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Geoffrey Bilder
Director of Strategic Initiatives
Barcelona, 2014
CrossRef Helps
Small Publishers
Who am I?
Let’s play a
game...
Barcelona 2014: CrossRef Tools for Small Publishers by Geoffrey Bilder
Barcelona 2014: CrossRef Tools for Small Publishers by Geoffrey Bilder
Part II
Barcelona 2014: CrossRef Tools for Small Publishers by Geoffrey Bilder
Barcelona 2014: CrossRef Tools for Small Publishers by Geoffrey Bilder
BrandIs it relevant?
Is it good?
Is it important?
provenanceinfrastructure
•What is it?	

•Where can I
get it?	

•What refers
to it?	

•What does
it refer to?
•What has
been done
to it?	

•Who
provides
stewardship
of it?	

•Who funded
it?	

•What can I
do with it?
•Who do we
credit it to?	

•What are
their
credentials?
CrossRef DOIs
Barcelona 2014: CrossRef Tools for Small Publishers by Geoffrey Bilder
Barcelona 2014: CrossRef Tools for Small Publishers by Geoffrey Bilder
http://www.easel.com/foo/bar/blat.html
Tim Berners-Lee (1998). "Cool URIs Don’t Change"
Litigation	

Transfer	

Poverty	

Forgetfulness
Divorce	

Death...
List of university and college mergers in the
United States
From Wikipedia, the free encyclopedia
This is a list of mergers of universities and/or colleges in the United States with the name of the
surviving institution, predecessors, and effective date.
This list is incomplete; you can help by expanding it (http://en.wikipedia.org/w/index.php?
title=List_of_university_and_college_mergers_in_the_United_States&action=edit) .
Contents
1 A through D
2 E through M
3 N through Z
4 See also
5 References
A through D
Alliant International University - merger of California School of Professional Psychology and
United States International University, 2001
Azusa Pacific College - absorbed Arlington College, 1968
Azusa Pacific College - merger of Azusa College and Los Angeles Pacific College, 1965
University of Baltimore - absorbed Eastern College, 1970
Benedictine College - merger of Mount Saint Scholastica College and St. Benedict's College -
1971
Boston University School of Medicine - absorbed Boston Female Medical School, 1874
Brevard College - merger of Brevard Institute, Weaverville College, and Rutherford College,
1934
University of California, Berkeley - merger of the College of California and the Agricultural,
Mining, and Mechanical Arts College, 1853
Carson-Newman College - merger of Carson College and Newman College for Women, 1889
Case Western Reserve University - merger of Case Tech and Western Reserve, 1971-72
The Catholic University of America - absorbed Columbus University, 1954
Central Nazarene College - absorbed Nazarene Bible Institute (1911)
Chicago College of Performing Arts - absorbed Roosevelt University School of Music, 1954
University of Cincinnati - absorbed Medical College of Ohio 1896; Cincinnati College of
Pharmacy, 1954
Clark Atlanta University - merger of Clark College and Atlanta University, 1988
Davenport University - merger of Davenport College, Detroit College of Business, and Great
Lakes College, 2000.
University of Delaware - merger of Newark College and Women's College of Delaware, 1921
DePaul University - absorbed Barat College, 2001
List of university and college name changes in
the United States
From Wikipedia, the free encyclopedia
Here follows a list of renamings of universities and colleges in the United States.
Contents:
A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
Top of Page — See also
Current Name
Former
Name(s)
Year of Change
Alabama Agricultural and
Mechanical University
Agricultural and
Mechanical
College of
Alabama
Alcorn State University
Alcorn
Agricultural and
Mechanical
College
1974
Amridge University
Southern
Christian
University
Alliant International University
California
Western
Appalachian State University
Appalachian State
Teachers College;
Appalachian
Training School
for Teachers;
Appalachian State
Normal School;
Watauga
Academy
1967 [1]
Apollo College
American
Institute of
Health
Technology
2005 [2]
Arcadia University Beaver College 2001
Arizona State University
Tempe Normal
School
1958
University of North Texas Libraries
CyberCemetery Home
Search the CyberCemetery
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Related Resources
Contact Us
Digital Collections Home
Browse the CyberCemetery: Agencies by Date
Expired
2009 | 2008 | 2007 | 2006 | 2005 | 2004 | 2003 | 2002 | 2001 | 2000 | 1999 |
1998 | 1997 | 1996 | 1995
2009
National Prison Rape Elimination Commission (August 2009)
2008
