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Sample records for action contractor rac

  1. 77 FR 11127 - Medicaid Program; Announcement of Medicaid Recovery Audit Contractors (RACs) Contingency Fee Update

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-24

    ... Recovery Audit Contractors (RACs) Contingency Fee Update AGENCY: Centers for Medicare & Medicaid Services... Recovery Audit Contractors (RAC) by State Medicaid programs as authorized by section 1902(a)(42)(B) of the... that ties the Medicaid RAC contingency fee to the Medicare Recovery Audit Program with an...

  2. Specificity and mechanism of action of EHT 1864, a novel small molecule inhibitor of Rac family small GTPases.

    PubMed

    Shutes, Adam; Onesto, Cercina; Picard, Virginie; Leblond, Bertrand; Schweighoffer, Fabien; Der, Channing J

    2007-12-07

    There is now considerable experimental evidence that aberrant activation of Rho family small GTPases promotes the uncontrolled proliferation, invasion, and metastatic properties of human cancer cells. Therefore, there is considerable interest in the development of small molecule inhibitors of Rho GTPase function. However, to date, most efforts have focused on inhibitors that indirectly block Rho GTPase function, by targeting either enzymes involved in post-translational processing or downstream protein kinase effectors. We recently determined that the EHT 1864 small molecule can inhibit Rac function in vivo. In this study, we evaluated the biological and biochemical specificities and biochemical mechanism of action of EHT 1864. We determined that EHT 1864 specifically inhibited Rac1-dependent platelet-derived growth factor-induced lamellipodia formation. Furthermore, our biochemical analyses with recombinant Rac proteins found that EHT 1864 possesses high affinity binding to Rac1, as well as the related Rac1b, Rac2, and Rac3 isoforms, and this association promoted the loss of bound nucleotide, inhibiting both guanine nucleotide association and Tiam1 Rac guanine nucleotide exchange factor-stimulated exchange factor activity in vitro. EHT 1864 therefore places Rac in an inert and inactive state, preventing its engagement with downstream effectors. Finally, we evaluated the ability of EHT 1864 to block Rac-dependent growth transformation, and we determined that EHT 1864 potently blocked transformation caused by constitutively activated Rac1, as well as Rac-dependent transformation caused by Tiam1 or Ras. Taken together, our results suggest that EHT 1864 selectively inhibits Rac downstream signaling and transformation by a novel mechanism involving guanine nucleotide displacement.

  3. 10 CFR 707.17 - Permissible actions in the event of contractor noncompliance.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 4 2010-01-01 2010-01-01 false Permissible actions in the event of contractor... Procedures § 707.17 Permissible actions in the event of contractor noncompliance. Actions available to DOE in the event of contractor noncompliance with the provisions of this part or otherwise performing in...

  4. 10 CFR 707.17 - Permissible actions in the event of contractor noncompliance.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 4 2011-01-01 2011-01-01 false Permissible actions in the event of contractor... Procedures § 707.17 Permissible actions in the event of contractor noncompliance. Actions available to DOE in the event of contractor noncompliance with the provisions of this part or otherwise performing in...

  5. 10 CFR 707.17 - Permissible actions in the event of contractor noncompliance.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 4 2012-01-01 2012-01-01 false Permissible actions in the event of contractor... Procedures § 707.17 Permissible actions in the event of contractor noncompliance. Actions available to DOE in the event of contractor noncompliance with the provisions of this part or otherwise performing in...

  6. 10 CFR 707.17 - Permissible actions in the event of contractor noncompliance.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 4 2013-01-01 2013-01-01 false Permissible actions in the event of contractor... Procedures § 707.17 Permissible actions in the event of contractor noncompliance. Actions available to DOE in the event of contractor noncompliance with the provisions of this part or otherwise performing in...

  7. 10 CFR 707.17 - Permissible actions in the event of contractor noncompliance.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 Energy 4 2014-01-01 2014-01-01 false Permissible actions in the event of contractor noncompliance. 707.17 Section 707.17 Energy DEPARTMENT OF ENERGY WORKPLACE SUBSTANCE ABUSE PROGRAMS AT DOE SITES Procedures § 707.17 Permissible actions in the event of contractor noncompliance. Actions available to DOE...

  8. 75 FR 8397 - Notice of Utah's Resource Advisory Council (RAC)/Recreation RAC Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-24

    ... Bureau of Land Management Notice of Utah's Resource Advisory Council (RAC)/Recreation RAC Meeting AGENCY: Bureau of Land Management, Interior. ACTION: Notice of Utah's Resource Advisory Council (RAC)/Recreation... Management's (BLM) Utah Resource Advisory Council (RAC)/Recreation RAC will meet as indicated below....

  9. Post Remedial Action Report, Lansdowne Radioactive Residence Complex, Dismantlement/Removal Project. Volume 2. Contractor Operations

    DTIC Science & Technology

    1990-06-01

    time for reviein Inatruction. serching ewisting dat swc, gath ,)eriad nmntainn the datal needed, and comleting and r evewng the co action Bf...Management andl lUdgt. Paperwork Reducti/on Prolec (0704401160). Wasingtlon. CC 20503. 1. AGENCY’USE ONLY (Leave blank) 2. REPORT.DATE 3. REPORT TYPE AND...Driveway Replacement R . Jensen, Masonry Contractor GarageFoundations/Stucco J. Cunningham, Pavement Contractor Asphalt PavingWells Fargo Security Systems

  10. 76 FR 77055 - Affirmative Action and Nondiscrimination Obligations of Contractors and Subcontractors Regarding...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-09

    ... organizations and agencies requested that OFCCP strengthen the existing affirmative action requirements and... commenters addressed this issue. Of these, 37 said that hiring goals ``like those for race and gender... regulations. Existing paragraph (a) discusses the contractor's affirmative action obligations but does...

  11. 28 CFR 115.177 - Corrective action for contractors and volunteers.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 28 Judicial Administration 2 2012-07-01 2012-07-01 false Corrective action for contractors and volunteers. 115.177 Section 115.177 Judicial Administration DEPARTMENT OF JUSTICE (CONTINUED) PRISON RAPE ELIMINATION ACT NATIONAL STANDARDS Standards for Lockups Discipline § 115.177 Corrective action...

  12. 28 CFR 115.177 - Corrective action for contractors and volunteers.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 28 Judicial Administration 2 2014-07-01 2014-07-01 false Corrective action for contractors and volunteers. 115.177 Section 115.177 Judicial Administration DEPARTMENT OF JUSTICE (CONTINUED) PRISON RAPE ELIMINATION ACT NATIONAL STANDARDS Standards for Lockups Discipline § 115.177 Corrective action...

  13. 28 CFR 115.177 - Corrective action for contractors and volunteers.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 28 Judicial Administration 2 2013-07-01 2013-07-01 false Corrective action for contractors and volunteers. 115.177 Section 115.177 Judicial Administration DEPARTMENT OF JUSTICE (CONTINUED) PRISON RAPE ELIMINATION ACT NATIONAL STANDARDS Standards for Lockups Discipline § 115.177 Corrective action...

  14. 76 FR 23357 - Affirmative Action and Nondiscrimination Obligations of Contractors and Subcontractors Regarding...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-26

    ...The Office of Federal Contract Compliance Programs (OFCCP) is proposing to revise regulations implementing the affirmative action provisions of the Vietnam Era Veterans' Readjustment Assistance Act of 1974, as amended, which requires covered Federal contractors and subcontractors to take affirmative action in employment on behalf of specified categories of protected veterans. The proposed......

  15. Defense Contractors: Additional Actions Needed to Facilitate the Use of DOD’s Inventory of Contracted Services

    DTIC Science & Technology

    2014-11-01

    DEFENSE CONTRACTORS Additional Actions Needed to Facilitate the Use of DOD’s Inventory of Contracted Services...COVERED 00-00-2014 to 00-00-2014 4. TITLE AND SUBTITLE Defense Contractors: Additional Actions Needed to Facilitate the Use of DOD’s Inventory of...CONTRACTORS Additional Actions Needed to Facilitate the Use of DOD’s Inventory of Contracted Services Why GAO Did This Study DOD is the government’s

  16. 28 CFR 115.77 - Corrective action for contractors and volunteers.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 28 Judicial Administration 2 2014-07-01 2014-07-01 false Corrective action for contractors and volunteers. 115.77 Section 115.77 Judicial Administration DEPARTMENT OF JUSTICE (CONTINUED) PRISON RAPE ELIMINATION ACT NATIONAL STANDARDS Standards for Adult Prisons and Jails Discipline § 115.77 Corrective...

  17. 28 CFR 115.77 - Corrective action for contractors and volunteers.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 28 Judicial Administration 2 2013-07-01 2013-07-01 false Corrective action for contractors and volunteers. 115.77 Section 115.77 Judicial Administration DEPARTMENT OF JUSTICE (CONTINUED) PRISON RAPE ELIMINATION ACT NATIONAL STANDARDS Standards for Adult Prisons and Jails Discipline § 115.77 Corrective...

  18. 28 CFR 115.77 - Corrective action for contractors and volunteers.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 28 Judicial Administration 2 2012-07-01 2012-07-01 false Corrective action for contractors and volunteers. 115.77 Section 115.77 Judicial Administration DEPARTMENT OF JUSTICE (CONTINUED) PRISON RAPE ELIMINATION ACT NATIONAL STANDARDS Standards for Adult Prisons and Jails Discipline § 115.77 Corrective...

  19. 28 CFR 115.377 - Corrective action for contractors and volunteers.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 28 Judicial Administration 2 2012-07-01 2012-07-01 false Corrective action for contractors and volunteers. 115.377 Section 115.377 Judicial Administration DEPARTMENT OF JUSTICE (CONTINUED) PRISON RAPE ELIMINATION ACT NATIONAL STANDARDS Standards for Juvenile Facilities Discipline § 115.377 Corrective...

  20. 28 CFR 115.277 - Corrective action for contractors and volunteers.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 28 Judicial Administration 2 2014-07-01 2014-07-01 false Corrective action for contractors and volunteers. 115.277 Section 115.277 Judicial Administration DEPARTMENT OF JUSTICE (CONTINUED) PRISON RAPE ELIMINATION ACT NATIONAL STANDARDS Standards for Community Confinement Facilities Discipline §...

  1. 28 CFR 115.377 - Corrective action for contractors and volunteers.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 28 Judicial Administration 2 2014-07-01 2014-07-01 false Corrective action for contractors and volunteers. 115.377 Section 115.377 Judicial Administration DEPARTMENT OF JUSTICE (CONTINUED) PRISON RAPE ELIMINATION ACT NATIONAL STANDARDS Standards for Juvenile Facilities Discipline § 115.377 Corrective...

  2. 28 CFR 115.277 - Corrective action for contractors and volunteers.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 28 Judicial Administration 2 2013-07-01 2013-07-01 false Corrective action for contractors and volunteers. 115.277 Section 115.277 Judicial Administration DEPARTMENT OF JUSTICE (CONTINUED) PRISON RAPE ELIMINATION ACT NATIONAL STANDARDS Standards for Community Confinement Facilities Discipline §...

  3. 28 CFR 115.377 - Corrective action for contractors and volunteers.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 28 Judicial Administration 2 2013-07-01 2013-07-01 false Corrective action for contractors and volunteers. 115.377 Section 115.377 Judicial Administration DEPARTMENT OF JUSTICE (CONTINUED) PRISON RAPE ELIMINATION ACT NATIONAL STANDARDS Standards for Juvenile Facilities Discipline § 115.377 Corrective...

  4. 28 CFR 115.277 - Corrective action for contractors and volunteers.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 28 Judicial Administration 2 2012-07-01 2012-07-01 false Corrective action for contractors and volunteers. 115.277 Section 115.277 Judicial Administration DEPARTMENT OF JUSTICE (CONTINUED) PRISON RAPE ELIMINATION ACT NATIONAL STANDARDS Standards for Community Confinement Facilities Discipline §...

  5. 78 FR 58613 - Affirmative Action and Nondiscrimination Obligations of Contractors and Subcontractors Regarding...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-24

    ... effective March 24, 2014. FOR FURTHER INFORMATION CONTACT: Debra A. Carr, Director, Division of Policy... enforcement of personnel policies that support the contractor's affirmative action obligations, maintenance of...\\ Broad public policy considerations also exist related to the decreased demand for and cost of...

  6. Comment and response document for the final remedial action plan site design for stabilization of the Inactive Uranium Mill Tailings Sites at Slick Rock, Colorado

    SciTech Connect

    1995-09-01

    This document consists of comments and responses; the reviewers are the U.S. Nuclear Regulatory Commission (NRC), Colorado Dept. of Public Health and Environment, and the remedial action contractor (RAC).

  7. Remedial action plan and site design for stabilization of the inactive uranium mill tailings site at Tuba City, Arizona. [Uranium Mill Tailings Remedial Action (UMTRA) Project

    SciTech Connect

    Not Available

    1987-05-01

    This appendix assesses the present conditions and data for the inactive uranium mill site near Tuba City, Arizona. It consolidates available engineering, radiological, geotechnical, hydrological, meterological, and other information pertinent to the design of the Remedial Action Plan (RAP). The data characterize conditions at the mill and tailings site so that the Remedial Action Contractor (RAC) may complete final designs of the remedial actions.

  8. 42 CFR 455.508 - Eligibility requirements for Medicaid RACs.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 4 2012-10-01 2012-10-01 false Eligibility requirements for Medicaid RACs. 455.508 Section 455.508 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN... Contractors Program § 455.508 Eligibility requirements for Medicaid RACs. An entity that wishes to perform...

  9. 42 CFR 455.508 - Eligibility requirements for Medicaid RACs.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 4 2013-10-01 2013-10-01 false Eligibility requirements for Medicaid RACs. 455.508 Section 455.508 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN... Contractors Program § 455.508 Eligibility requirements for Medicaid RACs. An entity that wishes to perform...

  10. 42 CFR 455.508 - Eligibility requirements for Medicaid RACs.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 4 2011-10-01 2011-10-01 false Eligibility requirements for Medicaid RACs. 455.508 Section 455.508 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN... Contractors Program § 455.508 Eligibility requirements for Medicaid RACs. An entity that wishes to perform...

  11. The RAC program: are you ready?

    PubMed

    Machisko, Francine; Snecinski, Jane

    2008-01-01

    Providers should take these steps to prepare for an RAC review: Educate physicians and all direct care staff on the basic infrastructure for the provision of care as well as the RAC initiative itself. Create compliance assessment tools and programs and conduct internal assessment. Develop and implement a corrective action plan based on findings from internal reviews.

  12. Remedial action plan and site design for stabilization of the inactive uranium mill tailings site at Tuba City, Arizona. Apendix D, Site characteriztion

    SciTech Connect

    Not Available

    1987-05-01

    This appendix assesses the present conditions and data for the inactive uranium mill site near Tuba City, Arizona. It consolidates available engineering, radiological, geotechnical, hydrological, meterological, and other information pertinent to the design of the Remedial Action Plan (RAP). The data characterize conditions at the mill and tailings site so that the Remedial Action Contractor (RAC) may complete final designs of the remedial actions.

  13. 78 FR 58681 - Affirmative Action and Nondiscrimination Obligations of Contractors and Subcontractors Regarding...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-24

    ... deficiencies in their employment practices. Because the existing regulations implementing section 503 do not... the existing requirement that contractors invite applicants to voluntarily self-identify after...\\ Broad public policy considerations also exist related to the decreased demand for and cost of...

  14. 42 CFR 455.510 - Payments to RACs.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL ASSISTANCE PROGRAMS PROGRAM INTEGRITY: MEDICAID Medicaid Recovery Audit Contractors Program § 455... and recovery of Medicaid provider overpayments. (1) The contingency fees paid to Medicaid RACs must...

  15. 42 CFR 455.510 - Payments to RACs.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL ASSISTANCE PROGRAMS PROGRAM INTEGRITY: MEDICAID Medicaid Recovery Audit Contractors Program § 455... and recovery of Medicaid provider overpayments. (1) The contingency fees paid to Medicaid RACs must...

  16. 42 CFR 455.510 - Payments to RACs.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL ASSISTANCE PROGRAMS PROGRAM INTEGRITY: MEDICAID Medicaid Recovery Audit Contractors Program § 455... and recovery of Medicaid provider overpayments. (1) The contingency fees paid to Medicaid RACs must...

  17. 42 CFR 455.510 - Payments to RACs.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL ASSISTANCE PROGRAMS PROGRAM INTEGRITY: MEDICAID Medicaid Recovery Audit Contractors Program § 455... and recovery of Medicaid provider overpayments. (1) The contingency fees paid to Medicaid RACs must...

  18. Remedial action plan and site design for stabilization of the inactive uranium mill tailings sites at Rifle, Colorado

    SciTech Connect

    Not Available

    1992-02-01

    This appendix assesses the present conditions and data gathered about the two inactive uranium mill tailings sites near Rifle, Colorado, and the designated disposal site six miles north of Rifle in the area of Estes Gulch. It consolidates available engineering, radiological, geotechnical, hydrological, meteorological, and other information pertinent to the design of the Remedial Action Plan (RAP). The data characterize conditions at the mill, tailings, and disposal site so that the Remedial Action Contractor (RAC) may complete final designs for the remedial actions.

  19. The impact of RAC audits on US hospitals.

    PubMed

    Harrison, Jeffrey P; Barksdale, Rachel M

    2013-01-01

    The Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA) authorized a three-year demonstration program using recovery audit contractors (RACs) to identify and correct improper payments in the Medicare Fee-For-Service program. More recently, Section 6411 of the Affordable Care Act (ACA) expanded the RAC program to include the Medicaid program. This shows the Cent ers for Medicare & Medicaid Services (CMS) believe RAC audits are a cost-effective method to ensure health care providers are paid correctly and thereby protect the Medicare Trust Fund. RAC audits are highly complex and require significant manpower to handle the large volume of requests received during a short period of time. Additionally, the RAC audit appeal process is complicated and requires a high level of technical expertise. The demonstration project found that RAC audits resulted in sizeable amounts of overpayments collected ("take-backs") from many providers. This research study assesses the potential impact of the RAC audit program on US acute care hospitals. Data obtained from CMS show that RAC overpayments collected for FY 2010 were $75.4 million, increased to $797.4 million in FY 2011, and increased to $986.2 million in the first six months of FY 2012. According to the American Hospital Association (AHA) RACTrac audit survey, the vast majority of these collections represent complex denials where hospitals are required to provide medical record documents in support of their billed claims. This study found that the RAC audit program collections are increasing significantly over time. As a result, these collections are having a significant negative impact on the profitability of US hospitals.

  20. 38 CFR 46.8 - Independent contractors.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2010-07-01 2010-07-01 false Independent contractors... contractors. Independent contractors acting on behalf of the Department of Veterans Affairs are subject to the... provide the contractor with notice that a report of a clinical privileges action will be filed with...

