented in the PSP port.
On September 9th, 2010, a version of game with enhanced graphics (dubbed Chinatown Wars HD) was released for use on the iPad.
GTA III 10th Anniversary Edition
In October 2011, Rockstar Games announced a 10th Anniversary Edition of Grand Theft Auto III would be released for mobile phones and tablets, including the iPhone, iPad, and a selection of Android devices, due to be released in autumn of 2011 (Northern Hemisphere).
The only iOS devices that support the game are those with with the A4 or newer processor. These include the iPhone 4 and later, iPod Touch fourth generation and later, and all versions of the iPad.
GTA Vice City: 10th Anniversary Edition
The 10th Anniversary Mobile Edition of Grand Theft Auto: Vice City was released on December 6th, 2012 on select iOS devices alongside the Android version.
GTA Vice City supports the same devices as the iOS version of GTA III: The iPhone 4 and later, iPod Touch fourth generation and later, and all versions of the iPad.
Wikipedia has an article on:
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Bibliography: Alien Expedition
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Title: Alien Expedition
Author: Pamela F. Service
Year: 2009
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Contributions
Kalypso 1037 commits Sep 2006 to Present
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Click on a word to bring up parses, dictionary entries, and frequency statistics
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Part 10
Diastasis of the bones may be recognized by examining the part where the vein which runs along the arm divides.
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CMD sent two reporters to track ALEC in Oklahoma
Click here to help support our future investigations.
Fredrick D. Palmer
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Fredrick D. Palmer is Senior Vice President of Government Relations of Peabody Energy.[1] He is also a member of the Board of Directors of the U.S. Chamber of Commerce.[2]
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Family:David Newell and Emaranda Rowles (1)
Watchers
b. 1803? Kentucky
b. 1817?
d. BET MAR 1849 AND JUN 1850 Davis County?, Iowa
m. 18 Feb 1849 Monroe County, Iowa
Facts and Events
Marriage[1] 18 Feb 1849 Monroe County, Iowa(his 2nd? wife, her 2nd husband)
Children
BirthDeath
References
1. Monroe, Iowa, United States. Marriages, Bk. 1, p. 16.
2. Davis County, Iowa. 1850 U.S. Census Population Schedule, Wicondah Twp, p. 294.
Emaranda is not listed in 1850 census, though she married David Newell less than a year before; was she dead or were they already separated?
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Place:Orland Hills, Cook, Illinois, United States
Watchers
NameOrland Hills
Alt namesWesthavensource: USGS, GNIS Digital Gazetteer (1994) GNIS17020996
TypeVillage
Coordinates41.589°N 87.841°W
Located inCook, Illinois, United States
source: Getty Thesaurus of Geographic Names
the text in this section is copied from an article in Wikipedia
Orland Hills (formerly Westhaven) is a village in Cook County, Illinois, United States. The population was 6,779 at the 2000 census.
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Source link: http://archive.mises.org/13242/is-more-consumer-debt-the-key-to-economic-recovery/
Is More Consumer Debt the Key to Economic Recovery?
July 12, 2010 by
The mainstream media is reporting that low consumer credit scores are hurting the economic recovery.
Today I appeared on CNBC’s Street Signs to argue the opposite view: that lower credit scores, and thus less consumer debt, are a good thing and the only way to real long-term prosperity. Have the “experts” learned nothing from our recent experience?
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"warc_url": "http://crantastic.org/packages/ade4"
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ade4 (1.5-2)
2 users
Analysis of Ecological Data : Exploratory and Euclidean methods in Environmental sciences.
http://pbil.univ-lyon1.fr/ADE-4
Mailing list: http://listes.univ-lyon1.fr/wws/info/adelist
http://cran.r-project.org/web/packages/ade4
Multivariate data analysis and graphical display.