Citizens' Health Care Working Group (June 2008)
2007
Antitrust Modernization Commission (May 2007)
2006
Texas Tax Reform Commission (March 2006)
2005
Select Bipartisan Committee to Investigate the Preparation for and
Response to Hurricane Katrina (December 2005)
President's Advisory Panel on Federal Tax Reform (November 2005)
Commission on Systemic Interoperability (October 2005)
Commission on Review of Overseas Military Facility Structure of the
United States: Overseas Basing Commission (August 2005)
Return to Flight Task Group (August 2005)
White House Conference on Cooperative Conservation (August 2005)
Commission on the Intelligence Capabilities of the United States Regarding
Weapons of Mass Destruction (March 2005)
University of North Texas
Libraries
Government Documents Dept.
P.O. Box 305190
Denton, TX 76203-5190
Phone: (940) 565-2870
Fax: (940) 565-2599
http://www.library.unt.edu/govinfo
Geographical renaming
From Wikipedia, the free encyclopedia
Geographical renaming is the act of changing the name of a geographical feature or area. This can
range from the uncontroversial change of a street name to a highly disputed change to the name of a
country. Some names are changed locally but are not recognised by other countries, especially when
there is a difference in language. Other names may not be officially recognised but remain in common
use.
There are many reasons to undertake renaming, with political motivation being the primary cause, such
as renaming places to honour Stalin, and reverting to the original names (see de-Stalinization). One of
the most common reasons for a country changing its name is newly acquired independence. When
borders are changed, sometimes due to a country splitting or two countries joining together, the name
of the areas can change. This, however, is more the creation of a different entity than an act of
geographical renaming.
Other more unusual reasons for renaming have included:
To stop having an unusual or embarrassing name
As part of a sponsorship deal or publicity stunt
A change might see a completely different name being adopted or may simply be just a slightly
different spelling.
In some cases established institutions preserve the old names of the renamed places in their names,
such as the Pusan National University in Busan, South Korea; the Peking University in Beijing,
People's Republic of China; Bombay Stock Exchange, IIT Bombay and the Bombay High Court in
Mumbai, Republic of India; Persian Gulf, south of Iran (formerly Persia); and the University of
Madras, Madras Stock Exchange, the Madras High Court, and IIT Madras in Chennai, Republic of
India.
U.N. Member States
U.S. State Department
List of Independent
States
Mapping.com's list of
Worldwide Country and
City Name Changes
Since 1990
Internet Domains from
the Internet Assigned
Numbers Authority (an
agency under ICANN,
the Internet Corporation
for Assigned Names
and Numbers)
All the Airport Codes
In The World (about
36,000 codes!)
ISO3166-defined
country codes 240 2-
letter codes, 3-letter
codes, and RIPE NCC
Service Region
Flags of the World, and
other information,
keyed to each country's
ISO3166 Code
Country Information
from the CIA World
Name Changes Since 1990: Countries, Cities, and More
An admittedly incomplete and imperfect list of new countries
and cities, and various name changes
Search For Cities and Countries Not Listed Here:
Search
Web mapping.com
1. "New" Countries Since 1990
FORMER USSR:
Estonia
Latvia
Lithuania
Belarus
Ukraine
Moldova
Georgia
Armenia
Cheap
International
Calls
Get A Free Lebara
SIM (Was £2.99)
Limited Offer -
Order Yours
Online!
www.Lebara-Mobile.co.uk
Montenegro
Property
Choose from over
185,000 properties
at the UK's
leading holiday
portal!
Holiday-Rentals.co.uk
country brand
positioning
Acanchi, founded
by Fiona Gilmore,
specialists in
country
positioning.
www.acanchi.com
Russian River
Cruises
The only 5-star
vessel on the
Russian
waterways
www.exeterinternational.com
http://www.foo.com
Barcelona 2014: CrossRef Tools for Small Publishers by Geoffrey Bilder
http://www.txt2pic.com/
PQ7797.B635.B5213 2000
(persistent catalog #)
(current physical location)
Hayden Library, 3rd floor, shelf # 53
The Renear/Palmer article states....
http://dx.doi.org/10.1002/meet.2009.1450460141
http://www.sciencemag.org/cgi/doi/10.1126/science.1157784
(persistent URI)
(current web location)
Library card catalog maps catalog# to current physical location of content CrossRef maps DOI to current web location of content
• PURL	