  1. Remedial action plan and site design for stabilization of the inactive uranium mill tailings sites at Rifle, Colorado. Volume 2, Appendices D and E: Final report

    SciTech Connect

    Not Available

    1992-02-01

    This appendix assesses the present conditions and data gathered about the two inactive uranium mill tailings sites near Rifle, Colorado, and the designated disposal site six miles north of Rifle in the area of Estes Gulch. It consolidates available engineering, radiological, geotechnical, hydrological, meteorological, and other information pertinent to the design of the Remedial Action Plan (RAP). The data characterize conditions at the mill, tailings, and disposal site so that the Remedial Action Contractor (RAC) may complete final designs for the remedial actions.

  2. Uranium Mill Tailings Remedial Action Project Safety Advancement Field Effort (SAFE) Program

    SciTech Connect

    Not Available

    1994-02-01

    In 1992, the Uranium Mill Tailings Remedial Action (UMTRA) Project experienced several health and safety related incidents at active remediation project sites. As a result, the U.S. Department of Energy (DOE) directed the Technical Assistance Contractor (TAC) to establish a program increasing the DOE`s overall presence at operational remediation sites to identify and minimize risks in operations to the fullest extent possible (Attachments A and B). In response, the TAC, in cooperation with the DOE and the Remedial Action Contractor (RAC), developed the Safety Advancement Field Effort (SAFE) Program.

  3. The Contractor's Role in Competitive Bid Construction.

    ERIC Educational Resources Information Center

    Toy, G. Arlan

    1986-01-01

    In a competitive bid situation, the general contractor's first priority is controlling construction costs. The actions the general contractor take focus on adequate control, effective communication, efficient use of resources, and prevention of delays. (MLF)

  4. Provider experiences with RAC appeals point to opportunities for program improvement.

    PubMed

    Jacobs, Robert; Scott, Bonnie; Flood, Elizabeth; Scott, Ellen

    2011-03-01

    Review by an administrative law judge (ALJ) constitutes the third level of appeal for healthcare providers seeking to overturn reverse recovery audit contractor (RAC) findings of overpayment of Medicare claims. An analysis of the results of RAC appeals submitted by 30 New York hospitals during the demonstration project has disclosed two deficiencies in the ALJ review process: inconsistent ALJ decision making and a lack of an appropriate feedback mechanism to correct erroneous overpayment determinations. The Centers for Medicare & Medicaid Services should take advantage of feedback from such studies as an impetus to reevaluate and streamline the RAC appeals process.

  5. 77 FR 17098 - Proposed Extension of Existing Information Collection; Independent Contractor Registration and...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-03-23

    ... Contractor Registration and Identification AGENCY: Mine Safety and Health Administration, Labor. ACTION..., Independent Contractor Register. OMB last approved this information collection request (ICR) on March 10, 2009... (facsimile). SUPPLEMENTARY INFORMATION: I. Background Independent contractors (contractors) perform...

  6. Economic impact study of the Uranium Mill Tailings Remedial Action project in Colorado: Colorado state fiscal year 1995

    SciTech Connect

    1995-12-01

    This Colorado economic impact study summarizes employment and economic benefits to the state from activities associated with the Uranium Mill Tailings Remedial Action (UMTRA) Project during Colorado state fiscal year (FY) 1995 (1 July 1994 through 30 June 1995). To capture employment information, a questionnaire was distributed to subcontractor employees at the active UMTRA Project sites of Grand Junction, Gunnison, Maybell, Naturita, Rifle, and Slick Rock, Colorado. Economic data were requested from the Remedial Action Contractor (RAC), the Technical Assistance Contractor (TAC) and the US Department of Energy (DOE). The most significant benefits associated with the UMTRA Project in Colorado are summarized.

  7. 40 CFR 35.6600 - Contractor claims.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Contractor claims. 35.6600 Section 35... Actions Procurement Requirements Under A Cooperative Agreement § 35.6600 Contractor claims. (a) General... prepared by the contractor to support a claim against the recipient; and (4) The award official...

  8. 42 CFR 455.506 - Activities to be conducted by Medicaid RACs and States.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... States. 455.506 Section 455.506 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL ASSISTANCE PROGRAMS PROGRAM INTEGRITY: MEDICAID Medicaid Recovery Audit Contractors Program § 455.506 Activities to be conducted by Medicaid RACs and States....

  9. 42 CFR 455.514 - Federal share of State expense of the Medicaid RAC program.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... program. 455.514 Section 455.514 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL ASSISTANCE PROGRAMS PROGRAM INTEGRITY: MEDICAID Medicaid Recovery Audit Contractors Program § 455.514 Federal share of State expense of the Medicaid RAC program....

  10. 42 CFR 455.514 - Federal share of State expense of the Medicaid RAC program.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... program. 455.514 Section 455.514 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL ASSISTANCE PROGRAMS PROGRAM INTEGRITY: MEDICAID Medicaid Recovery Audit Contractors Program § 455.514 Federal share of State expense of the Medicaid RAC program....

  11. 42 CFR 455.514 - Federal share of State expense of the Medicaid RAC program.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... program. 455.514 Section 455.514 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL ASSISTANCE PROGRAMS PROGRAM INTEGRITY: MEDICAID Medicaid Recovery Audit Contractors Program § 455.514 Federal share of State expense of the Medicaid RAC program....

  12. 42 CFR 455.506 - Activities to be conducted by Medicaid RACs and States.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... States. 455.506 Section 455.506 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL ASSISTANCE PROGRAMS PROGRAM INTEGRITY: MEDICAID Medicaid Recovery Audit Contractors Program § 455.506 Activities to be conducted by Medicaid RACs and States....

  13. 42 CFR 455.514 - Federal share of State expense of the Medicaid RAC program.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... program. 455.514 Section 455.514 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL ASSISTANCE PROGRAMS PROGRAM INTEGRITY: MEDICAID Medicaid Recovery Audit Contractors Program § 455.514 Federal share of State expense of the Medicaid RAC program....

  14. 42 CFR 455.506 - Activities to be conducted by Medicaid RACs and States.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... States. 455.506 Section 455.506 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL ASSISTANCE PROGRAMS PROGRAM INTEGRITY: MEDICAID Medicaid Recovery Audit Contractors Program § 455.506 Activities to be conducted by Medicaid RACs and States....

  15. 42 CFR 455.506 - Activities to be conducted by Medicaid RACs and States.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... States. 455.506 Section 455.506 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL ASSISTANCE PROGRAMS PROGRAM INTEGRITY: MEDICAID Medicaid Recovery Audit Contractors Program § 455.506 Activities to be conducted by Medicaid RACs and States....

  16. 75 FR 52551 - Notice of Utah's Resource Advisory Council (RAC) Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-26

    ..., mandate, and purpose of rapid ecoregional assessments; a discussion on the governor's balanced resources... Bureau of Land Management Notice of Utah's Resource Advisory Council (RAC) Meeting AGENCY: Bureau of Land Management, Interior. ACTION: Notice of Utah's Resource Advisory Council (RAC) Meeting. SUMMARY:...

  17. 76 FR 8334 - White Pine-Nye County Resource Advisory Committee (RAC)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-02-14

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF AGRICULTURE Forest Service White Pine-Nye County Resource Advisory Committee (RAC) AGENCY: Forest Service, USDA. ACTION: Notice of meeting. SUMMARY: The White Pine-Nye County Resource Advisory Committee (RAC) will...

  18. 76 FR 85 - Nye/White Pine County Resource Advisory Committee (RAC)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-03

    ... Forest Service Nye/White Pine County Resource Advisory Committee (RAC) AGENCY: Forest Service, USDA. ACTION: Notice of meeting. SUMMARY: The Nye/White Pine County Resource Advisory Committee (RAC) will hold...: The meeting will be held in Nye County at the Bureau of Land Management, 1553 S. Erie Main...

  19. 76 FR 13600 - White Pine-Nye County Resource Advisory Committee (RAC)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-14

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF AGRICULTURE Forest Service White Pine-Nye County Resource Advisory Committee (RAC) AGENCY: Forest Service, USDA. ACTION: Notice of meeting. SUMMARY: The White Pine-Nye County Resource Advisory Committee (RAC) will...

  20. 41 CFR 60-741.68 - Reinstatement of ineligible contractors.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... ineligible contractors. 60-741.68 Section 60-741.68 Public Contracts and Property Management Other Provisions..., DEPARTMENT OF LABOR 741-AFFIRMATIVE ACTION AND NONDISCRIMINATION OBLIGATIONS OF CONTRACTORS AND... Reinstatement of ineligible contractors. (a) Application for reinstatement. A contractor debarred from...

  1. 41 CFR 60-300.68 - Reinstatement of ineligible contractors.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... ineligible contractors. 60-300.68 Section 60-300.68 Public Contracts and Property Management Other Provisions..., DEPARTMENT OF LABOR 300-AFFIRMATIVE ACTION AND NONDISCRIMINATION OBLIGATIONS OF CONTRACTORS AND... ineligible contractors. (a) Application for reinstatement. A contractor debarred from further contracts...

  2. 41 CFR 60-250.68 - Reinstatement of ineligible contractors.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... ineligible contractors. 60-250.68 Section 60-250.68 Public Contracts and Property Management Other Provisions..., DEPARTMENT OF LABOR 250-AFFIRMATIVE ACTION AND NONDISCRIMINATION OBLIGATIONS OF CONTRACTORS AND... ineligible contractors. (a) Application for reinstatement. A contractor debarred from further contracts...

  3. [RAC3 overexpression is a transforming and proliferative signal that contributes to tumoral development].

    PubMed

    Alvarado, Cecilia V; Micenmacher, Sabrina; Ruiz Grecco, Marina; Rubio, Maria F; Fernandez Larrosa, Nicolas; Costas, Monica A

    2011-01-01

    RAC3 has been firstly characterized as a nuclear receptor coactivator that is found in limited amounts in normal cells, but is over-expressed in tumors and is also an NF-kB coactivator. Although the mechanisms involved in its over-expression are not clear, it is well known that it enhances resistance to apoptosis. In this work, we investigated if there are any additional mechanisms by which RAC3 may contribute to tumor development and if TNF-a, an inflammatory cytokine that is found at high levels in cancer could increase RAC3 levels. We found that enhancement of RAC3 levels by transfection of HEK293 cells with a RAC3 expression vector induces a significant increase of cell proliferation not only in the presence, but also in the absence of serum growth factors. Moreover, the cells were transformed showing an anchorage independent growth, similar to that observed in tumoral cells. The treatment of HEK293 cells with TNF-a induced an increase in the protein levels of RAC3 and this was blocked by an NF-kB specific inhibitor, suggesting that this transcription factor is involved in the cytokine effect. We conclude that RAC3, in addition to is anti-apoptotic action, is a transforming factor that promotes the proliferation and growth independent of anchorage, and that its levels could be elevated by the action of inflammatory cytokines that are involved in the anti-tumoral response.

  4. Remedial action plan and site conceptual design for stabilization of the inactive uranium mill tailings sites at Rifle, Colorado. Appendix D, Final report

    SciTech Connect

    1992-02-01

    This appendix assesses the present conditions and data gathered about the two designated inactive uranium mill tailings sites near Rifle, Colorado, and the proposed disposal site six miles north of Rifle in the area of Estes Gulch. It consolidates available engineering, radiological, geotechnical, hydrological, meteorological, and other information pertinent to the design of the Remedial Action Plan (RAP). The data characterize conditions at the mill, tailings, and disposal site so that the Remedial Action Contractor (RAC) may complete final designs for the remedial actions.

  5. Rac[e] to the pole

    PubMed Central

    Collins, Caitlin; Tzima, Ellie

    2014-01-01

    Mechanical forces influence many biological processes via activation of signaling molecules, including the family of Rho GTPases. Within the endothelium, the mechanical force of fluid shear stress regulates the spatiotemporal activation of Rho GTPases, including Rac1. Shear stress-induced Rac1 activation is required for numerous essential biological processes, including changes in permeability, alignment of the actin cytoskeleton, redox signaling, and changes in gene expression. Thus, identifying mechanisms of Rac1 activation and the spatial cues that direct proper localization of the GTPase is essential in order to gain a comprehensive understanding the role of Rac1 in shear stress responses. This commentary will highlight our current understanding of how Rac1 activity is regulated in response to shear stress, as well as the downstream consequences of Rac1 activation. PMID:25202973

  6. Mitigation action plan for remedial action at the Uranium Mill Tailing Sites and Disposal Site, Rifle, Colorado

    SciTech Connect

    Not Available

    1992-07-01

    The Estes Gulch disposal site is approximately 10 kilometers (6 miles) north of the town of Rifle, off State Highway 13 on Federal land administered by the Bureau of Land Management. The Department of Energy (DOE) will transport the residual radioactive materials (RRM) by truck to the Estes Gulch disposal site via State Highway 13 and place it in a partially below-grade disposal cell. The RRM will be covered by an earthen radon barrier, frost protection layers, and a rock erosion protection layer. A toe ditch and other features will also be constructed to control erosion at the disposal site. After removal of the RRM and disposal at the Estes Gulch site, the disturbed areas at all three sites will be backfilled with clean soils, contoured to facilitate surface drainage, and revegetated. Wetlands areas destroyed at the former Rifle processing sites will be compensated for by the incorporation of now wetlands into the revegetation plan at the New Rifle site. The UMTRA Project Office, supported by the Remedial Action Contractor (RAC) and the Technical Assistance Contractor (TAC), oversees the implementation of the MAP. The RAC executes mitigation measures in the field. The TAC provides monitoring of the mitigation actions in cases where mitigation measures are associated with design features. Site closeout and inspection compliance will be documented in the site completion report.

  7. Cdc42, Rac1, and Rac2 Display Distinct Patterns of Activation during PhagocytosisV⃞

    PubMed Central

    Hoppe, Adam D.; Swanson, Joel A.

    2004-01-01

    The small G proteins Cdc42, Rac1, and Rac2 regulate the rearrangements of actin and membrane necessary for Fcγ receptor-mediated phagocytosis by macrophages. Activated, GTP-bound Cdc42, Rac1, and Rac2 bind to the p21-binding domain (PBD) of PAK1, and this interaction provided a basis for microscopic methods to localize activation of these G proteins inside cells. Fluorescence resonance energy transfer-based stoichiometry of fluorescent chimeras of actin, PBD, Cdc42, Rac1, and Rac2 was used to quantify G protein activation relative to actin movements during phagocytosis of IgG-opsonized erythrocytes. The activation dynamics of endogenous G proteins, localized using yellow fluorescent protein-labeled PBD, was restricted to phagocytic cups, with a prominent spike of activation over an actin-poor region at the base of the cup. Refinements of fluorescence resonance energy transfer stoichiometry allowed calculation of the fractions of activated GTPases in forming phagosomes. Cdc42 activation was restricted to the leading margin of the cell, whereas Rac1 was active throughout the phagocytic cup. During phagosome closure, activation of Rac1 and Rac2 increased uniformly and transiently in the actin-poor region of phagosomal membrane. These distinct roles for Cdc42, Rac1, and Rac2 in the component activities of phagocytosis indicate mechanisms by which their differential regulation coordinates rearrangements of actin and membranes. PMID:15169870

  8. Rho family GTPase Rnd2 interacts and co-localizes with MgcRacGAP in male germ cells.

    PubMed

    Naud, Nathalie; Touré, Aminata; Liu, Jianfeng; Pineau, Charles; Morin, Laurence; Dorseuil, Olivier; Escalier, Denise; Chardin, Pierre; Gacon, Gérard

    2003-05-15

    The male-germ-cell Rac GTPase-activating protein gene (MgcRacGAP) was initially described as a human RhoGAP gene highly expressed in male germ cells at spermatocyte stage, but exhibits significant levels of expression in most cell types. In somatic cells, MgcRacGAP protein was found to both concentrate in the midzone/midbody and be required for cytokinesis. As a RhoGAP, MgcRacGAP has been proposed to down-regulate RhoA, which is localized to the cleavage furrow and midbody during cytokinesis. Due to embryonic lethality in MgcRacGAP -null mutant mice and to the lack of an in vitro model of spermatogenesis, nothing is known regarding the role and mode of action of MgcRacGAP in male germ cells. We have analysed the expression, subcellular localization and molecular interactions of MgcRacGAP in male germ cells. Whereas MgcRacGAP was found only in spermatocytes and early spermatids, the widespread RhoGTPases RhoA, Rac1 and Cdc42 (which are, to various extents, in vitro substrates for MgcRacGAP activity) were, surprisingly, not detected at these stages. In contrast, Rnd2, a Rho family GTPase-deficient G-protein was found to be co-expressed with MgcRacGAP in spermatocytes and spermatids. MgcRacGAP was detected in the midzone of meiotic cells, but also, unexpectedly, in the Golgi-derived pro-acrosomal vesicle, co-localizing with Rnd2. In addition, a stable Rnd2-MgcRacGAP molecular complex could be evidenced by glutathione S-transferase pull-down and co-immunoprecipitation experiments. We conclude that Rnd2 is a probable physiological partner of MgcRacGAP in male germ cells and we propose that MgcRacGAP, and, quite possibly, other RhoGAPs, may participate in signalling pathways involving Rnd family proteins.

  9. Characterization of EHT 1864, a novel small molecule inhibitor of Rac family small GTPases.

    PubMed

    Onesto, Cercina; Shutes, Adam; Picard, Virginie; Schweighoffer, Fabien; Der, Channing J

    2008-01-01

    There is now considerable experimental evidence that aberrant activation of Rho family small GTPases promotes uncontrolled proliferation, invasion, and metastatic properties of human cancer cells. Therefore, there is considerable interest in the development of small molecule inhibitors of Rho GTPase function. However, to date, most efforts have focused on inhibitors that block Rho GTPase function indirectly, either by targeting enzymes involved in post-translational processing or downstream protein kinase effectors. We have reported the identification and characterization of the EHT 1864 small molecule as an inhibitor of Rac family small GTPases, placing Rac1 in an inert and inactive state and then impairing Rac1-mediated functions in vivo. Our work suggests that EHT 1864 selectively inhibits Rac1 downstream signaling and cellular transformation by a novel mechanism involving guanine nucleotide displacement. This chapter provides the details for some of the biochemical and biological methods used to characterize the mode of action of EHT 1864 on Rac1 and its impact on Rac1-dependent cellular functions.