Maintainer: Simon Penel
Author(s): Daniel Chessel, Anne-Beatrice Dufour <anne-beatrice.dufour@univ-lyon1.fr> and Stephane Dray <stephane.dray@univ-lyon1.fr>, with contributions from Thibaut Jombart, Jean R. Lobry, Sebastien Ollier, Sandrine Pavoine and Jean Thioulouse.
License: GPL (>= 2)
Uses: ade4TkGUI, deldir, maptools, pixmap, spdep, splancs, waveslim, ape, MASS
Reverse depends: ade4TkGUI, adegenet, adehabitat, adehabitatHR, adehabitatHS, adehabitatLT, adephylo, aspace, clusterSim, FactoClass, FD, FunNet, genoPlotR, hierfstat, kernelPop, Laterality, Momocs, msap, MVPARTwrap, oncomodel, pamctdp, PopGenReport, RcmdrPlugin.pointG, restlos, rmetasim, RVAideMemoire, sideChannelAttack, svcR
Reverse suggests: adegenet, adephylo, biomod2, Guerry, GUniFrac, mefa, phylobase, polysat, seqinr
Released about 1 month ago.
9 previous versions
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Related packages: vegan, ape, cocorresp, e1071, VGAM, xgobi, MASS, adehabitat, amap, cluster, ecodist, fso, labdsv, lme4, mclust, mvpart, nlme, ouch, party, pastecs(20 best matches, based on common tags.)
Search for ade4 on google, google scholar, r-help, r-devel.
Visit ade4 on R Graphical Manual.
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Debugging The Linux Kernel Using Gdb
From eLinux.org
Revision as of 17:34, 25 November 2008 by Keesj (Talk | contribs)
Jump to: navigation, search
Contents
Debugging the linux kernels using gdb
The majority of day to day kernel debugging is done by adding print statements to code by using the famous printk function. Using printk it as it is relatively simple and effective and cheap technique to use. There are many other linux grown techniques that take the debugging and profiling approach to a higher level. On this page we will discuss using the gnu debugger to do kernel debugging. Overall starting using gdb to do kernel debugging is relatively easy.
Most of the examples here will work in two (open source) situations. when using JTAG and when using qemu system emulation. As the second option does not require any hardware you could go on and try it right away!
The open source jtag debugging world is not that big. One project stands out in terms of debugging capabilities is OpenOCD and this is the tool used in this documentation.
vmlinuz zImage and CO
Loading a kernel in memory
Getting the kernel log buffer
Debugging a kernel module (.o and .ko )
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"warc_url": "http://elinux.org/index.php?title=Version_Control&action=info"
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Information for "Version Control"
Jump to: navigation, search
Basic information
Display titleVersion Control
Default sort keyVersion Control
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Page ID21938
Page content languageEnglish (en)
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Page creatorAlecthegeek (Talk | contribs)
Date of page creation21:05, 26 April 2012
Latest editorAlecthegeek (Talk | contribs)
Date of latest edit22:52, 27 May 2012
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Research highlight
Somatic signals counteract reproductive aging in females
Ronald E Ellis1* and Qing Wei1,2
Author Affiliations
1 Department of Molecular Biology, The University of Medicine and Dentistry of New Jersey, B303 Science Center, 2 Medical Center Drive, Stratford, NJ 08084, USA
2 Graduate School of Biomedical Sciences, The University of Medicine and Dentistry of New Jersey, B303 Science Center, 2 Medical Center Drive, Stratford, NJ 08084, USA
For all author emails, please log on.
Genome Biology 2010, 11:142 doi:10.1186/gb-2010-11-11-142
The electronic version of this article is the complete one and can be found online at: http://genomebiology.com/2010/11/11/142
Published:30 November 2010
© 2010 BioMed Central Ltd
Abstract
Recent research shows that declining oocyte quality with age is not inevitable in nematodes, and similar signals might regulate reproductive aging in women.