• XRI	

• Numly Numbers	

• NOIDs	

• URL Shorteners
?
“Persistence” isn’t a
technical issue, it is a
social issue.
“CrossRef links are as persistent as CrossRef staff”
• Members must assign DOIs and deposit metadata 	

• Members are expected to assign DOIs and deposit metadata on a current basis (i.e. content should be
deposited in CrossRef as soon as possible after being published) 	

• Members have an obligation to maintain the metadata and URLs associated with all registered DOIs.	

• Members have an obligation to link references in the journal articles they deposit via CrossRef	

• Before a member may retrieve DOIs for references in an article from a particular journal, the member
must be depositing articles from that journal on a current basis.	

• DOI-routed reference links enabled by CrossRef must resolve to a response page containing no less than
complete bibliographic information about the target content, with information about how the content can
be acquired and/or a hyperlink leading to the content itself.
CrossRef
Demographics
< $1 million revenue
$275 annual membership fee
80% members are “small”
publishers
New CR Members are
• Small	

• Open Access	

• From BRIC or Developing Countries
Reduce
Financial
Burden
Barcelona 2014: CrossRef Tools for Small Publishers by Geoffrey Bilder
Barcelona 2014: CrossRef Tools for Small Publishers by Geoffrey Bilder
Other options
• Continue to hold line on
fees	