  10. A critical role of the small GTPase Rac1 in Akt2-mediated GLUT4 translocation in mouse skeletal muscle.

    PubMed

    Takenaka, Nobuyuki; Izawa, Rumi; Wu, Junyuan; Kitagawa, Kaho; Nihata, Yuma; Hosooka, Tetsuya; Noguchi, Tetsuya; Ogawa, Wataru; Aiba, Atsu; Satoh, Takaya

    2014-03-01

    Insulin promotes glucose uptake in skeletal muscle by inducing the translocation of the glucose transporter GLUT4 to the plasma membrane. The serine/threonine kinase Akt2 has been implicated as a key regulator of this insulin action. However, the mechanisms whereby Akt2 regulates multiple steps of GLUT4 translocation remain incompletely understood. Recently, the small GTPase Rac1 has been identified as a skeletal muscle-specific regulator of insulin-stimulated glucose uptake. Here, we show that Rac1 is a critical downstream component of the Akt2 pathway in mouse skeletal muscle as well as cultured myocytes. GLUT4 translocation induced by constitutively activated Akt2 was totally dependent on the expression of Rac1 in L6 myocytes. Moreover, we observed the activation of Rac1 when constitutively activated Akt2 was ectopically expressed. Constitutively activated Akt2-triggered Rac1 activation was diminished by knockdown of FLJ00068, a guanine nucleotide exchange factor for Rac1. Knockdown of Akt2, on the other hand, markedly reduced Rac1 activation by a constitutively activated mutant of phosphoinositide 3-kinase. In mouse skeletal muscle, constitutively activated mutants of Akt2 and phosphoinositide 3-kinase, when ectopically expressed, induced GLUT4 translocation. Muscle-specific rac1 knockout markedly diminished Akt2- or phosphoinositide 3-kinase-induced GLUT4 translocation, highlighting a crucial role of Rac1 downstream of Akt2. Taken together, these results strongly suggest a novel regulatory link between Akt2 and Rac1 in insulin-dependent signal transduction leading to glucose uptake in skeletal muscle.

  11. Critical roles for Rac1 and Rac2 GTPases in B cell development and signaling.

    PubMed

    Walmsley, Marita J; Ooi, Steen K T; Reynolds, Lucinda F; Smith, Susan Harless; Ruf, Sandra; Mathiot, Anne; Vanes, Lesley; Williams, David A; Cancro, Michael P; Tybulewicz, Victor L J

    2003-10-17

    The Rac1 guanosine triphosphatase (GTPase) has been implicated in multiple cellular functions, including actin dynamics, proliferation, apoptosis, adhesion, and migration resulting from signaling by multiple receptors, including the B cell antigen receptor (BCR). We used conditional gene targeting to generate mice with specific Rac1 deficiency in the B cell lineage. In the absence of both Rac1 and the highly related Rac2, B cell development was almost completely blocked. Both GTPases were required to transduce BCR signals leading to proliferation, survival and up-regulation of BAFF-R, a receptor for BAFF, a key survival molecule required for B cell development and maintenance.

  12. Redox regulation of Rac1 by thiol oxidation

    PubMed Central

    Hobbs, G. Aaron; Mitchell, Lauren E.; Arrington, Megan E.; Gunawardena, Harsha P.; DeCristo, Molly J.; Loeser, Richard F.; Chen, Xian; Cox, Adrienne D.; Campbell, Sharon L.

    2016-01-01

    The Rac1 GTPase is an essential and ubiquitous protein that signals through numerous pathways to control critical cellular processes, including cell growth, morphology, and motility. Rac1 deletion is embryonic lethal, and its dysregulation or mutation can promote cancer, arthritis, cardiovascular disease, and neurological disorders. Rac1 activity is highly regulated by modulatory proteins and posttranslational modifications. Whereas much attention has been devoted to guanine nucleotide exchange factors that act on Rac1 to promote GTP loading and Rac1 activation, cellular oxidants may also regulate Rac1 activation by promoting guanine nucleotide exchange. Herein, we show that Rac1 contains a redox-sensitive cysteine (Cys18) that can be selectively oxidized at physiological pH because of its lowered pKa. Consistent with these observations, we show that Rac1 is glutathiolated in primary chondrocytes. Oxidation of Cys18 by glutathione greatly perturbs Rac1 guanine nucleotide binding and promotes nucleotide exchange. As aspartate substitutions have been previously used to mimic cysteine oxidation, we characterized the biochemical properties of Rac1C18D. We also evaluated Rac1C18S as a redox-insensitive variant and found that it retains structural and biochemical properties similar to those of Rac1WT but is resistant to thiol oxidation. In addition, Rac1C18D, but not Rac1C18S, shows greatly enhanced nucleotide exchange, similar to that observed for Rac1 oxidation by glutathione. We employed Rac1C18D in cell-based studies to assess whether this fast-cycling variant, which mimics Rac1 oxidation by glutathione, affects Rac1 activity and function. Expression of Rac1C18D in Swiss 3T3 cells showed greatly enhanced GTP-bound Rac1 relative to Rac1WT and the redox-insensitive Rac1C18S variant. Moreover, expression of Rac1C18D in HEK-293T cells greatly promoted lamellipodia formation. Our results suggest that Rac1 oxidation at Cys18 is a novel posttranslational modification that

  13. Contractor Integrity: Stronger Safeguards Needed for Contractor Access to Sensitive Information

    DTIC Science & Technology

    2010-09-01

    contract actions at three agencies found areas where sensitive information is not fully safeguarded and thus may remain at risk of unauthorized...business proprietary rights, national security, and law enforcement. The risks associated with contractor misuse of sensitive information have been the...access to sensitive information, you asked us to review safeguards in the federal acquisition system to manage risks and control contractor access

  14. 76 FR 17106 - Secure Rural Schools Resource Advisory Committee (RAC) Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-28

    ..., Olustee, Florida 32072. FOR FURTHER INFORMATION CONTACT: Denise Rains, Public Services Staff Officer, 850... Forest Service Secure Rural Schools Resource Advisory Committee (RAC) Meeting AGENCY: Forest Service, U.S.D.A. ACTION: Announcement of Meeting; Federal Advisory Committee meeting to be held authorized...

  15. Contingency contractor optimization.

    SciTech Connect

    Gearhart, Jared Lee; Adair, Kristin Lynn; Jones, Katherine A.; Bandlow, Alisa; Detry, Richard Joseph; Durfee, Justin David.; Jones, Dean A.; Martin, Nathaniel; Nanco, Alan Stewart; Nozick, Linda Karen

    2013-06-01

    The goal of Phase 3 the OSD ATL Contingency Contractor Optimization (CCO) project is to create an engineering prototype of a tool for the contingency contractor element of total force planning during the Support for Strategic Analysis (SSA). An optimization model was developed to determine the optimal mix of military, Department of Defense (DoD) civilians, and contractors that accomplishes a set of user defined mission requirements at the lowest possible cost while honoring resource limitations and manpower use rules. An additional feature allows the model to understand the variability of the Total Force Mix when there is uncertainty in mission requirements.

  16. Contingency contractor optimization.

    SciTech Connect

    Gearhart, Jared Lee; Adair, Kristin Lynn; Jones, Katherine A.; Bandlow, Alisa; Durfee, Justin David.; Jones, Dean A.; Martin, Nathaniel; Detry, Richard Joseph; Nanco, Alan Stewart; Nozick, Linda Karen

    2013-10-01

    The goal of Phase 3 the OSD ATL Contingency Contractor Optimization (CCO) project is to create an engineering prototype of a tool for the contingency contractor element of total force planning during the Support for Strategic Analysis (SSA). An optimization model was developed to determine the optimal mix of military, Department of Defense (DoD) civilians, and contractors that accomplishes a set of user defined mission requirements at the lowest possible cost while honoring resource limitations and manpower use rules. An additional feature allows the model to understand the variability of the Total Force Mix when there is uncertainty in mission requirements.

  17. Differential Rac1 signalling by guanine nucleotide exchange factors implicates FLII in regulating Rac1-driven cell migration

    PubMed Central

    Marei, Hadir; Carpy, Alejandro; Woroniuk, Anna; Vennin, Claire; White, Gavin; Timpson, Paul; Macek, Boris; Malliri, Angeliki

    2016-01-01

    The small GTPase Rac1 has been implicated in the formation and dissemination of tumours. Upon activation by guanine nucleotide exchange factors (GEFs), Rac1 associates with a variety of proteins in the cell thereby regulating various functions, including cell migration. However, activation of Rac1 can lead to opposing migratory phenotypes raising the possibility of exacerbating tumour progression when targeting Rac1 in a clinical setting. This calls for the identification of factors that influence Rac1-driven cell motility. Here we show that Tiam1 and P-Rex1, two Rac GEFs, promote Rac1 anti- and pro-migratory signalling cascades, respectively, through regulating the Rac1 interactome. In particular, we demonstrate that P-Rex1 stimulates migration through enhancing the interaction between Rac1 and the actin-remodelling protein flightless-1 homologue, to modulate cell contraction in a RhoA-ROCK-independent manner. PMID:26887924

  18. 48 CFR 450.303-1 - Contractor requests.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 4 2010-10-01 2010-10-01 false Contractor requests. 450.303-1 Section 450.303-1 Federal Acquisition Regulations System DEPARTMENT OF AGRICULTURE CONTRACT MANAGEMENT EXTRAORDINARY CONTRACTUAL ACTIONS Contract Adjustments 450.303-1 Contractor requests....

  19. Seeing Glass Contractors Clearly.

    ERIC Educational Resources Information Center

    Deliberato, Jerry

    2003-01-01

    Offers seven tips for finding and working with an effective glass contractor. For example, schools should consider the company's reputation and longevity of service, and whether it has in-house engineering capabilities. (EV)

  20. 77 FR 13153 - Information Collection; NASA Contractor Financial Management Reports

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-03-05

    ... SPACE ADMINISTRATION Information Collection; NASA Contractor Financial Management Reports AGENCY: National Aeronautics and Space Administration (NASA). ACTION: Notice of information collection. SUMMARY... collection instrument(s) and instructions should be directed to Ms. Frances Teel, NASA Clearance...

  1. 48 CFR 2922.101-4 - Removal of items from contractor facilities affected by work stoppages.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... contractor facilities affected by work stoppages. 2922.101-4 Section 2922.101-4 Federal Acquisition... ACQUISITIONS Basic Labor Policies 2922.101-4 Removal of items from contractor facilities affected by work stoppages. Before initiating any action under FAR 22.101-4 for removal of items from contractors'...

  2. Regulation of Rac1 GTPase activity by quinine through G-protein and bitter taste receptor T2R4.

    PubMed

    Sidhu, Crystal; Jaggupilli, Appalaraju; Chelikani, Prashen; Bhullar, Rajinder P

    2017-02-01

    Rac1 belongs to the Rho family of small GTPases and regulates actin cytoskeleton reorganization. T2R4 is a bitter taste receptor belonging to the G protein-coupled receptor family of proteins. In addition to mediating bitter taste perception from the tongue, T2R4s are found in extra-oral tissues, e.g., nasal epithelium, airways, brain, testis suggesting a much broader physiological function for these receptors. Anti-malarial drug and a bitter tasting compound, quinine, is a known agonist for T2R4, whereas BCML (Nα,Nα-Bis(carboxymethyl)-L-lysine) acts as an inverse agonist. Using western blot and Ca(++) mobilization assays, the effects of quinine on Rac1 activity in HEK293T cells stably expressing T2R4/Gα16/44, T2R4, or Gα16/44 and transiently transfected with HA-Rac1 were investigated. Quinine treatment caused a significant reduction in the amount of active Rac1, whereas in the presence of BCML, quinine failed to cause any significant change in active Rac1. No significant change in Rac1 activity was observed in BAPTA-AM plus quinine-treated Gα16/44 cells, suggesting possibility of a pathway in addition to the canonical Ca(++)-dependent pathway. A noticeable role for Gα16/44 independent of T2R4 is observed in quinine-mediated Rac1 inactivation. Further, a significant difference in quinine-induced Ca(++) response in T2R4/Gα16/44 or T2R4 cells was observed validating the partial role of calcium and importance of Gα16/44. This study is the first to show an inhibitory downstream action of a T2R4 agonist on Rac1 function. Further investigation will help in better understanding the downstream signal transduction network of T2R4 and its extra-oral physiological roles.

  3. Unions, Contractors and CTE

    ERIC Educational Resources Information Center

    Jarosz, Francesca

    2006-01-01

    Across Illinois, in places where unions thrive, construction industry professionals and career and technical education (CTE) teachers are working together in promoting work-based learning program to students. Likewise, the outreach program provides union-supported contractors with qualified candidates for future employment. Programs such as the…

  4. 78 FR 11164 - Policy on Contractor Profits

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-15

    ... Defense Acquisition Regulations System Policy on Contractor Profits AGENCY: Defense Acquisition... Year 2013. Section 804, Department of Defense Policy on Contractor Profits, included a requirement for... that are necessary to ensure an appropriate link between contractor profit and contractor...

  5. Hydrogen Contractors Meeting

    SciTech Connect

    Fitzsimmons, Tim

    2006-05-16

    This volume highlights the scientific content of the 2006 Hydrogen Contractors Meeting sponsored by the Division of Materials Sciences and Engineering (DMS&E) on behalf of the Office of Basic Energy Sciences (BES) of the U. S. Department of Energy (DOE). Hydrogen Contractors Meeting held from May 16-19, 2006 at the Crystal Gateway Marriott Hotel Arlington, Virginia. This meeting is the second in a series of research theme-based Contractors Meetings sponsored by DMS&E held in conjunction with our counterparts in the Office of Energy Efficiency and Renewable Energy (EERE) and the first with the Hydrogen, Fuel Cells and Infrastructure Technologies Program. The focus of this year’s meeting is BES funded fundamental research underpinning advancement of hydrogen storage. The major goals of these research efforts are the development of a fundamental scientific base in terms of new concepts, theories and computational tools; new characterization capabilities; and new materials that could be used or mimicked in advancing capabilities for hydrogen storage.

  6. Rac1 is deactivated at integrin activation sites through an IQGAP1–filamin-A–RacGAP1 pathway

    PubMed Central

    Jacquemet, Guillaume; Morgan, Mark R.; Byron, Adam; Humphries, Jonathan D.; Choi, Colin K.; Chen, Christopher S.; Caswell, Patrick T.; Humphries, Martin J.

    2013-01-01

    Summary Cell migration makes a fundamental contribution to both normal physiology and disease pathogenesis. Integrin engagement with extracellular ligands spatially controls, via the cyclical activation and deactivation of the small GTPase Rac1, the dynamic membrane protrusion and cytoskeletal reorganization events that are required for directional migration. Although the pathways that control integrin-mediated Rac1 activation are reasonably well defined, the mechanisms that are responsible for switching off activity are poorly understood. Here, proteomic analysis of activated integrin-associated complexes suggests filamin-A and IQ-motif-containing GTPase-activating protein 1 (IQGAP1) as candidates that link β1 integrin to Rac1. siRNA-mediated knockdown of either filamin-A or IQGAP1 induced high, dysregulated Rac1 activity during cell spreading on fibronectin. Using immunoprecipitation and immunocytochemistry, filamin-A and IQGAP1 were shown to be part of a complex that is recruited to active β1 integrin. Mass spectrometric analysis of individual filamin-A, IQGAP1 and Rac1 pull-downs and biochemical analysis, identified RacGAP1 as a novel IQGAP1 binding partner. Further immunoprecipitation and immunocytochemistry analyses demonstrated that RacGAP1 is recruited to IQGAP1 and active β1 integrin, and that suppression of RacGAP1 expression triggered elevated Rac1 activity during spreading on fibronectin. Consistent with these findings, reduced expression of filamin-A, IQGAP1 or RacGAP1 triggered unconstrained membrane protrusion and disrupted directional cell migration on fibrillar extracellular matrices. These findings suggest a model whereby integrin engagement, followed by filamin-A, IQGAP1 and RacGAP1 recruitment, deactivates Rac1 to constrain its activity spatially and thereby coordinate directional cell migration. PMID:23843620

  7. 42 CFR 455.202 - Limitation on contractor liability.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 455.202 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN... contractor will not be held to have violated any criminal law and will not be held liable in any civil action... connection with the defense of a suit, action, or proceeding, if the following conditions are met: (1)...

  8. 42 CFR 455.202 - Limitation on contractor liability.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 455.202 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN... contractor will not be held to have violated any criminal law and will not be held liable in any civil action... connection with the defense of a suit, action, or proceeding, if the following conditions are met: (1)...

  9. Government - contractor interaction

    NASA Technical Reports Server (NTRS)

    Thomas, D. M.

    1983-01-01

    The development of the Administrative Contracting Officer represents an advance in the Government system of contract management because it provides an individual with knowledge, time, and a specialized function to insure performance of Government contracts. However, the development has created a dichotomy between the award and the post-award function which increases the adversary relationship with Government contractors. This paper advocates that this adversary relationship can be decreased if PCOs and ACOs are provided with opportunities to serve in the assignments of the other.

  10. 7 CFR 1788.12 - Contractors' bonds.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 12 2010-01-01 2010-01-01 false Contractors' bonds. 1788.12 Section 1788.12... Insurance for Contractors, Engineers, and Architects, Electric Borrowers § 1788.12 Contractors' bonds. Electric borrowers shall require contractors to obtain contractors' bonds when required by part...

  11. 20 CFR 401.90 - Contractors.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 20 Employees' Benefits 2 2010-04-01 2010-04-01 false Contractors. 401.90 Section 401.90 Employees... Privacy Act § 401.90 Contractors. (a) All contracts which require a contractor to maintain, or on behalf... requiring the contractor to comply with the Privacy Act and this part. (b) A contractor and any employee...

  12. Characterization of Novel Molecular Mechanisms Favoring Rac1 Membrane Translocation.

    PubMed

    Castro-Castro, Antonio; Muriel, Olivia; Del Pozo, Miguel A; Bustelo, Xosé R

    2016-01-01

    The Rac1 GTPase plays key roles in cytoskeletal organization, cell motility and a variety of physiological and disease-linked responses. Wild type Rac1 signaling entails dissociation of the GTPase from cytosolic Rac1-Rho GDP dissociation inhibitor (GDI) complexes, translocation to membranes, activation by exchange factors, effector binding, and activation of downstream signaling cascades. Out of those steps, membrane translocation is the less understood. Using transfections of a expression cDNA library in cells expressing a Rac1 bioreporter, we previously identified a cytoskeletal feedback loop nucleated by the F-actin binding protein coronin 1A (Coro1A) that promotes Rac1 translocation to the plasma membrane by facilitating the Pak-dependent dissociation of Rac1-Rho GDI complexes. This screening identified other potential regulators of this process, including WDR26, basigin, and TMEM8A. Here, we show that WDR26 promotes Rac1 translocation following a Coro1A-like and Coro1A-dependent mechanism. By contrast, basigin and TMEM8A stabilize Rac1 at the plasma membrane by inhibiting the internalization of caveolin-rich membrane subdomains. This latter pathway is F-actin-dependent but Coro1A-, Pak- and Rho GDI-independent.