Research highlight
Females are born with their complete complement of oocytes or egg cells. Although these oocytes can remain arrested for decades, during aging they decline in quality or undergo programmed cell deaths. Using the nematode Caenorhabditis elegans as a model, Luo et al. [1] showed recently that mutations in the insulin/insulin-like growth factor (IGF) and transforming growth factor (TGF)β signal transduction pathways improve oocyte quality in older females. Furthermore, genetic mosaic analyses revealed that each of these regulatory pathways acts in a different somatic tissue to control reproductive aging. Thus, declining oocyte quality is not inevitable in these worms, but seems to be determined by regulatory controls that balance somatic and reproductive needs. Given that the insulin/IGF and TGFβ signaling pathways are conserved, these results raise the possibility that somatic signals regulate the quality of oocytes in older women.
Conservation of declining reproductive success from worms to humans
As a woman ages, her chance of conceiving a healthy child declines precipitously (reviewed in [2]). During this period, many of her oocytes are lost through programmed cell death, but reproductive problems predate their complete depletion. In particular, even oocytes that survive and mature are of lower quality than those found in young women. Defects in these oocytes lead to a decreasing chance of fertilization and an increasing risk of miscarriage or of a child with birth defects. Much of this decline in oocyte quality is due to errors in handling chromosomes that lead to aneuploidy or triploidy (reviewed in [3]). Additional factors also contribute to lower oocyte quality but remain poorly understood.
Although nematodes have very short lifespans, several assays reveal that their oocytes also decline in quality with age. Perhaps the simplest method is to measure the probability that an oocyte will produce a healthy worm after fertilization. Using this definition, oocyte quality declines during normal aging in nematodes [4], as it does in women. In this new study, Luo et al. [1] extended these observations by showing that the frequency of non-disjunction in oocytes also increases with age in nematodes, as in women. Furthermore, the size of oocytes and their ability to be fertilized decline with age (Figure 1), and morphological defects increase in frequency.
Figure 1. Mutations in the insulin/IGF or TGFβ signaling pathways alleviate many symptoms of female reproductive aging. The outline of an adult hermaphrodite is shown at the top, with the gonad in gray. One arm of the gonad is shown in detail below. The distal tip cell (yellow) promotes mitosis. Developing oocytes are in gray, with the darkness of shading indicating their age. Sperm are shown in blue and are located in the spermatheca. Oocytes are numbered backwards from the proximal end; the -1 oocyte is undergoing maturation and the -2 to -7 oocytes are arrested in diakinesis (the last stage of prophase). Red text indicates the changes that are seen in insulin/IGF or TGFβ pathway mutants.
Improvement in oocyte quality by lowering TGFβ or insulin/IGF signaling
Genes that regulate oocyte quality are hard to identify by mutant screens. Because oocytes are among the most complex cells in existence, thousands of genetic or physical changes can decrease their ability to function. Thus, Luo et al. [1] tested regulatory genes that were known to influence the animal's development or lifespan to see whether they also affected reproductive aging. They found that changes in two different regulatory pathways improve oocytes in older females.
First, they tested a mutation that lowers the activity of the daf-2 gene, which encodes the C. elegans ortholog of the insulin/IGF receptor (reviewed in [5]). Lowering the activity of this signal transduction pathway increases the animals' lifespan by allowing the translocation of the DAF-16/FOXO transcription factor to nuclei, and also extends the reproductive span by several days [6]. Luo et al. [1] showed that decreasing daf-2 activity prevents the normal decline in oocyte quality with age, and that it also lowers the frequency of oocytes with chromosomal abnormalities.
Second, they [1] analyzed a mutation in sma-2, which encodes a SMAD protein that acts in the TGFβ Sma/Mab signal transduction pathway. Although these genes regulate body size and do not affect lifespan, decreasing their activity can extend the reproductive span of these nematodes [7], improve oocyte quality and decrease the frequency of chromosome loss [1].
These mutations in the insulin/IGF and TGFβ signal transduction pathways have broad effects on reproduction (Figure 1) because they also promote the proliferation of germline stem cells in older animals [1,8] and help alleviate the effects of γ-irradiation on oocyte quality [1].