• More sponsoring entities
and service providers	

• Bundle DOIs with
membership
Reduce
Technical
Burden
Members have an obligation to link references in the
journal articles they deposit via CrossRef.
http://goo.gl/ZV3t3l
Cited By
Helping The
Small
Publisher
Depositor
Tools
Barcelona 2014: CrossRef Tools for Small Publishers by Geoffrey Bilder
Barcelona 2014: CrossRef Tools for Small Publishers by Geoffrey Bilder
Barcelona 2014: CrossRef Tools for Small Publishers by Geoffrey Bilder
Investigation of the Staphylococcus aureus GraSR
Regulon Reveals Novel Links to Virulence, Stress
Response and Cell Wall Signal Transduction Pathways
Me´lanie Falord1,2
, Ulrike Ma¨der3
, Aure´lia Hiron1,2
, Michel Dbarbouille´1,2
, Tarek Msadek1,2
*
1 Institut Pasteur, Biology of Gram-Positive Pathogens, Department of Microbiology, Paris, France, 2 CNRS, URA 2172, Paris, France, 3 Interfaculty Institute for Genetics and
Functional Genomics, Department for Functional Genomics, Ernst Moritz Arndt University, Greifswald, Germany
Abstract
The GraS/GraR two-component system has been shown to control cationic antimicrobial peptide (CAMP) resistance in the
major human pathogen Staphylococcus aureus. We demonstrated that graX, also involved in CAMP resistance and
cotranscribed with graRS, encodes a regulatory cofactor of the GraSR signaling pathway, effectively constituting a three-
component system. We identified a highly conserved ten base pair palindromic sequence (59 ACAAA TTTGT 39) located
upstream from GraR-regulated genes (mprF and the dlt and vraFG operons), which we show to be essential for
transcriptional regulation by GraR and induction in response to CAMPs, suggesting it is the likely GraR binding site.
Genome-based predictions and transcriptome analysis revealed several novel GraR target genes. We also found that the
GraSR TCS is required for growth of S. aureus at high temperatures and resistance to oxidative stress. The GraSR system has
previously been shown to play a role in S. aureus pathogenesis and we have uncovered previously unsuspected links with
the AgrCA peptide quorum-sensing system controlling virulence gene expression. We also show that the GraSR TCS controls
stress reponse and cell wall metabolism signal transduction pathways, sharing an extensive overlap with the WalKR regulon.
This is the first report showing a role for the GraSR TCS in high temperature and oxidative stress survival and linking this
system to stress response, cell wall and pathogenesis control pathways.
Citation: Falord M, Ma¨der U, Hiron A, De´barbouille´ M, Msadek T (2011) Investigation of the Staphylococcus aureus GraSR Regulon Reveals Novel Links to
Virulence, Stress Response and Cell Wall Signal Transduction Pathways. PLoS ONE 6(7): e21323. doi:10.1371/journal.pone.0021323
Editor: Malcolm James Horsburgh, University of Liverpool, United Kingdom
Received May 4, 2011; Accepted May 25, 2011; Published July 1, 2011
Copyright: ß 2011 Falord et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by research funds from the European Commission (StaphDynamics [LHSM-CT-2006-019064] and BaSysBio [LSHG-CT-2006-
037469] grants), the Centre National de la Recherche Scientifique (CNRS URA 2172), Agence Nationale de la Recherche (ANR GrabIron and NaBab), and the Institut
Pasteur (PTR Nu256 and PTR Nu336). Me´lanie Falord received a Young Scientist Fellowship from the Conseil Pasteur-Weizmann. The funders had no role in study
design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: tmsadek@pasteur.fr
Introduction
The opportunistic pathogen Staphylococcus aureus is both a
commensal and a major Gram-positive pathogen, causing a variety
of infections ranging from superficial skin abscesses to more serious
diseases such as pneumonia, meningitis, endocarditis, septicemia
and toxic shock syndrome [1]. The ubiquitous nature of this
pathogen stems mostly from its capacity to survive a large variety of
environmental conditions as well as an impressive ability to resist
host innate immune defense mechanisms and produce systemic
infections, often in healthy humans [2,3]. This unique adaptive
potential has made S. aureus one of the major causes of nosocomial
infections today, compounded by the rapid emergence of multiple
antibiotic-resistant strains over the past few decades [4], particularly
methicillin and vancomycin-intermediate resistant strains (MRSA
and VISA). Until recently, vancomycin had remained the weapon
of last resort, but the recent appearance of the enterococcal vanA
vancomycin-resistance gene cluster in S. aureus highlights the
growing threat this bacterium poses to human health and the
urgent need for developing novel therapeutic approaches [5,6].
Cationic antimicrobial peptides (CAMPs) are an important
component of host innate immunity and understanding the
molecular mechanisms involved in resistance is a key factor in
staphylococcal treatment research. CAMPs have both cationic and
amphipathic properties and are classified according to their length
and secondary structure [7]. They are produced by certain
immune, skin and epithelial cells in all living kingdoms, as defenses
against microbial proliferation, and many are known to act by
forming pores in the cell membrane, through interactions with
bacterial cell envelope components [8]. However, recent work has
shown that several CAMPs, including indolicidin and colistin, can
also kill by inhibiting intracellular processes such as protein and
DNA synthesis as well as septum formation and division [9].
To counteract CAMP antimicrobial activity during infection,
Gram-positive bacteria have developed several resistance mecha-
nisms, including degradation, sequestration or electrostatic repulsion
[10]. In Bacillus subtilis and related Gram-positive bacteria, D-
alanylation of wall teichoic acids (WTAs) and lipoteichoic acids
(LTAs), mediated by the DltABCD enzymes, as well as MprF-
dependent lysylination of phosphatidylglycerol, prevent CAMP-
binding by increasing the bacterial surface positive charge [10,11].
Two-component systems (TCSs) play an important role in these
mechanisms by coordinating the expression of resistance genes,
when CAMPs are detected at the cell surface. TCSs are typically
composed of a membrane histidine kinase (HK), acting as a signal
sensor/transducer, through phosphorylation of its cognate response
PLoS ONE | www.plosone.org 1 July 2011 | Volume 6 | Issue 7 | e21323
Barcelona 2014: CrossRef Tools for Small Publishers by Geoffrey Bilder
Barcelona 2014: CrossRef Tools for Small Publishers by Geoffrey Bilder
Barcelona 2014: CrossRef Tools for Small Publishers by Geoffrey Bilder
Barcelona 2014: CrossRef Tools for Small Publishers by Geoffrey Bilder
Barcelona 2014: CrossRef Tools for Small Publishers by Geoffrey Bilder

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Barcelona 2014: CrossRef Tools for Small Publishers by Geoffrey Bilder