  13. Rac1 modulates cardiomyocyte adhesion during mouse embryonic development.

    PubMed

    Abu-Issa, Radwan

    2015-01-24

    Rac1, a member of the Rho subfamily of small GTPases, is involved in morphogenesis and differentiation of many cell types. Here we define a role of Rac1 in cardiac development by specifically deleting Rac1 in the pre-cardiac mesoderm using the Nkx2.5-Cre transgenic driver line. Rac1-conditional knockout embryos initiate heart development normally until embryonic day 11.5 (E11.5); their cardiac mesoderm is specified, and the heart tube is formed and looped. However, by E12.5-E13.5 the mutant hearts start failing and embryos develop edema and hemorrhage which is probably the cause for the lethality observed soon after. The hearts of Rac1-cKO embryos exhibit disorganized and thin myocardial walls and defects in outflow tract alignment. No significant differences of cardiomyocyte death or proliferation were found between developing control and mutant embryos. To uncover the role of Rac1 in the heart, E11.5 primary heart cells were cultured and analyzed in vitro. Rac1-deficient cardiomyocytes were less spread, round and loosely attached to the substrate and to each other implying that Rac1-mediated signaling is required for appropriate cell-cell and/or cellmatrix adhesion during cardiac development.

  14. Characterization of Novel Molecular Mechanisms Favoring Rac1 Membrane Translocation

    PubMed Central

    Castro-Castro, Antonio; Muriel, Olivia; del Pozo, Miguel A.

    2016-01-01

    The Rac1 GTPase plays key roles in cytoskeletal organization, cell motility and a variety of physiological and disease-linked responses. Wild type Rac1 signaling entails dissociation of the GTPase from cytosolic Rac1-Rho GDP dissociation inhibitor (GDI) complexes, translocation to membranes, activation by exchange factors, effector binding, and activation of downstream signaling cascades. Out of those steps, membrane translocation is the less understood. Using transfections of a expression cDNA library in cells expressing a Rac1 bioreporter, we previously identified a cytoskeletal feedback loop nucleated by the F-actin binding protein coronin 1A (Coro1A) that promotes Rac1 translocation to the plasma membrane by facilitating the Pak-dependent dissociation of Rac1-Rho GDI complexes. This screening identified other potential regulators of this process, including WDR26, basigin, and TMEM8A. Here, we show that WDR26 promotes Rac1 translocation following a Coro1A-like and Coro1A-dependent mechanism. By contrast, basigin and TMEM8A stabilize Rac1 at the plasma membrane by inhibiting the internalization of caveolin-rich membrane subdomains. This latter pathway is F-actin-dependent but Coro1A-, Pak- and Rho GDI-independent. PMID:27835684

  15. Roles of Rac1 and Rac3 GTPases during the development of cortical and hippocampal GABAergic interneurons.

    PubMed

    de Curtis, Ivan

    2014-01-01

    Rac GTPases are regulators of the cytoskeleton that play an important role in several aspects of neuronal and brain development. Two distinct Rac GTPases are expressed in the developing nervous system, the widely expressed Rac1 and the neural-specific Rac3 proteins. Recent experimental evidence supports a central role of these two Rac proteins in the development of inhibitory GABAergic interneurons, important modulatory elements of the brain circuitry. The combined inactivation of the genes for the two Rac proteins has profound effects on distinct aspects of interneuron development, and has highlighted a synergistic contribution of the two proteins to the postmitotic maturation of specific populations of cortical and hippocampal interneurons. Rac function is modulated by different types of regulators, and can influence the activity of specific effectors. Some of these proteins have been associated to the development and maturation of interneurons. Cortical interneuron dysfunction is implicated in several neurological and psychiatric diseases characterized by cognitive impairment. Therefore the description of the cellular processes regulated by the Rac GTPases, and the identification of the molecular networks underlying these processes during interneuron development is relevant to the understanding of the role of GABAergic interneurons in cognitive functions.

  16. 48 CFR 1609.471 - Contractor certification.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 6 2010-10-01 2010-10-01 true Contractor certification... EMPLOYEES HEALTH BENEFITS ACQUISITION REGULATION ACQUISITION PLANNING CONTRACTOR QUALIFICATIONS Debarment, Suspension, and Ineligibility 1609.471 Contractor certification. All FEHBP carriers and applicant...

  17. 48 CFR 1845.502 - Contractor responsibility.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 6 2010-10-01 2010-10-01 true Contractor responsibility. 1845.502 Section 1845.502 Federal Acquisition Regulations System NATIONAL AERONAUTICS AND SPACE... Contractors 1845.502 Contractor responsibility....

  18. KAI1/CD82 decreases Rac1 expression and cell proliferation through PI3K/Akt/mTOR pathway in H1299 lung carcinoma cells.

    PubMed

    Choi, Un-Jong; Jee, Bo-Keun; Lim, Young; Lee, Kweon-Haeng

    2009-01-01

    Although the KAI1/CD82 protein has been reported to inhibit cell metastasis in many studies, its mechanism of action has not yet been fully elucidated. In the present study, we investigated the possible effects of KAI1/CD82 on the metastatic phenotype in H1299 lung carcinoma cells. These studies were based on the pivotal role that the acquisition of motile phenotype plays on the initial steps of metastasis. KAI1/CD82-mediated morphological changes were observed using phase contrast microscopy. We report here, that a KAI1/CD82-induced phenotypic change was involved in the decrease of Rac1 expression and GTPase activity. However, we found that KAI1/CD82 did not regulate Rac1 mRNA levels. This suggests the existence of another regulatory mechanism of Rac1 protein maturation or activation. To identify the signaling pathway of Rac1 regulation, we investigated the PI3K/Akt/mTOR pathway, since the PI3K/Akt pathway regulates Rac1 activation and mTOR is known to play a regulatory role in protein translation. H1299/CD82-transfectants showed lower mTOR expression and cell growth than the control group. The data obtained from this study suggested that KAI1/CD82 decreased the metastatic phenotype of H1299 lung carcinoma cells by down-regulating Rac1 expression through the PI3K/Akt/mTOR pathway.

  19. Optogenetics: optical control of a photoactivatable Rac in living cells.

    PubMed

    Yin, Taofei; Wu, Yi I

    2015-01-01

    Recent developments in optogenetics have extended optical control of signaling to intracellular proteins, including Rac, a small G protein in the Rho family. A blue light-sensing LOV (light, oxygen, or voltage) domain derived from Avena sativa (oat) phototropin was fused to the N-terminus of a constitutively active mutant of Rac, via an α-helix (Jα) that is conserved among plant phototropins. The fused LOV domain occluded binding of downstream effectors to Rac in the dark. Exposure to blue light caused a conformational change of the LOV domain and unwinding of the Jα helix, relieving steric inhibition. The LOV domain incorporates a flavin as the photon-absorbing cofactor and can be activated by light in a reversible and repeatable fashion. In cultured cells, global illumination with blue light rapidly activated Rac and led to cell spreading and membrane ruffling. Localized and pulsed illumination generated a gradient of Rac activity and induced directional migration. In this chapter, we will describe the techniques in detail and present some examples of applications of using photoactivatable Rac (PA-Rac) in living cells.

  20. Rac1 activity regulates proliferation of aggressive metastatic melanoma

    SciTech Connect

    Bauer, Natalie N. Chen Yihwen; Samant, Rajeev S.; Shevde, Lalita A.; Fodstad, Oystein

    2007-11-01

    Molecular mechanisms underlying the different capacity of two in vivo selected human melanoma cell variants to form experimental metastases were studied. The doubling times of the FEMX-I and FEMX-V cell sublines in vitro were 15 and 25 h, respectively. The invasive capacity of FEMX-I cells was 8-fold higher than FEMX-V cells, and the time to form approximately 10 mm s.c. tumors in nude mice was 21 versus 35 days. FEMX-I displayed a spindle-like formation in vitro, whereas FEMX-V cells had a rounded shape. Hence, we examined known determinants of cell shape and proliferation, the small GTPases. The four studied showed equal expression in both cell types, but Rac1 activity was significantly decreased in FEMX-V cells. Rac1 stimulates NF{kappa}B, and we found that endogenous NF{kappa}B activity of FEMX-V cells was 2% of that of FEMX-I cells. Inhibition of Rac1 resulted in blocked NF{kappa}B activity. Specific inhibition of either Rac1 or NF{kappa}B significantly reduced proliferation and invasion of FEMX-I cells, the more pronounced effects observed with Rac1 inhibition. These data indicate that Rac1 activity in FEMX cells regulates cell proliferation and invasion, in part via its effect on NF{kappa}B, signifying Rac1 as a key molecule in melanoma progression and metastasis.

  1. Rac1 modulates cardiomyocyte adhesion during mouse embryonic development

    SciTech Connect

    Abu-Issa, Radwan

    2015-01-24

    Highlights: • Conditional knockout of Rac1 using Nkx2.5 Cre line is lethal at E13.5. • The myocardium of the mutant is thin and disorganized. • The phenotype is not due to cardiomyocyte low proliferation or apoptosis. • The phenotype is due to specific defect in cardiomyocyte adhesion. - Abstract: Rac1, a member of the Rho subfamily of small GTPases, is involved in morphogenesis and differentiation of many cell types. Here we define a role of Rac1 in cardiac development by specifically deleting Rac1 in the pre-cardiac mesoderm using the Nkx2.5-Cre transgenic driver line. Rac1-conditional knockout embryos initiate heart development normally until embryonic day 11.5 (E11.5); their cardiac mesoderm is specified, and the heart tube is formed and looped. However, by E12.5-E13.5 the mutant hearts start failing and embryos develop edema and hemorrhage which is probably the cause for the lethality observed soon after. The hearts of Rac1-cKO embryos exhibit disorganized and thin myocardial walls and defects in outflow tract alignment. No significant differences of cardiomyocyte death or proliferation were found between developing control and mutant embryos. To uncover the role of Rac1 in the heart, E11.5 primary heart cells were cultured and analyzed in vitro. Rac1-deficient cardiomyocytes were less spread, round and loosely attached to the substrate and to each other implying that Rac1-mediated signaling is required for appropriate cell–cell and/or cellmatrix adhesion during cardiac development.

  2. Rac1 Regulates Endometrial Secretory Function to Control Placental Development.

    PubMed

    Davila, Juanmahel; Laws, Mary J; Kannan, Athilakshmi; Li, Quanxi; Taylor, Robert N; Bagchi, Milan K; Bagchi, Indrani C

    2015-08-01

    During placenta development, a succession of complex molecular and cellular interactions between the maternal endometrium and the developing embryo ensures reproductive success. The precise mechanisms regulating this maternal-fetal crosstalk remain unknown. Our study revealed that the expression of Rac1, a member of the Rho family of GTPases, is markedly elevated in mouse decidua on days 7 and 8 of gestation. To investigate its function in the uterus, we created mice bearing a conditional deletion of the Rac1 gene in uterine stromal cells. Ablation of Rac1 did not affect the formation of the decidua but led to fetal loss in mid gestation accompanied by extensive hemorrhage. To gain insights into the molecular pathways affected by the loss of Rac1, we performed gene expression profiling which revealed that Rac1 signaling regulates the expression of Rab27b, another GTPase that plays a key role in targeting vesicular trafficking. Consequently, the Rac1-null decidual cells failed to secrete vascular endothelial growth factor A, which is a critical regulator of decidual angiogenesis, and insulin-like growth factor binding protein 4, which regulates the bioavailability of insulin-like growth factors that promote proliferation and differentiation of trophoblast cell lineages in the ectoplacental cone. The lack of secretion of these key factors by Rac1-null decidua gave rise to impaired angiogenesis and dysregulated proliferation of trophoblast cells, which in turn results in overexpansion of the trophoblast giant cell lineage and disorganized placenta development. Further experiments revealed that RAC1, the human ortholog of Rac1, regulates the secretory activity of human endometrial stromal cells during decidualization, supporting the concept that this signaling G protein plays a central and conserved role in controlling endometrial secretory function. This study provides unique insights into the molecular mechanisms regulating endometrial secretions that mediate stromal

  3. Rac1 Regulates Endometrial Secretory Function to Control Placental Development

    PubMed Central

    Davila, Juanmahel; Laws, Mary J.; Kannan, Athilakshmi; Li, Quanxi; Taylor, Robert N.; Bagchi, Milan K.; Bagchi, Indrani C.

    2015-01-01

    During placenta development, a succession of complex molecular and cellular interactions between the maternal endometrium and the developing embryo ensures reproductive success. The precise mechanisms regulating this maternal-fetal crosstalk remain unknown. Our study revealed that the expression of Rac1, a member of the Rho family of GTPases, is markedly elevated in mouse decidua on days 7 and 8 of gestation. To investigate its function in the uterus, we created mice bearing a conditional deletion of the Rac1 gene in uterine stromal cells. Ablation of Rac1 did not affect the formation of the decidua but led to fetal loss in mid gestation accompanied by extensive hemorrhage. To gain insights into the molecular pathways affected by the loss of Rac1, we performed gene expression profiling which revealed that Rac1 signaling regulates the expression of Rab27b, another GTPase that plays a key role in targeting vesicular trafficking. Consequently, the Rac1-null decidual cells failed to secrete vascular endothelial growth factor A, which is a critical regulator of decidual angiogenesis, and insulin-like growth factor binding protein 4, which regulates the bioavailability of insulin-like growth factors that promote proliferation and differentiation of trophoblast cell lineages in the ectoplacental cone. The lack of secretion of these key factors by Rac1-null decidua gave rise to impaired angiogenesis and dysregulated proliferation of trophoblast cells, which in turn results in overexpansion of the trophoblast giant cell lineage and disorganized placenta development. Further experiments revealed that RAC1, the human ortholog of Rac1, regulates the secretory activity of human endometrial stromal cells during decidualization, supporting the concept that this signaling G protein plays a central and conserved role in controlling endometrial secretory function. This study provides unique insights into the molecular mechanisms regulating endometrial secretions that mediate stromal

  4. Report on audit of Department of Energy`s contractor salary increase fund

    SciTech Connect

    1997-04-04

    The Department of Energy (Department) uses contractors to operate its facilities and compensates contractor employees based on their skills, complexity of jobs, and work performance. Thirty-one of the Department`s major contractors reported a total payroll of $4.3 billion and $4.4 billion during 1994 and 1995, respectively. The 31 contractors also reported awarding salary increases of $18 million for 1994 and $200 million for 1995. The purpose of the audit was to review the process used to determine and approve the amount of salary increases for contractor employees. The specific audit objective was to determine whether salary increases received by contractor employees were in accordance with Departmental policies and procedures. The Department of Energy Acquisition Regulation (DEAR) requires that contractor salary actions be within specific limitations, supportable, and approved prior to incurrence of costs. In addition, the Secretary of Energy imposed a 1 year salary freeze on the merit portion of management and operating contractor employee salaries for each contractor`s Fiscal Year 1994 compensation year. However, a fund for promotions and adjustments was approved but limited to 0.5 percent of payroll for the year. A review of eight major contractors showed that six complied with the Department`s policies on salary increases. The other two gave salary increases that were not always in accordance with Departmental policies. This resulted in both contractors not fully complying with the pay freeze in 1994 and exceeding their salary increase fund budgets in 1995. If these two contractors had implemented Department and contract requirements and contracting officers had properly performed their contract administrative responsibilities concerning salary increase funds, both contractors would have frozen salary increases and would not have exceeded their annual budgets.

  5. Phosphorylation of Rac1 T108 by Extracellular Signal-Regulated Kinase in Response to Epidermal Growth Factor: a Novel Mechanism To Regulate Rac1 Function

    PubMed Central

    Tong, Junfeng; Li, Laiji; Ballermann, Barbara

    2013-01-01

    Accumulating evidence has implicated Rho GTPases, including Rac1, in many aspects of cancer development. Recent findings suggest that phosphorylation might further contribute to the tight regulation of Rho GTPases. Interestingly, sequence analysis of Rac1 shows that Rac1 T108 within the 106PNTP109 motif is likely an extracellular signal-regulated kinase (ERK) phosphorylation site and that Rac1 also has an ERK docking site, 183KKRKRKCLLL192 (D site), at the C terminus. Indeed, we show here that both transfected and endogenous Rac1 interacts with ERK and that this interaction is mediated by its D site. Green fluorescent protein (GFP)-Rac1 is threonine (T) phosphorylated in response to epidermal growth factor (EGF), and EGF-induced Rac1 threonine phosphorylation is dependent on the activation of ERK. Moreover, mutant Rac1 with the mutation of T108 to alanine (A) is not threonine phosphorylated in response to EGF. In vitro ERK kinase assay further shows that pure active ERK phosphorylates purified Rac1 but not mutant Rac1 T108A. We also show that Rac1 T108 phosphorylation decreases Rac1 activity, partially due to inhibiting its interaction with phospholipase C-γ1 (PLC-γ1). T108 phosphorylation targets Rac1 to the nucleus, which isolates Rac1 from other guanine nucleotide exchange factors (GEFs) and hinders Rac1's role in cell migration. We conclude that Rac1 T108 is phosphorylated by ERK in response to EGF, which plays an important role in regulating Rac1. PMID:24043306

  6. Loss of Either Rac1 or Rac3 GTPase Differentially Affects the Behavior of Mutant Mice and the Development of Functional GABAergic Networks

    PubMed Central

    Pennucci, Roberta; Talpo, Francesca; Astro, Veronica; Montinaro, Valentina; Morè, Lorenzo; Cursi, Marco; Castoldi, Valerio; Chiaretti, Sara; Bianchi, Veronica; Marenna, Silvia; Cambiaghi, Marco; Tonoli, Diletta; Leocani, Letizia; Biella, Gerardo; D'Adamo, Patrizia; de Curtis, Ivan

    2016-01-01

    Rac GTPases regulate the development of cortical/hippocampal GABAergic interneurons by affecting the early development and migration of GABAergic precursors. We have addressed the function of Rac1 and Rac3 proteins during the late maturation of hippocampal interneurons. We observed specific phenotypic differences between conditional Rac1 and full Rac3 knockout mice. Rac1 deletion caused greater generalized hyperactivity and cognitive impairment compared with Rac3 deletion. This phenotype matched with a more evident functional impairment of the inhibitory circuits in Rac1 mutants, showing higher excitability and reduced spontaneous inhibitory currents in the CA hippocampal pyramidal neurons. Morphological analysis confirmed a differential modification of the inhibitory circuits: deletion of either Rac caused a similar reduction of parvalbumin-positive inhibitory terminals in the pyramidal layer. Intriguingly, cannabinoid receptor-1-positive terminals were strongly increased only in the CA1 of Rac1-depleted mice. This increase may underlie the stronger electrophysiological defects in this mutant. Accordingly, incubation with an antagonist for cannabinoid receptors partially rescued the reduction of spontaneous inhibitory currents in the pyramidal cells of Rac1 mutants. Our results show that Rac1 and Rac3 have independent roles in the formation of GABAergic circuits, as highlighted by the differential effects of their deletion on the late maturation of specific populations of interneurons. PMID:26582364

  7. 78 FR 13394 - 30-Day Notice of Proposed Information Collection: Office of Language Services Contractor...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-27

    ... Notice of Proposed Information Collection: Office of Language Services Contractor Application Form ACTION... Language Services Contractor Application Form. OMB Control Number: 1405-0191. Type of Request: Extension of... U.S. Department of State, Office of Language Services, the information collected is used to...