The insulin/IGF and TGFβ signaling pathways act in the soma to control oocyte quality
To determine where these genes act to regulate oocyte quality, Luo et al. [1] used a variety of techniques to create genetic mosaic animals and measured their reproductive spans and studied the morphologies of developing oocytes.
The DAF-2 receptor acts by repressing the DAF-16/FOXO transcription factor. Thus, mutations in daf-16 block the extension of the reproductive span caused by lowering daf-2 activity. However, Luo et al. [1] show that the expression of DAF-16 in either the muscle or the intestine allows the extension of the reproductive span (Figure 2). These results imply that insulin/IGF signals work in these somatic tissues to control the somatic expression of DAF-16. However, what target genes DAF-16 regulates, and how these target genes influence the quality of oocytes in the germline, remain unknown. Moreover, independent studies of germ cell proliferation indicate that DAF-16 functions in the germline to regulate this trait [8]. Thus, the insulin/IGF pathway might act in both the soma and germline to control oogenesis. How its effects on germ cell proliferation, reproductive span and oocyte quality are related is unclear.
Figure 2. Somatic signals control female reproductive aging. A diagrammatic cross-section of an adult hermaphrodite is shown, with the hypodermis and nerve cords in yellow, the four muscle quadrants in orange and the intestine in green. The two sections of the gonad are gray, with the distal one containing numerous oocytes in pachytene and the proximal one containing a single large oocyte arrested in diakinesis. Insulin/IGF signals (IIS) and TGFβ Sma/Mab signals are shown in red, with question marks to indicate that the means of communication with the germline remain unknown.
Similar studies suggest that the TGFβ pathway acts in the hypodermis to regulate oocyte quality (Figure 2). Furthermore, this effect can be separated from its influence on body size. To generate a list of genes that might be involved in reproductive aging, Luo et al. [1] used microarray analysis to compare transcripts found in oocytes laid by old wild-type or sma-2 mutant animals. Although these unfertilized oocytes had probably undergone maturation and endomitosis (replication of chromosomes without cell division), it is possible that their transcript profile still resembled that of immature oocytes in the germline. Indeed, many of the genes identified have conserved roles in oogenesis [1]. Furthermore, decreasing the activity of some of the genes that were upregulated in sma-2 oocytes shortened the reproductive span. Given that these transcripts might encode important components of oocytes or early embryos, knocking them down would be expected to cause problems. Thus, a critical test for the future will be determining whether the upregulation of any of these genes can slow reproductive aging.
Nematodes as a model for human female reproductive aging
C. elegans was originally chosen as a model animal because it grows quickly, has many offspring and can self-fertilize. These traits depend on the production of new oocytes in adults, which does not occur in humans. However, many critical aspects of oogenesis are similar in these two species [9] and might reflect a conserved program for oogenesis that can be dissected in worms.
In both nematodes and the human fetus, germline stem cells are maintained in a protected niche by the somatic gonad. Furthermore, when germ cells first enter meiosis, human and nematode oocytes each share cytoplasm with their neighbors. Later, many oocytes in each species undergo programmed cell death during prophase of meiosis I. Moreover, both human and nematode oocytes arrest near the end of prophase and wait for a signal to mature. In each species this signal activates the mitogen activated protein kinase pathway. Finally, oocytes in both species are fertilized before meiosis has been completed and then extrude polar bodies. These common features imply that nematodes could be an excellent model for many aspects of human reproductive biology.
In summary, recent findings show that conserved regulatory pathways control oocyte quality in aging nematodes, including the insulin/IGF and TGFβ pathways described by Luo et al. [1], the DNA-damage response pathway (reviewed in [10]) and the core apoptotic pathway [4]. These findings might shed light on the molecular nature of reproductive aging in human females.