  • 1. Geoffrey Bilder Director of Strategic Initiatives Barcelona, 2014 CrossRef Helps Small Publishers
  • 9. BrandIs it relevant? Is it good? Is it important? provenanceinfrastructure •What is it? •Where can I get it? •What refers to it? •What does it refer to? •What has been done to it? •Who provides stewardship of it? •Who funded it? •What can I do with it? •Who do we credit it to? •What are their credentials?
  • 13. http://www.easel.com/foo/bar/blat.html Tim Berners-Lee (1998). "Cool URIs Don’t Change" Litigation Transfer Poverty Forgetfulness Divorce Death...
  • 14. List of university and college mergers in the United States From Wikipedia, the free encyclopedia This is a list of mergers of universities and/or colleges in the United States with the name of the surviving institution, predecessors, and effective date. This list is incomplete; you can help by expanding it (http://en.wikipedia.org/w/index.php? title=List_of_university_and_college_mergers_in_the_United_States&action=edit) . Contents 1 A through D 2 E through M 3 N through Z 4 See also 5 References A through D Alliant International University - merger of California School of Professional Psychology and United States International University, 2001 Azusa Pacific College - absorbed Arlington College, 1968 Azusa Pacific College - merger of Azusa College and Los Angeles Pacific College, 1965 University of Baltimore - absorbed Eastern College, 1970 Benedictine College - merger of Mount Saint Scholastica College and St. Benedict's College - 1971 Boston University School of Medicine - absorbed Boston Female Medical School, 1874 Brevard College - merger of Brevard Institute, Weaverville College, and Rutherford College, 1934 University of California, Berkeley - merger of the College of California and the Agricultural, Mining, and Mechanical Arts College, 1853 Carson-Newman College - merger of Carson College and Newman College for Women, 1889 Case Western Reserve University - merger of Case Tech and Western Reserve, 1971-72 The Catholic University of America - absorbed Columbus University, 1954 Central Nazarene College - absorbed Nazarene Bible Institute (1911) Chicago College of Performing Arts - absorbed Roosevelt University School of Music, 1954 University of Cincinnati - absorbed Medical College of Ohio 1896; Cincinnati College of Pharmacy, 1954 Clark Atlanta University - merger of Clark College and Atlanta University, 1988 Davenport University - merger of Davenport College, Detroit College of Business, and Great Lakes College, 2000. University of Delaware - merger of Newark College and Women's College of Delaware, 1921 DePaul University - absorbed Barat College, 2001 List of university and college name changes in the United States From Wikipedia, the free encyclopedia Here follows a list of renamings of universities and colleges in the United States. Contents: A B C D E F G H I J K L M N O P Q R S T U V W X Y Z Top of Page — See also Current Name Former Name(s) Year of Change Alabama Agricultural and Mechanical University Agricultural and Mechanical College of Alabama Alcorn State University Alcorn Agricultural and Mechanical College 1974 Amridge University Southern Christian University Alliant International University California Western Appalachian State University Appalachian State Teachers College; Appalachian Training School for Teachers; Appalachian State Normal School; Watauga Academy 1967 [1] Apollo College American Institute of Health Technology 2005 [2] Arcadia University Beaver College 2001 Arizona State University Tempe Normal School 1958 University of North Texas Libraries CyberCemetery Home Search the CyberCemetery Browse the CyberCemetery Related Resources Contact Us Digital Collections Home Browse the CyberCemetery: Agencies by Date Expired 2009 | 2008 | 2007 | 2006 | 2005 | 2004 | 2003 | 2002 | 2001 | 2000 | 1999 | 1998 | 1997 | 1996 | 1995 2009 National Prison Rape Elimination Commission (August 2009) 2008 Citizens' Health Care Working Group (June 2008) 2007 Antitrust Modernization Commission (May 2007) 2006 Texas Tax Reform Commission (March 2006) 2005 Select Bipartisan Committee to Investigate the Preparation for and Response to Hurricane Katrina (December 2005) President's Advisory Panel on Federal Tax Reform (November 2005) Commission on Systemic Interoperability (October 2005) Commission on Review of Overseas Military Facility Structure of the United States: Overseas Basing Commission (August 2005) Return to Flight Task Group (August 2005) White House Conference on Cooperative Conservation (August 2005) Commission on the Intelligence Capabilities of the United States Regarding Weapons of Mass Destruction (March 2005) University of North Texas Libraries Government Documents Dept. P.O. Box 305190 