  8. Contractor Accountability Act

    THOMAS, 111th Congress

    Rep. Sutton, Betty [D-OH-13

    2009-03-05

    05/04/2009 Referred to the Subcommittee on Government Management, Organization, and Procurement. (All Actions) Tracker: This bill has the status IntroducedHere are the steps for Status of Legislation:

  9. Debarment and suspension. [of contractors

    NASA Technical Reports Server (NTRS)

    Whelan, Thomas J.

    1987-01-01

    The changing Government attitude toward contractor debarment and suspension is examined, with emphasis on the fact that the Government is more alert to fraud, waste, and abuse. Consideration is given to causes of debarment or suspension, procedures and due process hearings, settlement agreements, compliance programs, and recent related legislation. It is concluded that the change in the Government contracting environment in recent years should be sufficient incentive for contractors to monitor their operations more closely.

  10. Federal Contractors and Sticky Costs

    DTIC Science & Technology

    2014-11-05

    NPS-CM-14-188 ACQUISITION RESEARCH PROGRAM SPONSORED REPORT SERIES Federal Contractors and Sticky Costs 5 November 2014 Stephen C. Hansen...average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed...Public Policy - iv - Naval Postgraduate School NPS-CM-14-188 Acquisition Research Program Sponsored Report Series Federal Contractors and

  11. 49 CFR 10.27 - Government contractors.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 1 2010-10-01 2010-10-01 false Government contractors. 10.27 Section 10.27... INDIVIDUALS Maintenance of Records § 10.27 Government contractors. When the Department provides by a contract..., Criminal Penalties, any such contractor and any employee of the contractor are considered, in...

  12. 22 CFR 136.6 - Contractors.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Contractors. 136.6 Section 136.6 Foreign... Contractors. To the extent that contractors enjoy importation or tax privileges in a foreign country because... provisions in their contracts that require the contractors to observe the requirements of these...

  13. 49 CFR 199.115 - Contractor employees.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 3 2010-10-01 2010-10-01 false Contractor employees. 199.115 Section 199.115... § 199.115 Contractor employees. With respect to those employees who are contractors or employed by a contractor, an operator may provide by contract that the drug testing, education, and training required...

  14. 49 CFR 199.245 - Contractor employees.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 3 2010-10-01 2010-10-01 false Contractor employees. 199.245 Section 199.245... Prevention Program § 199.245 Contractor employees. (a) With respect to those covered employees who are contractors or employed by a contractor, an operator may provide by contract that the alcohol...

  15. 7 CFR 1726.27 - Contractor's bonds.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 11 2010-01-01 2010-01-01 false Contractor's bonds. 1726.27 Section 1726.27... AGRICULTURE ELECTRIC SYSTEM CONSTRUCTION POLICIES AND PROCEDURES General § 1726.27 Contractor's bonds. (a) RUS Form 168b, Contractor's Bond, shall be used when a contractor's bond is required by RUS Forms 200,...

  16. 48 CFR 252.229-7004 - Status of contractors as a direct contractor (Spain).

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... direct contractor (Spain). 252.229-7004 Section 252.229-7004 Federal Acquisition Regulations System... contractor (Spain). As prescribed in 229.402-70(d), use the following clause: Status of Contractor as a Director Contractor (Spain) (JUN 1997) (a) “Direct Contractor,” as used in this clause, means an...

  17. 48 CFR 252.229-7004 - Status of contractors as a direct contractor (Spain).

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... direct contractor (Spain). 252.229-7004 Section 252.229-7004 Federal Acquisition Regulations System... contractor (Spain). As prescribed in 229.402-70(d), use the following clause: Status of Contractor as a Director Contractor (Spain) (JUN 1997) (a) “Direct Contractor,” as used in this clause, means an...

  18. 48 CFR 252.229-7004 - Status of contractors as a direct contractor (Spain).

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... direct contractor (Spain). 252.229-7004 Section 252.229-7004 Federal Acquisition Regulations System... contractor (Spain). As prescribed in 229.402-70(d), use the following clause: Status of Contractor as a Director Contractor (Spain) (JUN 1997) (a) “Direct Contractor,” as used in this clause, means an...

  19. 48 CFR 252.229-7004 - Status of contractors as a direct contractor (Spain).

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... direct contractor (Spain). 252.229-7004 Section 252.229-7004 Federal Acquisition Regulations System... contractor (Spain). As prescribed in 229.402-70(d), use the following clause: Status of Contractor as a Director Contractor (Spain) (JUN 1997) (a) “Direct Contractor,” as used in this clause, means an...

  20. Neuronal Rac1 Is Required for Learning-Evoked Neurogenesis

    PubMed Central

    Anderson, Matthew P.; Freewoman, Julia; Cord, Branden; Babu, Harish; Brakebusch, Cord

    2013-01-01

    Hippocampus-dependent learning and memory relies on synaptic plasticity as well as network adaptations provided by the addition of adult-born neurons. We have previously shown that activity-induced intracellular signaling through the Rho family small GTPase Rac1 is necessary in forebrain projection neurons for normal synaptic plasticity in vivo, and here we show that selective loss of neuronal Rac1 also impairs the learning-evoked increase in neurogenesis in the adult mouse hippocampus. Earlier work has indicated that experience elevates the abundance of adult-born neurons in the hippocampus primarily by enhancing the survival of neurons produced just before the learning event. Loss of Rac1 in mature projection neurons did reduce learning-evoked neurogenesis but, contrary to our expectations, these effects were not mediated by altering the survival of young neurons in the hippocampus. Instead, loss of neuronal Rac1 activation selectively impaired a learning-evoked increase in the proliferation and accumulation of neural precursors generated during the learning event itself. This indicates that experience-induced alterations in neurogenesis can be mechanistically resolved into two effects: (1) the well documented but Rac1-independent signaling cascade that enhances the survival of young postmitotic neurons; and (2) a previously unrecognized Rac1-dependent signaling cascade that stimulates the proliferative production and retention of new neurons generated during learning itself. PMID:23884931

  1. Technical Assistance Contractor management plan. Revision 1

    SciTech Connect

    1995-08-01

    The Technical Assistance Contractor (TAC) for the Uranium Mill Tailings Remedial Action (UMTRA) Project comprises Jacobs Engineering Group Inc. (JEG) as the prime contractor and three teaming partner subcontractors: Roy F. Weston, Inc. (RFW), AGRA Earth and Environmental, Inc. (AGRA), and Geraghty and Miller, Inc. (G and M). The TAC contract`s scope is to provide technical, analytical, environmental, engineering, design, inspection, and management support services to the US Department of Energy (DOE) for both Surface and Ground Water Projects. The TAC team supports the DOE in completing surface remedial action and initiating ground water remediation work for start-up, characterization, compliance planning, design, construction oversight, and remedial operations. The TAC provides the DOE UMTRA Project Team with a dedicated management, scientific, and technical resource base in Albuquerque, New Mexico, which is supplemented by corporate resources. A carefully developed and maintained staff of technical experts is available to assess, analyze, develop, and execute cost-effective solutions to the demanding technical and institutional problems presented by the UMTRA Project.

  2. Program Oversight of Contractors on the Battlefield

    DTIC Science & Technology

    2011-03-23

    has a full understanding of it.7 The extensive use of contractors on the battlefields of Iraq and Afghanistan has engendered strong emotion and...contractors in Iraq and Afghanistan . These steps include tracking contracting data, coordinating the movements of contractors throughout the battle space...workforce to manage contractors in Iraq and Afghanistan and updating DoD doctrine to incorporate the role of contractors. However, some of these efforts

  3. Purification, crystallization and preliminary X-ray crystallographic analysis of a rice Rac/Rop GTPase, OsRac1

    PubMed Central

    Kosami, Ken-ichi; Ohki, Izuru; Hayashi, Kokoro; Tabata, Ryo; Usugi, Sayaka; Kawasaki, Tsutomu; Fujiwara, Toshimichi; Nakagawa, Atsushi; Shimamoto, Ko; Kojima, Chojiro

    2014-01-01

    Small GTPases regulate a large variety of key cellular processes. Plant small Rac/Rop GTPases have recently received broad attention as it is becoming clear that these enzymes regulate various plant cellular processes. OsRac1, a rice Rac/Rop protein, is a key regulator of reactive oxygen species (ROS) production and induces immune responses. Although four structures of plant small GTPases have been reported, all of these were of the inactive form. Here, OsRac1 was purified and co-crystallized with the GTP analogue 5′-guanylyl imidodiphos­phate (GMPPNP). The crystal belonged to space group P212121 and a complete data set was collected to 1.9 Å resolution. PMID:24419631

  4. Overseas Contractor Reform Act

    THOMAS, 111th Congress

    Rep. Welch, Peter [D-VT-At Large

    2010-05-20

    09/16/2010 Received in the Senate and Read twice and referred to the Committee on Homeland Security and Governmental Affairs. (All Actions) Tracker: This bill has the status Passed HouseHere are the steps for Status of Legislation:

  5. Novel Activities of Select NSAID R-Enantiomers against Rac1 and Cdc42 GTPases

    PubMed Central

    Oprea, Tudor I.; Sklar, Larry A.; Agola, Jacob O.; Guo, Yuna; Silberberg, Melina; Roxby, Joshua; Vestling, Anna; Romero, Elsa; Surviladze, Zurab; Murray-Krezan, Cristina; Waller, Anna; Ursu, Oleg; Hudson, Laurie G.; Wandinger-Ness, Angela

    2015-01-01

    Rho family GTPases (including Rac, Rho and Cdc42) collectively control cell proliferation, adhesion and migration and are of interest as functional therapeutic targets in numerous epithelial cancers. Based on high throughput screening of the Prestwick Chemical Library® and cheminformatics we identified the R-enantiomers of two approved drugs (naproxen and ketorolac) as inhibitors of Rac1 and Cdc42. The corresponding S-enantiomers are considered the active component in racemic drug formulations, acting as non-steroidal anti-inflammatory drugs (NSAIDs) with selective activity against cyclooxygenases. Here, we show that the S-enantiomers of naproxen and ketorolac are inactive against the GTPases. Additionally, more than twenty other NSAIDs lacked inhibitory action against the GTPases, establishing the selectivity of the two identified NSAIDs. R-naproxen was first identified as a lead compound and tested in parallel with its S-enantiomer and the non-chiral 6-methoxy-naphthalene acetic acid (active metabolite of nabumetone, another NSAID) as a structural series. Cheminformatics-based substructure analyses—using the rotationally constrained carboxylate in R-naproxen—led to identification of racemic [R/S] ketorolac as a suitable FDA-approved candidate. Cell based measurement of GTPase activity (in animal and human cell lines) demonstrated that the R-enantiomers specifically inhibit epidermal growth factor stimulated Rac1 and Cdc42 activation. The GTPase inhibitory effects of the R-enantiomers in cells largely mimic those of established Rac1 (NSC23766) and Cdc42 (CID2950007/ML141) specific inhibitors. Docking predicts that rotational constraints position the carboxylate moieties of the R-enantiomers to preferentially coordinate the magnesium ion, thereby destabilizing nucleotide binding to Rac1 and Cdc42. The S-enantiomers can be docked but are less favorably positioned in proximity to the magnesium. R-naproxen and R-ketorolac have potential for rapid translation and

  6. Audit of health benefit costs at the Department`s Management and Operating Contractors

    SciTech Connect

    Not Available

    1994-06-23

    The audit disclosed that the Department and certain of its contractors had initiated several positive actions to contain health benefit costs: improving data collection, increasing training, reviewing changes to health plans, improving the language in one contract, increasing the employees, share of health costs at one contractor, and initiating self-insurance at another contractor. Despite these actions, further improvements are needed in the administration of the contractor employee health benefit plans. It was found that the Department did not have the policies and procedures necessary to ensure that the health benefit costs met the tests for reasonableness. The audit of $95 million in health benefit costs incurred at six Management and Operating contractors showed that $15.4 million of these costs were excessive compared to national norms.

  7. 77 FR 70475 - Comment Request for Information Collection for Contractor Information Gathering, Extension...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-11-26

    ... Employment and Training Administration Comment Request for Information Collection for Contractor Information Gathering, Extension Without Revisions AGENCY: Employment and Training Administration (ETA), Labor. ACTION: Notice. SUMMARY: The Department of Labor (Department), as part of its continuing effort to...

  8. Rac1 expression in epithelial ovarian cancer: effect on cell EMT and clinical outcome.

    PubMed

    Leng, Ruobing; Liao, Gang; Wang, Haixia; Kuang, Jun; Tang, Liangdan

    2015-02-01

    Ras-related C3 botulinum toxin substrate 1 (rac1) has been implicated in tumor epithelial-mesenchymal transition (EMT); however, limited information is available regarding the role of rac1 in epithelial ovarian cancer (EOC). This study aimed to evaluate the correlation of rac1 expression with EMT and EOC prognosis. Rac1 protein levels of 150 EOC specimens were evaluated by immunohistochemical staining. Survival analysis was performed to determine the correlation between rac1 expression and survival. Cellular and molecular changes were also examined after rac1 in ovarian cancer cells was silenced in vitro and in vivo. The mechanism of rac1 on EMT was investigated by Western blot analysis. Rac1 was highly expressed in EOC. Rac1 overexpression was closely associated with advanced stage based on International Federation of Gynecology and Obstetrics, poor grade, serum Ca-125, and residual tumor size. Survival analyses demonstrated that patients with high rac1 expression levels were more susceptible to early tumor recurrence with very poor prognosis. This study revealed that rac1 downregulation decreased cell EMT and proliferation capability in vitro and in vivo. Rac1 expression possibly altered cell EMT by interacting with p21-activated kinase 1 and p38 mitogen-activated protein kinase signaling pathways. The present study showed that rac1 overexpression is associated with cell EMT and poor EOC prognosis. Rac1 possibly plays an important role in predicting EOC metastasis.

  9. Rac GTPase signaling through the PP5 protein phosphatase

    PubMed Central

    Gentile, Saverio; Darden, Thomas; Erxleben, Christian; Romeo, Charles; Russo, Angela; Martin, Negin; Rossie, Sandra; Armstrong, David L.

    2006-01-01

    We have investigated the Rac-dependent mechanism of KCNH2 channel stimulation by thyroid hormone in a rat pituitary cell line, GH4C1, with the patch-clamp technique. Here we present physiological evidence for the protein serine/threonine phosphatase, PP5, as an effector of Rac GTPase signaling. We also propose and test a specific molecular mechanism for PP5 stimulation by Rac-GTP. Inhibition of PP5 with the microbial toxin, okadaic acid, blocked channel stimulation by thyroid hormone and by Rac, but signaling was restored by expression of a toxin-insensitive mutant of PP5, Y451A, which we engineered. PP5 is unique among protein phosphatases in that it contains an N-terminal regulatory domain with three tetratricopeptide repeats (TPR) that inhibit its activity. Expression of the TPR domain coupled to GFP blocked channel stimulation by the thyroid hormone. We also show that the published structures of the PP5 TPR domain and the TPR domain of p67, the Rac-binding subunit of NADPH oxidase, superimpose over 92 α carbons. Mutation of the PP5 TPR domain at two predicted contact points with Rac-GTP prevents the TPR domain from functioning as a dominant negative and blocks the ability of Y451A to rescue signaling in the presence of okadaic acid. PP5 stimulation by Rac provides a unique molecular mechanism for the antagonism of Rho-dependent signaling through protein kinases in many cellular processes, including metastasis, immune cell chemotaxis, and neuronal development. PMID:16549782

  10. Rac regulates vascular endothelial growth factor stimulated motility.

    PubMed

    Soga, N; Connolly, J O; Chellaiah, M; Kawamura, J; Hruska, K A

    2001-01-01

    During angiogenesis endothelial cells migrate towards a chemotactic stimulus. Understanding the mechanism of endothelial cell migration is critical to the therapeutic manipulation of angiogenesis and ultimately cancer prevention. Vascular endothelial growth factor (VEGF) is a potent chemotactic stimulus of endothelial cells during angiogenesis. The endothelial cell signal transduction pathway of VEGF represents a potential target for cancer therapy, but the mechanisms of post-receptor signal transduction including the roles of rho family GTPases in regulating the cytoskeletal effects of VEGF in endothelial cells are not understood. Here we analyze the mechanisms of cell migration in the mouse brain endothelial cell line (bEND3). Stable transfectants containing a tetracycline repressible expression vector were used to induce expression of Rac mutants. Endothelial cell haptotaxis was stimulated by constitutively active V12Rac on collagen and vitronectin coated supports, and chemotaxis was further stimulated by VEGF. Osteopontin coated supports were the most stimulatory to bEND3 haptotaxis, but VEGF was not effective in further increasing migration on osteopontin coated supports. Haptotaxis on support coated with collagen, vitronectin, and to a lesser degree osteopontin was inhibited by N17 Rac. N17 Rac expression blocked stimulation of endothelial cell chemotaxis by VEGF. As part of the chemotactic stimulation, VEGF caused a loss of actin organization at areas of cell-cell contact and increased stress fiber expression in endothelial cells which were directed towards pores in the transwell membrane. N17 Rac prevented the stimulation of cell-cell contact disruption and the stress fiber stimulation by VEGF. These data demonstrate two pathways of regulating endothelial cell motility, one in which Rac is activated by matrix/integrin stimulation and is a crucial modulator of endothelial cell haptotaxis. The other pathway, in the presence of osteopontin, is Rac independent

  11. Cocaine activates Rac1 to control structural and behavioral plasticity in caudate putamen.

    PubMed

    Li, Juan; Zhang, Lei; Chen, Zhenzhong; Xie, Minjuan; Huang, Lu; Xue, Jinhua; Liu, Yutong; Liu, Nuyun; Guo, Fukun; Zheng, Yi; Kong, Jiming; Zhang, Lin; Zhang, Lu

    2015-03-01

    Repeated exposure to cocaine was previously found to cause sensitized behavioral responses and structural remodeling on medium spiny neurons of the nucleus accumbens (NAc) and caudate putamen (CPu). Rac1 has emerged as a key integrator of environmental cues that regulates dendritic cytoskeletons. In this study, we investigated the role of Rac1 in cocaine-induced dendritic and behavioral plasticity in the CPu. We found that Rac1 activation was reduced in the NAc but increased in the CPu following repeated cocaine treatment. Inhibition of Rac1 activity by a Rac1-specific inhibitor NSC23766, overexpression of a dominant negative mutant of Rac1 (T17N-Rac1) or local knockout of Rac1 attenuated the cocaine-induced increase in dendrites and spine density in the CPu, whereas overexpression of a constitutively active Rac1 exert the opposite effect. Moreover, NSC23766 reversed the increased number of asymmetric spine synapses in the CPu following chronic cocaine exposure. Downregulation of Rac1 activity likewise attenuates behavioral reward responses to cocaine exposure, with activation of Rac1 producing the opposite effect. Thus, Rac1 signaling is differentially regulated in the NAc and CPu after repeated cocaine treatment, and induction of Rac1 activation in the CPu is important for cocaine exposure-induced dendritic remodeling and behavioral plasticity.