However, these studies also raise many new questions. To what extent are different aspects of reproductive aging in females related to each other? What regulatory changes occur in oocytes in response to the somatic signals described by Luo et al. [1]? How does the allocation of materials and nutrients to developing oocytes change during aging? What role do checkpoint processes have in maintaining oocyte quality in older worms? And most importantly, what processes cause the missegregation of chromosomes in older oocytes? Fortunately, the short lifespan of C. elegans will allow detailed studies of how oocyte quality changes during aging, which should lead to further breakthroughs.
Acknowledgements
This work was supported by NIH grant GM085282. We thank David Greenstein for comments.
References
1. Luo S, Kleemann GA, Ashraf JM, Shaw WM, Murphy CT: TGF-beta and insulin signaling regulate reproductive aging via oocyte and germline quality maintenance.
Cell 2010, 143:299-312. PubMed Abstract | Publisher Full Text
2. Broekmans FJ, Soules MR, Fauser BC: Ovarian aging: mechanisms and clinical consequences.
Endocr Rev 2009, 30:465-493. PubMed Abstract | Publisher Full Text
3. Hunt PA, Hassold TJ: Human female meiosis: what makes a good egg go bad?
Trends Genet 2008, 24:86-93. PubMed Abstract | Publisher Full Text
4. Andux S, Ellis RE: Apoptosis maintains oocyte quality in aging Caenorhabditis elegans females.
PLoS Genet 2008, 4:e1000295. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
5. Kenyon CJ: The genetics of ageing.
Nature 2010, 464:504-512. PubMed Abstract | Publisher Full Text
6. Hughes SE, Evason K, Xiong C, Kornfeld K: Genetic and pharmacological factors that influence reproductive aging in nematodes.
PLoS Genet 2007, 3:e25. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
7. Luo S, Shaw WM, Ashraf J, Murphy CT: TGF-beta Sma/Mab signaling mutations uncouple reproductive aging from somatic aging.
PLoS Genet 2009, 5:e1000789. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
8. Michaelson D, Korta DZ, Capua Y, Hubbard EJ: Insulin signaling promotes germline proliferation in C. elegans.
Development 2010, 137:671-680. PubMed Abstract | Publisher Full Text
9. Govindan JA, Nadarajan S, Kim S, Starich TA, Greenstein D: Somatic cAMP signaling regulates MSP-dependent oocyte growth and meiotic maturation in C. elegans.
Development 2009, 136:2211-2221. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
10. Gartner A, Boag PR, Blackwell TK: Germline survival and apoptosis. In WormBook. Edited by The C. elegans Research Community. WormBook; 2008. PubMed Abstract | Publisher Full Text
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HGE Comes To GNU/Linux !
Posted on 7th August 2011 in Uncategorized
Ryan Gordon who ported many games to GNU/Linux including those of The Humble Indie Bundle #1 #2 and #3 has made a guest post on the Wolfire Blog : This is a guest post from Ryan Gordon, announcing the release of Haaf’s Game Engine (HGE) for Mac and Linux. HGE is the 2d engine that [...]
The Chzo Mythos For GNU/Linux Released !
Posted on 11th August 2010 in Uncategorized
Hamish Paul Wilson started let me know of his porting of The Chzo Mythos to GNU/Linux at May 2010, and updated me on his progress at June 2010, now finally the porting is done and The Chzo Mythos is available for GNU/Linux free of charge ! Hamish Paul Wilson sent me this email today : [...]
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Sunday, May 31, 2009
Pal. Moderation (Not Really)
Rami Khoury writes:
The emergence of Zionist-Jewish colonialism - otherwise euphemistically called "Israeli settlements" - as the litmus test of relations between Israel and the United States...[but where are those "settlements"? Elder of Ziyon has an example:
in case you have difficulty, that map is of all Israel, pre- and post-1967]
...The freezing of modern Zionist colonialism in occupied Arab lands is now a priority of American foreign policy. Three significant dimensions of this dynamic should be appreciated.
The first is the apparent change in US policy...