Denton, TX 76203-5190 Phone: (940) 565-2870 Fax: (940) 565-2599 http://www.library.unt.edu/govinfo Geographical renaming From Wikipedia, the free encyclopedia Geographical renaming is the act of changing the name of a geographical feature or area. This can range from the uncontroversial change of a street name to a highly disputed change to the name of a country. Some names are changed locally but are not recognised by other countries, especially when there is a difference in language. Other names may not be officially recognised but remain in common use. There are many reasons to undertake renaming, with political motivation being the primary cause, such as renaming places to honour Stalin, and reverting to the original names (see de-Stalinization). One of the most common reasons for a country changing its name is newly acquired independence. When borders are changed, sometimes due to a country splitting or two countries joining together, the name of the areas can change. This, however, is more the creation of a different entity than an act of geographical renaming. Other more unusual reasons for renaming have included: To stop having an unusual or embarrassing name As part of a sponsorship deal or publicity stunt A change might see a completely different name being adopted or may simply be just a slightly different spelling. In some cases established institutions preserve the old names of the renamed places in their names, such as the Pusan National University in Busan, South Korea; the Peking University in Beijing, People's Republic of China; Bombay Stock Exchange, IIT Bombay and the Bombay High Court in Mumbai, Republic of India; Persian Gulf, south of Iran (formerly Persia); and the University of Madras, Madras Stock Exchange, the Madras High Court, and IIT Madras in Chennai, Republic of India. U.N. Member States U.S. State Department List of Independent States Mapping.com's list of Worldwide Country and City Name Changes Since 1990 Internet Domains from the Internet Assigned Numbers Authority (an agency under ICANN, the Internet Corporation for Assigned Names and Numbers) All the Airport Codes In The World (about 36,000 codes!) ISO3166-defined country codes 240 2- letter codes, 3-letter codes, and RIPE NCC Service Region Flags of the World, and other information, keyed to each country's ISO3166 Code Country Information from the CIA World Name Changes Since 1990: Countries, Cities, and More An admittedly incomplete and imperfect list of new countries and cities, and various name changes Search For Cities and Countries Not Listed Here: Search Web mapping.com 1. "New" Countries Since 1990 FORMER USSR: Estonia Latvia Lithuania Belarus Ukraine Moldova Georgia Armenia Cheap International Calls Get A Free Lebara SIM (Was £2.99) Limited Offer - Order Yours Online! www.Lebara-Mobile.co.uk Montenegro Property Choose from over 185,000 properties at the UK's leading holiday portal! Holiday-Rentals.co.uk country brand positioning Acanchi, founded by Fiona Gilmore, specialists in country positioning. www.acanchi.com Russian River Cruises The only 5-star vessel on the Russian waterways www.exeterinternational.com
  • 18. PQ7797.B635.B5213 2000 (persistent catalog #) (current physical location) Hayden Library, 3rd floor, shelf # 53 The Renear/Palmer article states.... http://dx.doi.org/10.1002/meet.2009.1450460141 http://www.sciencemag.org/cgi/doi/10.1126/science.1157784 (persistent URI) (current web location) Library card catalog maps catalog# to current physical location of content CrossRef maps DOI to current web location of content
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  • 37. Investigation of the Staphylococcus aureus GraSR Regulon Reveals Novel Links to Virulence, Stress Response and Cell Wall Signal Transduction Pathways Me´lanie Falord1,2 , Ulrike Ma¨der3 , Aure´lia Hiron1,2 , Michel Dbarbouille´1,2 , Tarek Msadek1,2 * 1 Institut Pasteur, Biology of Gram-Positive Pathogens, Department of Microbiology, Paris, France, 2 CNRS, URA 2172, Paris, France, 3 Interfaculty Institute for Genetics and Functional Genomics, Department for Functional Genomics, Ernst Moritz Arndt University, Greifswald, Germany Abstract The GraS/GraR two-component system has been shown to control cationic antimicrobial peptide (CAMP) resistance in the major human pathogen Staphylococcus aureus. We demonstrated that graX, also involved in CAMP resistance and cotranscribed with graRS, encodes a regulatory cofactor of the GraSR signaling pathway, effectively constituting a three- component system. We identified a highly conserved ten base pair palindromic sequence (59 ACAAA TTTGT 39) located upstream from GraR-regulated genes (mprF and the dlt and vraFG operons), which we show to be essential for transcriptional