  12. Civilian Contractors under Military Law

    DTIC Science & Technology

    2007-01-01

    appropriate for combat-zone crimes such as rape , murder, and robbery, but not for contempt toward offi- cials, misconduct as a prisoner, or malingering. Thus...Baghdad Central Confinement Facility in Abu Ghraib. See “Abu Ghraib Contractor Sen- tenced for Child Porn ,” Associated Press, 25 May 2007, http

  13. 77 FR 59339 - Contractor Qualifications

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-27

    ... [Federal Register Volume 77, Number 188 (Thursday, September 27, 2012)] [Rules and Regulations] [Page 59339] [FR Doc No: 2012-23905] DEPARTMENT OF DEFENSE Defense Acquisition Regulations System 48 CFR Part 209 Contractor Qualifications CFR Correction In Title 48 of the Code of Federal...

  14. 76 FR 39015 - Contractor Performance Information

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-05

    ... AGENCY 48 CFR Part 1509, 1542 and 1552 Contractor Performance Information AGENCY: Environmental... procedures for recording and maintaining contractor performance information. EPA is issuing a final rule.... II. Background The EPA recently transitioned from the National Institutes of Health's...

  15. Overexpression of Rac1 in leukemia patients and its role in leukemia cell migration and growth

    SciTech Connect

    Wang, Jiying; Rao, Qing; Wang, Min; Wei, Hui; Xing, Haiyan; Liu, Hang; Wang, Yanzhong; Tang, Kejing; Peng, Leiwen; Tian, Zheng; Wang, Jianxiang

    2009-09-04

    Rac1 belongs to the Rho family that act as critical mediators of signaling pathways controlling cell migration and proliferation and contributes to the interactions of hematopoietic stem cells with their microenvironment. Alteration of Rac1 might result in unbalanced interactions and ultimately lead to leukemogenesis. In this study, we analyze the expression of Rac1 protein in leukemia patients and determine its role in the abnormal behaviours of leukemic cells. Rac1 protein is overexpressed in primary acute myeloid leukemia cells as compared to normal bone marrow mononuclear cells. siRNA-mediated silencing of Rac1 in leukemia cell lines induced inhibition of cell migration, proliferation, and colony formation. Additionally, blocking Rac1 activity by an inhibitor of Rac1-GTPase, NSC23766, suppressed cell migration and growth. We conclude that overexpression of Rac1 contributes to the accelerated migration and high proliferation potential of leukemia cells, which could be implicated in leukemia development and progression.

  16. Role of Rac GTPases in Chemokine-Stimulated Breast Carcinoma Metastasis

    DTIC Science & Technology

    2009-01-01

    during breast cancer progression. We have shown that Rac1b is induced under stress-related conditions, including hypoxia, ionizing radiation and serum...and ionizing radiation . We found that both hypoxia and application of CoCl2, which mimics hypoxic conditions, significantly induced Rac1b expression...in MCF10ADCIS cells (Figure 1A, B). Ionizing radiation (IR) also strongly induced Rac1b expression (Figure 2). 6 Figure 1: Rac1b is induced

  17. Rac1 is Required for Matrix Metalloproteinase-13 Production by Chondrocytes in Response to Fibronectin Fragments

    PubMed Central

    Long, David L.; Willey, Jeffrey S.; Loeser, Richard F.

    2013-01-01

    Summary Objective Matrix fragments, including fibronectin fragments (Fnf), accumulate during the development of osteoarthritis (OA) stimulating chondrocyte matrix metalloproteinase (MMP) production. The objective of this study was to determine the role of the small GTPase Rac1 in chondrocyte signaling stimulated by Fnf that results in MMP-13 production. Methods Normal human cartilage was from tissue donors and OA cartilage from knee arthroplasty specimens. Rac1 activity was modulated with a chemical inhibitor, siRNA knock-down, constitutively active (CA)-Rac or dominant negative (DN)-Rac adenovirus. Cells were treated with Fnf or without known Rac activators, epidermal growth factor (EGF) or transforming growth factorα (TGFα). Rac1 activity was measured with a colorometric activity ELISA, pulldown assay, and immunostaining with a monoclonal antibody against active Rac. Results Chemical inhibition of Rac1, as well as knockdown by siRNA and expression of DN-Rac blocked Fnf stimulated MMP-13 production while expression of CA-Rac increased MMP-13. Inhibition of Rho-associated kinase had no effect. EGF and TGFα, but not Fnf, increased Rac1 activity and promoted the increase in MMP-13 above that stimulated by Fnf alone. Active Rac was detected by immunostaining in OA cartilage. Conclusion Rac1 is required for Fnf induced signaling that results in increased MMP-13 production. EGF receptor ligands, which activate Rac, can promote this effect. The presence of active Rac in OA cartilage and the ability of Rac to stimulate MMP-13 production suggests that it could play a role in the cartilage matrix destruction seen in OA. PMID:23460186

  18. 40 CFR 68.87 - Contractors.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 15 2010-07-01 2010-07-01 false Contractors. 68.87 Section 68.87... ACCIDENT PREVENTION PROVISIONS Program 3 Prevention Program § 68.87 Contractors. (a) Application. This section applies to contractors performing maintenance or repair, turnaround, major renovation,...

  19. 32 CFR 1701.16 - Contractors.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 6 2010-07-01 2010-07-01 false Contractors. 1701.16 Section 1701.16 National... Under the Privacy Act of 1974 § 1701.16 Contractors. (a) Any approved contract for the operation of a... prescribed by the Federal Acquisition Regulations (FAR) at 48 CFR part 24, requiring the contractor to...

  20. 48 CFR 725.703 - Contractor employees.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Contractor employees. 725... SOCIOECONOMIC PROGRAMS FOREIGN ACQUISITION Source, Origin, and Nationality 725.703 Contractor employees. (a... on employees or consultants of either contractors or subcontractors providing services under an...

  1. 28 CFR 513.36 - Government contractors.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Government contractors. 513.36 Section... contractors. (a) No Bureau component may contract for the operation of a record system by or on behalf of the... component shall have the responsibility to ensure that the contractor complies with the...

  2. 4 CFR 83.19 - Government contractors.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 4 Accounts 1 2010-01-01 2010-01-01 false Government contractors. 83.19 Section 83.19 Accounts... contractors. When GAO provides by a contract for the operation by or on behalf of GAO of a system of personnel... of this part to be applied to such system. Any such contractor and any employee of such...

  3. 24 CFR 242.53 - Excluded contractors.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 24 Housing and Urban Development 2 2010-04-01 2010-04-01 false Excluded contractors. 242.53... MORTGAGE INSURANCE FOR HOSPITALS Construction § 242.53 Excluded contractors. (a) Contracts relating to the... participation in federal programs, including but not limited to: A general contractor, a subcontractor,...

  4. 34 CFR 5b.12 - Contractors.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 34 Education 1 2010-07-01 2010-07-01 false Contractors. 5b.12 Section 5b.12 Education Office of the Secretary, Department of Education PRIVACY ACT REGULATIONS § 5b.12 Contractors. (a) All contracts entered into on or after September 27, 1975 which require a contractor to maintain or on behalf of...

  5. 48 CFR 33.207 - Contractor certification.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Contractor certification... CONTRACTING REQUIREMENTS PROTESTS, DISPUTES, AND APPEALS Disputes and Appeals 33.207 Contractor certification. (a) Contractors shall provide the certification specified in paragraph (c) of this section...

  6. 32 CFR 310.12 - Government contractors.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 2 2013-07-01 2013-07-01 false Government contractors. 310.12 Section 310.12... PROGRAM DOD PRIVACY PROGRAM Systems of Records § 310.12 Government contractors. (a) Applicability to government contractors. (1) When a DoD Component contract requires the operation or maintenance of a...

  7. 32 CFR 310.12 - Government contractors.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 2 2012-07-01 2012-07-01 false Government contractors. 310.12 Section 310.12... PROGRAM DOD PRIVACY PROGRAM Systems of Records § 310.12 Government contractors. (a) Applicability to government contractors. (1) When a DoD Component contract requires the operation or maintenance of a...

  8. 32 CFR 310.12 - Government contractors.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 2 2011-07-01 2011-07-01 false Government contractors. 310.12 Section 310.12... PROGRAM DOD PRIVACY PROGRAM Systems of Records § 310.12 Government contractors. (a) Applicability to government contractors. (1) When a DoD Component contract requires the operation or maintenance of a...

  9. 32 CFR 310.12 - Government contractors.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 2 2014-07-01 2014-07-01 false Government contractors. 310.12 Section 310.12... PROGRAM DOD PRIVACY PROGRAM Systems of Records § 310.12 Government contractors. (a) Applicability to government contractors. (1) When a DoD Component contract requires the operation or maintenance of a...

  10. 45 CFR 5b.12 - Contractors.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 45 Public Welfare 1 2010-10-01 2010-10-01 false Contractors. 5b.12 Section 5b.12 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION PRIVACY ACT REGULATIONS § 5b.12 Contractors. (a) All contracts entered into on or after September 27, 1975 which require a contractor to maintain or on behalf of the Department to...

  11. 34 CFR 5b.12 - Contractors.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 34 Education 1 2012-07-01 2012-07-01 false Contractors. 5b.12 Section 5b.12 Education Office of the Secretary, Department of Education PRIVACY ACT REGULATIONS § 5b.12 Contractors. (a) All contracts entered into on or after September 27, 1975 which require a contractor to maintain or on behalf of...

  12. Space plasma contractor research, 1988

    NASA Technical Reports Server (NTRS)

    Williams, John D.; Wilbur, Paul J.

    1989-01-01

    Results of experiments conducted on hollow cathode-based plasma contractors are reported. Specific tests in which attempts were made to vary plasma conditions in the simulated ionospheric plasma are described. Experimental results showing the effects of contractor flowrate and ion collecting surface size on contactor performance and contactor plasma plume geometry are presented. In addition to this work, one-dimensional solutions to spherical and cylindircal space-charge limited double-sheath problems are developed. A technique is proposed that can be used to apply these solutions to the problem of current flow through elongated double-sheaths that separate two cold plasmas. Two conference papers which describe the essential features of the plasma contacting process and present data that should facilitate calibration of comprehensive numerical models of the plasma contacting process are also included.

  13. 42 CFR 455.516 - Exceptions from Medicaid RAC programs.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 4 2012-10-01 2012-10-01 false Exceptions from Medicaid RAC programs. 455.516 Section 455.516 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL ASSISTANCE PROGRAMS PROGRAM INTEGRITY: MEDICAID Medicaid Recovery...

  14. 42 CFR 455.512 - Medicaid RAC provider appeals.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 4 2012-10-01 2012-10-01 false Medicaid RAC provider appeals. 455.512 Section 455.512 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL ASSISTANCE PROGRAMS PROGRAM INTEGRITY: MEDICAID Medicaid Recovery Audit...

  15. 42 CFR 455.512 - Medicaid RAC provider appeals.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 4 2011-10-01 2011-10-01 false Medicaid RAC provider appeals. 455.512 Section 455.512 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL ASSISTANCE PROGRAMS PROGRAM INTEGRITY: MEDICAID Medicaid Recovery Audit...

  16. 42 CFR 455.516 - Exceptions from Medicaid RAC programs.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 4 2013-10-01 2013-10-01 false Exceptions from Medicaid RAC programs. 455.516 Section 455.516 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL ASSISTANCE PROGRAMS PROGRAM INTEGRITY: MEDICAID Medicaid Recovery...

  17. 42 CFR 455.512 - Medicaid RAC provider appeals.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 4 2013-10-01 2013-10-01 false Medicaid RAC provider appeals. 455.512 Section 455.512 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL ASSISTANCE PROGRAMS PROGRAM INTEGRITY: MEDICAID Medicaid Recovery Audit...

  18. 42 CFR 455.516 - Exceptions from Medicaid RAC programs.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 4 2011-10-01 2011-10-01 false Exceptions from Medicaid RAC programs. 455.516 Section 455.516 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL ASSISTANCE PROGRAMS PROGRAM INTEGRITY: MEDICAID Medicaid Recovery...

  19. 42 CFR 455.516 - Exceptions from Medicaid RAC programs.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 4 2014-10-01 2014-10-01 false Exceptions from Medicaid RAC programs. 455.516 Section 455.516 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL ASSISTANCE PROGRAMS PROGRAM INTEGRITY: MEDICAID Medicaid Recovery...

  20. 42 CFR 455.512 - Medicaid RAC provider appeals.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 4 2014-10-01 2014-10-01 false Medicaid RAC provider appeals. 455.512 Section 455.512 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL ASSISTANCE PROGRAMS PROGRAM INTEGRITY: MEDICAID Medicaid Recovery Audit...

  1. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma

    PubMed Central

    Krauthammer, Michael; Kong, Yong; Ha, Byung Hak; Evans, Perry; Bacchiocchi, Antonella; McCusker, James P; Cheng, Elaine; Davis, Matthew J; Goh, Gerald; Choi, Murim; Ariyan, Stephan; Narayan, Deepak; Dutton-Regester, Ken; Capatana, Ana; Holman, Edna C; Bosenberg, Marcus; Sznol, Mario; Kluger, Harriet M; Brash, Douglas E; Stern, David F; Materin, Miguel A; Lo, Roger S; Mane, Shrikant; Ma, Shuangge; Kidd, Kenneth K; Hayward, Nicholas K; Lifton, Richard P; Schlessinger, Joseph; Boggon, Titus J; Halaban, Ruth

    2012-01-01

    We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS. Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas. This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1P29S) in the highly conserved switch I domain. Crystal structures, and biochemical and functional studies of RAC1P29S showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration. These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit. PMID:22842228

  2. 77 FR 54608 - Southeast Oregon Resource Advisory Council (RAC); Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-05

    ... ecosystems of burned areas within the Southeast Oregon RAC jurisdictional boundary; updates on travel management planning in the Lakeview Resource Area, the Chiloquin Ranger District, and the Malheur National...; and a partial-day field tour to the Miller Homestead wildfire area near Frenchglen, Oregon....

  3. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma

    SciTech Connect

    Krauthammer, Michael; Kong, Yong; Ha, Byung Hak; Evans, Perry; Bacchiocchi, Antonella; McCusker, James P.; Cheng, Elaine; Davis, Matthew J.; Goh, Gerald; Choi, Murim; Ariyan, Stephan; Narayan, Deepak; Dutton-Regester, Ken; Capatana, Ana; Holman, Edna C.; Bosenberg, Marcus; Sznol, Mario; Kluger, Harriet M.; Brash, Douglas E.; Stern, David F.; Materin, Miguel A.; Lo, Roger S.; Mane, Shrikant; Ma, Shuangge; Kidd, Kenneth K.; Hayward, Nicholas K.; Lifton, Richard P.; Schlessinger, Joseph; Boggon, Titus J.; Halaban, Ruth

    2012-10-11

    We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS. Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas. This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1{sup P29S}) in the highly conserved switch I domain. Crystal structures, and biochemical and functional studies of RAC1{sup P29S} showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration. These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit.

  4. 76 FR 39434 - Notice of Utah's Resource Advisory Council (RAC)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-06

    ... August 4, the RAC will meet at the Park-N-Ride, Exit 405 (South Weber Drive), from Highway 89 (South Ogden). The South Weber Park & Ride is the first right crossing Highway 89 on the north side of South... opportunities of ``time control'' grazing. A presentation on data collected from DLL from Open Range...

  5. Debates, divisions, and decisions: recombinant DNA advisory committee (RAC) authorization of the first human gene transfer experiments.

    PubMed Central

    Carmen, I H

    1992-01-01

    Possibly the most far-reaching, controversial research currently being conducted in the international biological science community involves human gene therapy experimentation. In this paper, I report the dynamics of the political process which ultimately found the Recombinant DNA Advisory Committee (RAC) of the National Institutes of Health approving for the first time protocols of this genre. A full appreciation of the policy-making dialogue shows that significant participants perceived the process from very different vantage points regarding the way in which the American political system works and the way in which it ought to work. I argue that, if we are to understand how the RAC should proceed in orchestrating a human gene therapy policy agenda, then we must flesh out and critically analyze these competing vantage points. To that end, I postulate seven possible "action models" for characterizing how protocol assessments of the type at issue might be developed given the nature of our politics, reaching the conclusion that one of these models holds out the most promise for synthesizing efficaciously the key factors involved. In conclusion, I discuss how the RAC might profitably employ this preferred strategy in these and other cases. PMID:1734711

  6. Dynamic Control of Excitatory Synapse Development by a Rac1 GEF/GAP Regulatory Complex

    PubMed Central

    Um, Kyongmi; Niu, Sanyong; Duman, Joseph G.; Cheng, Jinxuan; Tu, Yen-Kuei; Schwechter, Brandon; Liu, Feng; Hiles, Laura; Narayanan, Anjana; Ash, Ryan T.; Mulherkar, Shalaka; Alpadi, Kannan; Smirnakis, Stelios M.; Tolias, Kimberley F.

    2014-01-01

    SUMMARY The small GTPase Rac1 orchestrates actin-dependent remodeling essential for numerous cellular processes including synapse development. While precise spatiotemporal regulation of Rac1 is necessary for its function, little is known about the mechanisms that enable Rac1 activators (GEFs) and inhibitors (GAPs) to act in concert to regulate Rac1 signaling. Here we identify a regulatory complex composed of a Rac-GEF (Tiam1) and a Rac-GAP (Bcr) that cooperate to control excitatory synapse development. Disruption of Bcr function within this complex increases Rac1 activity and dendritic spine remodeling, resulting in excessive synaptic growth that is rescued by Tiam1 inhibition. Notably, EphB receptors utilize the Tiam1-Bcr complex to control synaptogenesis. Following EphB activation, Tiam1 induces Rac1-dependent spine formation, whereas Bcr prevents Rac1-mediated receptor internalization, promoting spine growth over retraction. The finding that a Rac-specific GEF/GAP complex is required to maintain optimal levels of Rac1 signaling provides an important insight into the regulation of small GTPases. PMID:24960694

  7. Inhibition of Rac1 Activity in the Hippocampus Impairs the Forgetting of Contextual Fear Memory.

    PubMed

    Jiang, Lizhu; Mao, Rongrong; Zhou, Qixin; Yang, Yuexiong; Cao, Jun; Ding, Yuqiang; Yang, Yuan; Zhang, Xia; Li, Lingjiang; Xu, Lin

    2016-03-01

    Fear is crucial for survival, whereas hypermnesia of fear can be detrimental. Inhibition of the Rac GTPase is recently reported to impair the forgetting of initially acquired memory in Drosophila. Here, we investigated whether inhibition of Rac1 activity in rat hippocampus could contribute to the hypermnesia of contextual fear. We found that spaced but not massed training of contextual fear conditioning caused inhibition of Rac1 activity in the hippocampus and heightened contextual fear. Furthermore, intrahippocampal injection of the Rac1 inhibitor NSC23766 heightened contextual fear in massed training, while Rac1 activator CN04-A weakened contextual fear in spaced training rats. Our study firstly demonstrates that contextual fear memory in rats is actively regulated by Rac1 activity in the hippocampus, which suggests that the forgetting impairment of traumatic events in posttraumatic stress disorder may be contributed to the pathological inhibition of Rac1 activity in the hippocampus.