The second significant dimension of events these days is the battle of wills between the US and Israel on the issue of freezing settlements completely, and what this might mean for domestic politics in both countries...
The third and most important dimension in the medium and long term is about how the settlements issue fits into the wider demands of a comprehensive, negotiated peace between the Palestinians and Israelis. Freezing settlements is seen in Washington as critical to kick-starting an Arab-Israeli negotiating process; but any negotiations that hope to succeed will have to tackle the much more difficult issue of the status and rights of the Palestinian refugees. The danger is that so much political muscle and negotiating time will be expended on achieving a settlement freeze that prospects for getting the concessions needed on the refugees issue will lessen significantly.
...The emphasis on immediately freezing Israeli settlements is heartening, and it is reasonable to ask the Arabs to make a reciprocal gesture of equal magnitude on criminal activity from our side, such as clamping down hard on terrorism against civilians. If the US pursues a truly even-handed approach that recognizes that crimes by Israeli and Arabs must be condemned and stopped simultaneously, it will increase the likelihood that the rights of both sides can then be addressed in a more credible and fruitful manner.
As Barry Rubin notes:
It just shows how pushing on the settlements will not "moderate" the Palestinians. As I wrote in the article, they just go on to their next demand.
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Become a Fan
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Five sites for open source healthcare
Image by opensource.com
(3 votes)
If you're browsing the web looking for sites about open source healthcare, here are five I found interesting. There are a ton of sites out there, and I tried to stay away from those that talked strictly about software--instead focusing on those that tackled the issues in open source ways beyond technology.
Bonus: The Dana Blankenhorn blog at ZDNet Healthcare is also a great resource: http://healthcare.zdnet.com/
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grass's bookmarks
"To be yourself in a world that is constantly trying to make you something else is the greatest accomplishment."
Emerson, Ralph Waldo on achievement
191 fans of this quote
"You can tell more about a person by what he says about others than you can by what others say about him."
Aikman, Leo on action
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"For purposes of action nothing is more useful than narrowness of thought combined with energy of will."
Amiel, Henri Frederic on action
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This quotation can be viewed in the context of a book
"Great things are not done by impulse, but by a series of small things brought together."
Gogh, Vincent Van on achievement
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Cassie's quote collection
I'm female and made my book on 6th November 2008.
My book as a pdf
My feed
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"warc_url": "http://quotationsbook.com/quote/30813/"
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Quotation added by staff
Why not add this quote to your bookmarks?
A policy is a temporary creed liable to be changed, but while it holds good it has got to be pursued with apostolic zeal. Gandhi, Mahatma
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A bit about Gandhi, Mahatma ...
Mohandas Karamchand Gandhi (October 2, 1869 - January 30, 1948) was a major political and spiritual leader of India and the Indian independence movement. He was the pioneer and perfector of Satyagraha - resistance through mass civil disobedience strongly founded upon ahimsa (total non-violence). Gandhi is commonly known and addressed in India and across the world as Mahatma Gandhi (from Sanskrit, Mahatma: Great Soul) and as Bapu (in many Indian languages, Father).
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"warc_url": "http://quotationsbook.com/quote/31579/"
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As poverty has been reduced in terms of mere survival, it has become more profound in terms of our way of life. Vaneigem, Raoul
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Raoul Vaneigem (born 1934) is a Belgian writer and philosopher. He was born in Lessines (Hainaut, Belgium). After studying romance philology at the Universit Libre de Bruxelles from 1952 to 1956, he participated in the Situationist International from 1961 to 1970.
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Invest three percent of your income in yourself (self-development) in order to guarantee your future. Tracy, Brian
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A religion so cheerless, a philosophy so sorrowful, could never have succeeded with the masses of mankind if presented only as a system of metaphysics. Buddhism owed its success to its catholic spirit and its beautiful morality. Reade, W. Winwood
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That's metaphysics, my dear fellow. It's forbidden me by my doctor, my stomach won't take it. Pasternak, Boris
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