regulation by GraR and induction in response to CAMPs, suggesting it is the likely GraR binding site. Genome-based predictions and transcriptome analysis revealed several novel GraR target genes. We also found that the GraSR TCS is required for growth of S. aureus at high temperatures and resistance to oxidative stress. The GraSR system has previously been shown to play a role in S. aureus pathogenesis and we have uncovered previously unsuspected links with the AgrCA peptide quorum-sensing system controlling virulence gene expression. We also show that the GraSR TCS controls stress reponse and cell wall metabolism signal transduction pathways, sharing an extensive overlap with the WalKR regulon. This is the first report showing a role for the GraSR TCS in high temperature and oxidative stress survival and linking this system to stress response, cell wall and pathogenesis control pathways. Citation: Falord M, Ma¨der U, Hiron A, De´barbouille´ M, Msadek T (2011) Investigation of the Staphylococcus aureus GraSR Regulon Reveals Novel Links to Virulence, Stress Response and Cell Wall Signal Transduction Pathways. PLoS ONE 6(7): e21323. doi:10.1371/journal.pone.0021323 Editor: Malcolm James Horsburgh, University of Liverpool, United Kingdom Received May 4, 2011; Accepted May 25, 2011; Published July 1, 2011 Copyright: ß 2011 Falord et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by research funds from the European Commission (StaphDynamics [LHSM-CT-2006-019064] and BaSysBio [LSHG-CT-2006- 037469] grants), the Centre National de la Recherche Scientifique (CNRS URA 2172), Agence Nationale de la Recherche (ANR GrabIron and NaBab), and the Institut Pasteur (PTR Nu256 and PTR Nu336). Me´lanie Falord received a Young Scientist Fellowship from the Conseil Pasteur-Weizmann. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: tmsadek@pasteur.fr Introduction The opportunistic pathogen Staphylococcus aureus is both a commensal and a major Gram-positive pathogen, causing a variety of infections ranging from superficial skin abscesses to more serious diseases such as pneumonia, meningitis, endocarditis, septicemia and toxic shock syndrome [1]. The ubiquitous nature of this pathogen stems mostly from its capacity to survive a large variety of environmental conditions as well as an impressive ability to resist host innate immune defense mechanisms and produce systemic infections, often in healthy humans [2,3]. This unique adaptive potential has made S. aureus one of the major causes of nosocomial infections today, compounded by the rapid emergence of multiple antibiotic-resistant strains over the past few decades [4], particularly methicillin and vancomycin-intermediate resistant strains (MRSA and VISA). Until recently, vancomycin had remained the weapon of last resort, but the recent appearance of the enterococcal vanA vancomycin-resistance gene cluster in S. aureus highlights the growing threat this bacterium poses to human health and the urgent need for developing novel therapeutic approaches [5,6]. Cationic antimicrobial peptides (CAMPs) are an important component of host innate immunity and understanding the molecular mechanisms involved in resistance is a key factor in staphylococcal treatment research. CAMPs have both cationic and amphipathic properties and are classified according to their length and secondary structure [7]. They are produced by certain immune, skin and epithelial cells in all living kingdoms, as defenses against microbial proliferation, and many are known to act by forming pores in the cell membrane, through interactions with bacterial cell envelope components [8]. However, recent work has shown that several CAMPs, including indolicidin and colistin, can also kill by inhibiting intracellular processes such as protein and DNA synthesis as well as septum formation and division [9]. To counteract CAMP antimicrobial activity during infection, Gram-positive bacteria have developed several resistance mecha- nisms, including degradation, sequestration or electrostatic repulsion [10]. In Bacillus subtilis and related Gram-positive bacteria, D- alanylation of wall teichoic acids (WTAs) and lipoteichoic acids (LTAs), mediated by the DltABCD enzymes, as well as MprF- dependent lysylination of phosphatidylglycerol, prevent CAMP- binding by increasing the bacterial surface positive charge [10,11]. Two-component systems (TCSs) play an important role in these mechanisms by coordinating the expression of resistance genes, when CAMPs are detected at the cell surface. TCSs are typically composed of a membrane histidine kinase (HK), acting as a signal sensor/transducer, through phosphorylation of its cognate response PLoS ONE | www.plosone.org 1 July 2011 | Volume 6 | Issue 7 | e21323