  8. Affirmative Action Program Manual.

    ERIC Educational Resources Information Center

    Ventura County Community Coll. District, CA.

    Guidelines relating to the affirmative action program of the Ventura County Community College District are provided in this manual. Affirmative action is defined as, "A set of specific and result-oriented procedures to which a contractor commits himself/herself to apply every good faith effort. The objective of those procedures, plus such efforts,…

  9. Constitutive phosphorylation of a Rac GAP MgcRacGAP is implicated in v-Src-induced transformation of NIH3T3 cells.

    PubMed

    Doki, Noriko; Kawashima, Toshiyuki; Nomura, Yasushi; Tsuchiya, Akiho; Oneyama, Chitose; Akagi, Tsuyoshi; Nojima, Yoshihisa; Kitamura, Toshio

    2009-09-01

    MgcRacGAP plays critical roles in cell division through regulating Rho family small GTPases. As we previously reported, phosphorylation of MgcRacGAP on serine 387 (S387) is induced by Aurora B kinase at the midbody during cytokinesis, which is a critical step of cytokinesis. Phosphorylation of S387-MgcRacGAP converts it from RacGAP to RhoGAP, leading to completion of cytokinesis. Here we show that MgcRacGAP is prominently phosphorylated on S387 even in the interphase of v-Src-transformed NIH3T3 cells in the cytoplasm, but not in the interphase of parental NIH3T3 or H-RasV12-transformed NIH3T3 cells. Interestingly, levels of phosphorylation on S387 (pS387) correlated with soft agar colony-forming abilities of v-Src-transformed NIH3T3 cells. Expression of a phosphorylation-mimic mutant MgcRacGAP-S387D enhanced colony formation of v-Src-transformed NIH3T3 cells. Surprisingly, a Rac1 inhibitor but not kinase inhibitors including Aurora B kinase inhibitor specifically inhibited phosphorylation of S387-MgcRacGAP in v-Src-transformed NIH3T3 cells, suggesting the v-Src-induced pathological positive feedback mechanisms towards Rac1 activation using pS387-MgcRacGAP. These results indicated the difference in the mechanisms between v-Src- and H-RasV12-induced transformation, and should shed some light on pathological roles of disordered phosphorylation of MgcRacGAP at S387 in v-Src-induced cell transformation.

  10. Technical assistance contractor Management Plan. Final [report

    SciTech Connect

    Not Available

    1993-09-01

    The Technical Assistance Contractor (TAC) for the Uranium Mill Tailings Remedial Action (UMTRA) Project comprises Jacobs Engineering Group Inc. (JEG) and its major teaming partners [Roy F. Weston, Inc. (RFW), Sergent, Hauskins & Beckwith Agra, Inc. (SHB Agra), and Geraghty & Miller, Inc. (G&M)]. The first three companies have worked together effectively on the UMTRA Project for more than 10 years. With the initiation of the UMTRA Groundwater Project in April 1991, a need arose to increase the TAC`s groundwater technical breadth and depth, so G&M was brought in to augment the team`s capabilities. The TAC contract`s scope is to provide technical, analytical, environmental, engineering, design, inspection, and management support services to the US Department of Energy (DOE) for both surface and groundwater projects. The TAC team continues to support the DOE in completing surface remedial actions and initiating groundwater remediation work for start-up, characterization, design, construction oversight, and remedial operations. A key feature of the TAC`s management approach is the extensive set of communication systems implemented for the UMTRA Project. These systems assist all functional disciplines in performing UMTRA Project tasks associated with management, technical support, administrative support, and financial/project controls.

  11. Labor contractors: a conceptual overview.

    PubMed

    Martin, P M

    1996-01-01

    "The purpose of this paper is to provide an overview of labor brokering or contracting that helps to explain why employers turn to foreign workers to fill certain vacant jobs, and how the presence of foreign workers brought to a country by labor contractors can affect the size and duration of migration flows. The major conclusion is that East Asian policies that aim to avoid the settlement of unskilled foreign workers also make labor brokering a prominent feature of labor migration and migrant labor markets in the region."

  12. Government Contractors and Sticky SGA Costs

    DTIC Science & Technology

    2015-05-01

    Government Contractors and Sticky SGA Costs by Stephen C. Hansen Naval Postgraduate School These discussion comments reflect the private...2015 to 00-00-2015 4. TITLE AND SUBTITLE Government Contractors and Sticky SGA Costs 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT... contractors . Let Fseg = 1 if a company is a Federal Focus Firm. l ( SGAit ) L ( Revenueit ) og ’ =a0+a1 og ’ SGAi,t-1 Revenuei,t- 1 ( Revenue· t

  13. Profit Negotiations and Promotion of Contractor Efficiency.

    DTIC Science & Technology

    1981-03-01

    AOA097 06 ARMY POCUREMNT RESARCH OFFICE FORT LEE VA F/B 5/I PROFIT NEGOTIATIONS AND PROMOTION OF CONTRACTOR EFFICIENCY.(U) MAR 81 R W NICK, 6 A...08 0.5 FINAL PROFIT NEGOTIATIONS MD PROMOTION OF CONTRACTOR EFFICIENCY MARCH 1981 Approved for Public Release; Distribution Unlimited APRO iU. ANIr...DRXMC-PRO 2 April 1981 SUBJECT: Army Procurement Research Office Report APRO 80-08, Profit Negotiations and Promotion of Contractor Efficiency SEE

  14. National radon contractor proficiency program. Proficiency report

    SciTech Connect

    Not Available

    1991-02-01

    The report lists those individual contractors who have met the requirements of the Radon Contractor Proficiency (PCP) Program as of December 15, 1990. These requirements are designed to provide minimum proficiency criteria for individuals who design and supervise the installation of radon mitigation systems in buildings. The RCP Program measures the proficiency of an individual contractor, not their company. The report provides the program requirements, RCP mitigation guidelines, State Radon contacts, and information on how to use the RCP tables.

  15. Alpha1-chimaerin, a Rac1 GTPase-activating protein, is expressed at reduced mRNA levels in the brain of Alzheimer's disease patients

    PubMed Central

    Kato, Tomoko; Konishi, Yoshihiro; Shimohama, Shun; Beach, Thomas G.; Akatsu, Hiroyasu; Tooyama, Ikuo

    2015-01-01

    Alpha1-chimaerin is a GTPase-activating protein (GAP) for Rac1, a member of the Rho small GTPase family, whose action leads to the inactivation of Rac1. Rac1 activity is upregulated in Alzheimer's disease, but little is known about the role of α1-chimaerin. In this study, we investigated the expression and localization of α1-chimaerin mRNA in postmortem human brains from patients with Alzheimer's disease and control subjects. In situ hybridization studies demonstrated that α1-chimaerin was expressed by neurons in the neo-cortex of the temporal lobe and the hippocampus of both controls and Alzheimer's disease cases, with the signal intensity dramatically decreased in patients with Alzheimer's disease. Real-time PCR analysis confirmed a significant reduction of α1-chimaerin mRNA expression in the temporal cortex of Alzheimer's disease cases. In contrast, α2-chimaerin mRNA levels showed no significant difference between the groups. The present study showed reduced α1-chimaerin expression in the brain of Alzheimer's disease cases, suggesting a role in the upregulation of Rac1 activity during the disease process. PMID:25676811

  16. Superior Electrical Contractors Inc. Information Sheet

    EPA Pesticide Factsheets

    Superior Electrical Contractors Inc. (the Company) is located in Boise, Idaho. The settlement involves renovation activities conducted at a property constructed prior to 1978, located in Boise, Idaho.

  17. RAC1P29S is a spontaneously activating cancer-associated GTPase

    PubMed Central

    Davis, Matthew J.; Ha, Byung Hak; Holman, Edna C.; Halaban, Ruth; Schlessinger, Joseph; Boggon, Titus J.

    2013-01-01

    RAC1 is a small, Ras-related GTPase that was recently reported to harbor a recurrent UV-induced signature mutation in melanoma, resulting in substitution of P29 to serine (RAC1P29S), ranking this the third most frequently occurring gain-of-function mutation in melanoma. Although the Ras family GTPases are mutated in about 30% of all cancers, mutations in the Rho family GTPases have rarely been observed. In this study, we demonstrate that unlike oncogenic Ras proteins, which are primarily activated by mutations that eliminate GTPase activity, the activated melanoma RAC1P29S protein maintains intrinsic GTP hydrolysis and is spontaneously activated by substantially increased inherent GDP/GTP nucleotide exchange. Determination and comparison of crystal structures for activated RAC1 GTPases suggest that RAC1F28L—a known spontaneously activated RAC1 mutant—and RAC1P29S are self-activated in distinct fashions. Moreover, the mechanism of RAC1P29S and RAC1F28L activation differs from the common oncogenic mutations found in Ras-like GTPases that abrogate GTP hydrolysis. The melanoma RAC1P29S gain-of-function point mutation therefore represents a previously undescribed class of cancer-related GTPase activity. PMID:23284172

  18. Inhibition of Rac1 GTPase activity affects porcine oocyte maturation and early embryo development

    PubMed Central

    Song, Si-Jing; Wang, Qiao-Chu; Jia, Ru-Xia; Cui, Xiang-Shun; Kim, Nam-Hyung; Sun, Shao-Chen

    2016-01-01

    Mammalian oocyte asymmetric division relies on the eccentric positioning of the spindle, resulting in the polar body formation. Small signaling G protein Rac1 is a member of GTPases, which regulates a diverse array of cellular events, including the control of cell growth, cytoskeletal reorganization, and the activation of protein kinases. However, effects of Rac1 on the porcine oocyte maturation and early embryo development are not fully understood. In present study we investigated the role of Rac1 in oocyte maturation and embryo cleavage. We first found that Rac1 localized at the cortex of the porcine oocytes, and disrupting the Rac1 activities by treating with NSC 23766 led to the failure of polar body emission. In addition, a majority of treated oocytes exhibited abnormal spindle morphology, indicating that Rac1 may involve into porcine oocyte spindle formation. This might be due to the regulation of Rac1 on MAPK, since p-MAPK expression decreased after NSC 23766 treatments. Moreover, we found that the position of most meiotic spindles in treated oocytes were away from the cortex, indicating the roles of Rac1 on meiotic spindle positioning. Our results also showed that inhibition of Rac1 activity caused the failure of early embryo development. Therefore, our study showed the critical roles of Rac1 GTPase on porcine oocyte maturation and early embryo cleavage. PMID:27694954

  19. RAC1 activation drives pathologic interactions between the epidermis and immune cells

    PubMed Central

    Winge, Mårten C.G.; Ohyama, Bungo; Dey, Clara N.; Boxer, Lisa M.; Li, Wei; Ehsani-Chimeh, Nazanin; Truong, Allison K.; Wu, Diane; Armstrong, April W.; Makino, Teruhiko; Davidson, Matthew; Starcevic, Daniela; Nguyen, Ngon T.; Hashimoto, Takashi; Homey, Bernard; Khavari, Paul A.; Bradley, Maria; Waterman, Elizabeth A.; Marinkovich, M. Peter

    2016-01-01

    Interactions between the epidermis and the immune system govern epidermal tissue homeostasis. These epidermis-immune interactions are altered in the inflammatory disease psoriasis; however, the pathways that underlie this aberrant immune response are not well understood. Here, we determined that Ras-related C3 botulinum toxin substrate 1 (RAC1) is a key mediator of epidermal dysfunction. RAC1 activation was consistently elevated in psoriatic epidermis and primary psoriatic human keratinocytes (PHKCs) exposed to psoriasis-related stimuli, but not in skin from patients with basal or squamous cell carcinoma. Expression of a constitutively active form of RAC1 (RACV12) in mice resulted in the development of lesions similar to those of human psoriasis that required the presence of an intact immune system. RAC1V12-expressing mice and human psoriatic skin showed similar RAC1-dependent signaling as well as transcriptional overlap of differentially expressed epidermal and immune pathways. Coculture of PHKCs with immunocytes resulted in the upregulation of RAC1-dependent proinflammatory cytokines, an effect that was reproduced by overexpressing RAC1 in normal human keratinocytes. In keratinocytes, modulating RAC1 activity altered differentiation, proliferation, and inflammatory pathways, including STAT3, NFκB, and zinc finger protein 750 (ZNF750). Finally, RAC1 inhibition in xenografts composed of human PHKCs and immunocytes abolished psoriasiform hyperplasia and inflammation in vivo. These studies implicate RAC1 as a potential therapeutic target for psoriasis and as a key orchestrator of pathologic epidermis-immune interactions. PMID:27294528

  20. Rac-GTPases Regulate Microtubule Stability and Axon Growth of Cortical GABAergic Interneurons.

    PubMed

    Tivodar, Simona; Kalemaki, Katerina; Kounoupa, Zouzana; Vidaki, Marina; Theodorakis, Kostas; Denaxa, Myrto; Kessaris, Nicoletta; de Curtis, Ivan; Pachnis, Vassilis; Karagogeos, Domna

    2015-09-01

    Cortical interneurons are characterized by extraordinary functional and morphological diversity. Although tremendous progress has been made in uncovering molecular and cellular mechanisms implicated in interneuron generation and function, several questions still remain open. Rho-GTPases have been implicated as intracellular mediators of numerous developmental processes such as cytoskeleton organization, vesicle trafficking, transcription, cell cycle progression, and apoptosis. Specifically in cortical interneurons, we have recently shown a cell-autonomous and stage-specific requirement for Rac1 activity within proliferating interneuron precursors. Conditional ablation of Rac1 in the medial ganglionic eminence leads to a 50% reduction of GABAergic interneurons in the postnatal cortex. Here we examine the additional role of Rac3 by analyzing Rac1/Rac3 double-mutant mice. We show that in the absence of both Rac proteins, the embryonic migration of medial ganglionic eminence-derived interneurons is further impaired. Postnatally, double-mutant mice display a dramatic loss of cortical interneurons. In addition, Rac1/Rac3-deficient interneurons show gross cytoskeletal defects in vitro, with the length of their leading processes significantly reduced and a clear multipolar morphology. We propose that in the absence of Rac1/Rac3, cortical interneurons fail to migrate tangentially towards the pallium due to defects in actin and microtubule cytoskeletal dynamics.

  1. 48 CFR 252.229-7004 - Status of contractors as a direct contractor (Spain).

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ..., development, maintenance, and operation of Spanish-American installations and facilities. (b) The Contractor... this contract by reference. (c) The Contractor shall apply to the appropriate Spanish authorities for approval of status as a Direct Contractor in order to complete duty-free import of non-Spanish...

  2. 48 CFR 47.207-5 - Contractor responsibilities.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Contractor....207-5 Contractor responsibilities. Contractor responsibilities vary with the kinds of freight to be... furnished by the contractor. Otherwise, state that the contractor shall furnish clean and sound...

  3. 48 CFR 18.102 - Central contractor registration.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Central contractor... Central contractor registration. Contractors are not required to be registered in the Central Contractor.... (See 4.1102). However, contractors are required to register with CCR in order to gain access to...

  4. 48 CFR 1509.170-8 - Contractor Performance Report.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 6 2010-10-01 2010-10-01 true Contractor Performance... AGENCY ACQUISITION PLANNING CONTRACTOR QUALIFICATIONS Contractor Performance Evaluations 1509.170-8 Contractor Performance Report. (a) Contractor Performance Reports (interim and final) must be...

  5. 48 CFR 1845.502-70 - Contractor-acquired property.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 6 2010-10-01 2010-10-01 true Contractor-acquired... Possession of Contractors 1845.502-70 Contractor-acquired property. All contractor-acquired property must be... contractor-acquired. (2) Submission of DD Form 1419, DOD Industrial Plant Requisition, or equivalent...

  6. Rac[e] to the pole: setting up polarity in endothelial cells.

    PubMed

    Collins, Caitlin; Tzima, Ellie

    2014-01-01

    Mechanical forces influence many biological processes via activation of signaling molecules, including the family of Rho GTPases. Within the endothelium, the mechanical force of fluid shear stress regulates the spatiotemporal activation of Rho GTPases, including Rac1. Shear stress-induced Rac1 activation is required for numerous essential biological processes, including changes in permeability, alignment of the actin cytoskeleton, redox signaling, and changes in gene expression. Thus, identifying mechanisms of Rac1 activation and the spatial cues that direct proper localization of the GTPase is essential in order to gain a comprehensive understanding the role of Rac1 in shear stress responses. This commentary will highlight our current understanding of how Rac1 activity is regulated in response to shear stress, as well as the downstream consequences of Rac1 activation.

  7. 48 CFR 253.209 - Contractor qualifications.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 3 2010-10-01 2010-10-01 false Contractor qualifications. 253.209 Section 253.209 Federal Acquisition Regulations System DEFENSE ACQUISITION REGULATIONS SYSTEM, DEPARTMENT OF DEFENSE CLAUSES AND FORMS FORMS Prescription of Forms 253.209 Contractor qualifications....

  8. 30 CFR 874.16 - Contractor eligibility.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 3 2010-07-01 2010-07-01 false Contractor eligibility. 874.16 Section 874.16 Mineral Resources OFFICE OF SURFACE MINING RECLAMATION AND ENFORCEMENT, DEPARTMENT OF THE INTERIOR ABANDONED MINE LAND RECLAMATION GENERAL RECLAMATION REQUIREMENTS § 874.16 Contractor eligibility. To...

  9. 30 CFR 875.20 - Contractor eligibility.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 3 2010-07-01 2010-07-01 false Contractor eligibility. 875.20 Section 875.20 Mineral Resources OFFICE OF SURFACE MINING RECLAMATION AND ENFORCEMENT, DEPARTMENT OF THE INTERIOR ABANDONED MINE LAND RECLAMATION CERTIFICATION AND NONCOAL RECLAMATION § 875.20 Contractor eligibility....

  10. 48 CFR 53.209 - Contractor qualifications.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 2 2010-10-01 2010-10-01 false Contractor qualifications. 53.209 Section 53.209 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION (CONTINUED) CLAUSES AND FORMS FORMS Prescription of Forms 53.209 Contractor qualifications....

  11. 48 CFR 32.909 - Contractor inquiries.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Contractor inquiries. 32.909 Section 32.909 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION GENERAL CONTRACTING REQUIREMENTS CONTRACT FINANCING Prompt Payment 32.909 Contractor inquiries. (a) Direct...

  12. 48 CFR 1553.209 - Contractor qualifications.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 6 2010-10-01 2010-10-01 true Contractor qualifications. 1553.209 Section 1553.209 Federal Acquisition Regulations System ENVIRONMENTAL PROTECTION AGENCY CLAUSES AND FORMS FORMS Prescription of Forms 1553.209 Contractor qualifications....

  13. 48 CFR 4.102 - Contractor's signature.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Contractor's signature. 4.102 Section 4.102 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION GENERAL ADMINISTRATIVE MATTERS Contract Execution 4.102 Contractor's signature. (a) Individuals. A contract with...

  14. 49 CFR 10.27 - Government contractors.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 1 2012-10-01 2012-10-01 false Government contractors. 10.27 Section 10.27 Transportation Office of the Secretary of Transportation MAINTENANCE OF AND ACCESS TO RECORDS PERTAINING TO INDIVIDUALS Maintenance of Records § 10.27 Government contractors. When the Department provides by a...

  15. 4 CFR 83.19 - Government contractors.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 4 Accounts 1 2014-01-01 2013-01-01 true Government contractors. 83.19 Section 83.19 Accounts GOVERNMENT ACCOUNTABILITY OFFICE RECORDS PRIVACY PROCEDURES FOR PERSONNEL RECORDS § 83.19 Government contractors. When GAO provides by a contract for the operation by or on behalf of GAO of a system of...

  16. 49 CFR 10.27 - Government contractors.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 1 2013-10-01 2013-10-01 false Government contractors. 10.27 Section 10.27 Transportation Office of the Secretary of Transportation MAINTENANCE OF AND ACCESS TO RECORDS PERTAINING TO INDIVIDUALS Maintenance of Records § 10.27 Government contractors. When the Department provides by a...

  17. 49 CFR 10.27 - Government contractors.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 1 2014-10-01 2014-10-01 false Government contractors. 10.27 Section 10.27 Transportation Office of the Secretary of Transportation MAINTENANCE OF AND ACCESS TO RECORDS PERTAINING TO INDIVIDUALS Maintenance of Records § 10.27 Government contractors. When the Department provides by a...

  18. 49 CFR 10.27 - Government contractors.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 1 2011-10-01 2011-10-01 false Government contractors. 10.27 Section 10.27 Transportation Office of the Secretary of Transportation MAINTENANCE OF AND ACCESS TO RECORDS PERTAINING TO INDIVIDUALS Maintenance of Records § 10.27 Government contractors. When the Department provides by a...

  19. 4 CFR 83.19 - Government contractors.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 4 Accounts 1 2011-01-01 2011-01-01 false Government contractors. 83.19 Section 83.19 Accounts GOVERNMENT ACCOUNTABILITY OFFICE RECORDS PRIVACY PROCEDURES FOR PERSONNEL RECORDS § 83.19 Government contractors. When GAO provides by a contract for the operation by or on behalf of GAO of a system of...

  20. 4 CFR 83.19 - Government contractors.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 4 Accounts 1 2013-01-01 2013-01-01 false Government contractors. 83.19 Section 83.19 Accounts GOVERNMENT ACCOUNTABILITY OFFICE RECORDS PRIVACY PROCEDURES FOR PERSONNEL RECORDS § 83.19 Government contractors. When GAO provides by a contract for the operation by or on behalf of GAO of a system of...

  1. 4 CFR 83.19 - Government contractors.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 4 Accounts 1 2012-01-01 2012-01-01 false Government contractors. 83.19 Section 83.19 Accounts GOVERNMENT ACCOUNTABILITY OFFICE RECORDS PRIVACY PROCEDURES FOR PERSONNEL RECORDS § 83.19 Government contractors. When GAO provides by a contract for the operation by or on behalf of GAO of a system of...

  2. 48 CFR 4.102 - Contractor's signature.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 1 2011-10-01 2011-10-01 false Contractor's signature. 4... ADMINISTRATIVE MATTERS Contract Execution 4.102 Contractor's signature. (a) Individuals. A contract with an... be signed by that individual, and the signature shall be followed by the individual's typed,...

  3. 48 CFR 46.105 - Contractor responsibilities.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... CONTRACT MANAGEMENT QUALITY ASSURANCE General 46.105 Contractor responsibilities. (a) The contractor is responsible for carrying out its obligations under the contract by— (1) Controlling the quality of supplies or... contract requirements; (3) Ensuring that vendors or suppliers of raw materials, parts,...

  4. 48 CFR 46.105 - Contractor responsibilities.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... CONTRACT MANAGEMENT QUALITY ASSURANCE General 46.105 Contractor responsibilities. (a) The contractor is responsible for carrying out its obligations under the contract by— (1) Controlling the quality of supplies or... contract requirements; (3) Ensuring that vendors or suppliers of raw materials, parts,...

  5. 48 CFR 46.105 - Contractor responsibilities.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... CONTRACT MANAGEMENT QUALITY ASSURANCE General 46.105 Contractor responsibilities. (a) The contractor is responsible for carrying out its obligations under the contract by— (1) Controlling the quality of supplies or... contract requirements; (3) Ensuring that vendors or suppliers of raw materials, parts,...

  6. 48 CFR 46.105 - Contractor responsibilities.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... CONTRACT MANAGEMENT QUALITY ASSURANCE General 46.105 Contractor responsibilities. (a) The contractor is responsible for carrying out its obligations under the contract by— (1) Controlling the quality of supplies or... contract requirements; (3) Ensuring that vendors or suppliers of raw materials, parts,...

  7. 48 CFR 46.105 - Contractor responsibilities.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... CONTRACT MANAGEMENT QUALITY ASSURANCE General 46.105 Contractor responsibilities. (a) The contractor is responsible for carrying out its obligations under the contract by— (1) Controlling the quality of supplies or... contract requirements; (3) Ensuring that vendors or suppliers of raw materials, parts,...

  8. Government Contractors - Do We Really Need Them?

    DTIC Science & Technology

    2011-03-09

    pictures of drunken scantily clad US Embassy security contractors dancing around a fire while urinating.53 The photos also depicted the men engaged...html (accessed January 31, 2011). 57 Ibid. 58 Gary Schaub Jr. and Volker Franke, ―Contractors as Military Professionals?‖, Parameters 39, no.4

  9. Activated Rac1 requires gp130 for Stat3 activation, cell proliferation and migration

    SciTech Connect

    Arulanandam, Rozanne; Geletu, Mulu; Feracci, Helene; Raptis, Leda

    2010-03-10

    Rac1 (Rac) is a member of the Rho family of small GTPases which controls cell migration by regulating the organization of actin filaments. Previous results suggested that mutationally activated forms of the Rho GTPases can activate the Signal Transducer and Activator of Transcription-3 (Stat3), but the exact mechanism is a matter of controversy. We recently demonstrated that Stat3 activity of cultured cells increases dramatically following E-cadherin engagement. To better understand this pathway, we now compared Stat3 activity levels in mouse HC11 cells before and after expression of the mutationally activated Rac1 (Rac{sup V12}), at different cell densities. The results revealed for the first time a dramatic increase in protein levels and activity of both the endogenous Rac and Rac{sup V12} with cell density, which was due to inhibition of proteasomal degradation. In addition, Rac{sup V12}-expressing cells had higher Stat3, tyrosine-705 phosphorylation and activity levels at all densities, indicating that Rac{sup V12} is able to activate Stat3. Further examination of the mechanism of Stat3 activation showed that Rac{sup V12} expression caused a surge in mRNA of Interleukin-6 (IL6) family cytokines, known potent Stat3 activators. Knockdown of gp130, the common subunit of this family reduced Stat3 activity, indicating that these cytokines may be responsible for the Stat3 activation by Rac{sup V12}. The upregulation of IL6 family cytokines was required for cell migration and proliferation induced by Rac{sup V12}, as shown by gp130 knockdown experiments, thus demonstrating that the gp130/Stat3 axis represents an essential effector of activated Rac for the regulation of key cellular functions.

  10. The GTPase-activating protein n-chimaerin cooperates with Rac1 and Cdc42Hs to induce the formation of lamellipodia and filopodia.

    PubMed Central

    Kozma, R; Ahmed, S; Best, A; Lim, L

    1996-01-01

    n-Chimaerin is a GTPase-activating protein (GAP) mainly for Rac1 and less so for Cdc42Hs in vitro. The GAP activity of n-chimaerin is regulated by phospholipids and phorbol esters. Microinjection of Rac1 and Cdc42Hs into mammalian cells induces formation of the actin-based structures lamellipodia and filopodia, respectively, with the former being prevented by coinjection of the chimaerin GAP domain. Strikingly, microinjection of the full-length n-chimaerin into fibroblasts and neuroblastoma cells induces the simultaneous formation of lamellipodia and filopodia. These structures undergo cycles of dissolution and formation, resembling natural morphological events occurring at the leading edge of fibroblasts and neuronal growth cones. The effects of n-chimaerin on formation of lamellipodia and filopodia were inhibited by dominant negative Rac1(T17N) and Cdc42Hs(T17N), respectively. n-Chimaerin's effects were also inhibited by coinjection with Rho GDP dissociation inhibitor or by treatment with phorbol ester. A mutant n-chimaerin with no GAP activity and impaired p21 binding was ineffective in inducing morphological changes, while a mutant lacking GAP activity alone was effective. Microinjected n-chimaerin colocalized in situ with F-actin. Taken together, these results suggest that n-chimaerin acts synergistically with Rac1 and Cdc42Hs to induce actin-based morphological changes and that this action involves Rac1 and Cdc42Hs binding but not GAP activity. Thus, GAPs may have morphological functions in addition to downregulation of GTPases. PMID:8756665

  11. 77 FR 7579 - Debarment, Suspension, and Ineligibility of Contractors

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-13

    ... OFFICE Debarment, Suspension, and Ineligibility of Contractors AGENCY: Government Accountability Office... Acquisition Regulation (FAR) regarding the debarment, suspension, and ineligibility of government contractors..., and ineligibility of government contractors. Neither comment suggested any changes to GAO's...

  12. 48 CFR 970.4402 - Contractor purchasing system.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Contractor purchasing... SUPPLEMENTARY REGULATIONS DOE MANAGEMENT AND OPERATING CONTRACTS Management and Operating Contractor Purchasing 970.4402 Contractor purchasing system....

  13. 76 FR 37704 - Federal Acquisition Regulation; Documenting Contractor Performance

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-28

    ..., and 49 RIN 9000-AM09 Federal Acquisition Regulation; Documenting Contractor Performance AGENCY... performance ratings, and to require all past performance information be entered into the Contractor... memorandum dated July 29, 2009, Improving the Use of Contractor Performance Information. These...

  14. 76 FR 48776 - Federal Acquisition Regulation; Documenting Contractor Performance; Correction

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-09

    ... Federal Acquisition Regulation; Documenting Contractor Performance; Correction AGENCY: Department of... for Documenting Contractor Performance and extends the comment closing date by 30 days. DATES: The... proposed rule for Documenting Contractor Performance (75 FR 37704) and extends the comment closing date...

  15. 78 FR 12106 - Debarment, Suspension, and Ineligibility of Contractors

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-21

    ... MANAGEMENT Debarment, Suspension, and Ineligibility of Contractors AGENCY: U.S. Office of Personnel... (FAR) regarding the debarment, suspension, and ineligibility of government contractors. As an executive... those entities and individuals (hereinafter, contractors) who are responsible. To make clear that...

  16. Extending the Impact of RAC1b Overexpression to Follicular Thyroid Carcinomas

    PubMed Central

    Faria, Márcia; Capinha, Liliana; Simões-Pereira, Joana; Bugalho, Maria João; Silva, Ana Luísa

    2016-01-01

    RAC1b is a hyperactive variant of the small GTPase RAC1 known to be a relevant molecular player in different cancers. Previous studies from our group lead to the evidence that its overexpression in papillary thyroid carcinoma (PTC) is associated with an unfavorable prognosis. In the present study, we intended to extend the analysis of RAC1b expression to thyroid follicular neoplasms and to seek for clinical correlations. RAC1b expression levels were determined by RT-qPCR in thyroid follicular tumor samples comprising 23 follicular thyroid carcinomas (FTCs) and 33 follicular thyroid adenomas (FTAs). RAC1b was found to be overexpressed in 33% of carcinomas while no RAC1b overexpression was documented among follicular adenomas. Patients with a diagnosis of FTC were divided into two groups based on longitudinal evolution and final outcome. RAC1b overexpression was significantly associated with both the presence of distant metastases (P = 0.01) and poorer clinical outcome (P = 0.01) suggesting that, similarly to that previously found in PTCs, RAC1b overexpression in FTCs is also associated with worse outcomes. Furthermore, the absence of RAC1b overexpression in follicular adenomas hints its potential as a molecular marker likely to contribute, in conjunction with other putative markers, to the preoperative differential diagnosis of thyroid follicular lesions. PMID:27127508

  17. Will RAC change RCM? Hospital leaders are gearing up for the potential of RAC audits to impact the revenue cycle management process.

    PubMed

    Wagner, Steven K

    2010-05-01

    Hospital leaders making headway in anticipating the potential impact of possible RAC audits under the Medicare program are examining their revenue cycle management programs and making those RCM programs more rigorous and specific. Hospitals with experience in the early federal RAC audit demonstration project have accumulated numerous learnings from their participation in the early demo project. One clear learning has been the significant financial impact of going through a RAC audit. CIOs will need to work closely and productively with CFOs, health information management professionals, and others, in order to drill down to the levels at which revenue cycle management programs needto be examined in order to strengthen their effectiveness.

  18. Nectin-4 mutations causing ectodermal dysplasia with syndactyly perturb the rac1 pathway and the kinetics of adherens junction formation.

    PubMed

    Fortugno, Paola; Josselin, Emmanuelle; Tsiakas, Konstantinos; Agolini, Emanuele; Cestra, Gianluca; Teson, Massimo; Santer, René; Castiglia, Daniele; Novelli, Giuseppe; Dallapiccola, Bruno; Kurth, Ingo; Lopez, Marc; Zambruno, Giovanna; Brancati, Francesco

    2014-08-01

    Defective nectin-1 and -4 have been implicated in ectodermal dysplasia (ED) syndromes with variably associated features including orofacial and limb defects. In particular, nectin-1 mutations cause cleft lip/palate ED (CLPED1; OMIM#225060), whereas defective nectin-4 is associated with ED-syndactyly syndrome (EDSS1; OMIM#613573). Although the broad phenotypic overlap suggests a common mode of action of nectin-1 and -4, little is known about the pathogenic mechanisms involved. We report the identification of, to our knowledge, a previously undescribed nectin-4 homozygous p.Val242Met missense mutation in a patient with EDSS1. We used patient skin biopsy and primary keratinocytes, as well as nectin-4 ectopic expression in epithelial cell lines, to characterize functional consequences of p.Val242Met and p.Thr185Met mutations, the latter previously identified in compound heterozygosity with a truncating mutation. We show that nectin-4-altered expression perturbs nectin-1 clustering at keratinocyte contact sites and delays, but does not impede cell-cell aggregation and cadherin recruitment at adherens junctions (AJs). Moreover, trans-interaction of nectin-1 and -4 induces the activation of Rac1, a member of the Rho family of small GTPases, and regulates E-cadherin-mediated cell-cell adhesion. These data outline a synergistic action of nectin-1 and -4 in the early steps of AJ formation and implicate this interaction in modulating the Rac1 signaling pathway.

  19. Functional characterization and cellular dynamics of the CDC-42 - RAC - CDC-24 module in Neurospora crassa.

    PubMed

    Araujo-Palomares, Cynthia L; Richthammer, Corinna; Seiler, Stephan; Castro-Longoria, Ernestina

    2011-01-01

    Rho-type GTPases are key regulators that control eukaryotic cell polarity, but their role in fungal morphogenesis is only beginning to emerge. In this study, we investigate the role of the CDC-42 - RAC - CDC-24 module in Neurospora crassa. rac and cdc-42 deletion mutants are viable, but generate highly compact colonies with severe morphological defects. Double mutants carrying conditional and loss of function alleles of rac and cdc-42 are lethal, indicating that both GTPases share at least one common essential function. The defects of the GTPase mutants are phenocopied by deletion and conditional alleles of the guanine exchange factor (GEF) cdc-24, and in vitro GDP-GTP exchange assays identify CDC-24 as specific GEF for both CDC-42 and RAC. In vivo confocal microscopy shows that this module is organized as membrane-associated cap that covers the hyphal apex. However, the specific localization patterns of the three proteins are distinct, indicating different functions of RAC and CDC-42 within the hyphal tip. CDC-42 localized as confined apical membrane-associated crescent, while RAC labeled a membrane-associated ring excluding the region labeled by CDC42. The GEF CDC-24 occupied a strategic position, localizing as broad apical membrane-associated crescent and in the apical cytosol excluding the Spitzenkörper. RAC and CDC-42 also display distinct localization patterns during branch initiation and germ tube formation, with CDC-42 accumulating at the plasma membrane before RAC. Together with the distinct cellular defects of rac and cdc-42 mutants, these localizations suggest that CDC-42 is more important for polarity establishment, while the primary function of RAC may be maintaining polarity. In summary, this study identifies CDC-24 as essential regulator for RAC and CDC-42 that have common and distinct functions during polarity establishment and maintenance of cell polarity in N. crassa.

  20. NADPH Oxidase Contributes to Photoreceptor Degeneration in Constitutively Active RAC1 Mice

    PubMed Central

    Song, Hongman; Vijayasarathy, Camasamudram; Zeng, Yong; Marangoni, Dario; Bush, Ronald A.; Wu, Zhijian; Sieving, Paul A.

    2016-01-01

    Purpose The active form of small GTPase RAC1 is required for activation of NADPH oxidase (NOX), which in turn generates reactive oxygen species (ROS) in nonphagocytic cells. We explored whether NOX-induced oxidative stress contributes to rod degeneration in retinas expressing constitutively active (CA) RAC1. Methods Transgenic (Tg)–CA-RAC1 mice were given apocynin (10 mg/kg, intraperitoneal), a NOX inhibitor, or vehicle daily for up to 13 weeks. Superoxide production and oxidative damage were assessed by dihydroethidium staining and by protein carbonyls and malondialdehyde levels, respectively. Outer nuclear layer (ONL) cells were counted and electroretinogram (ERG) amplitudes measured in Tg-CA-RAC1 mice. Outer nuclear layer cells were counted in wild-type (WT) mice after transfer of CA-Rac1 gene by subretinal injection of AAV8-pOpsin-CA Rac1-GFP. Results Transgenic-CA-RAC1 retinas had significantly fewer photoreceptor cells and more apoptotic ONL cells than WT controls from postnatal week (Pw) 3 to Pw13. Superoxide accumulation and protein and lipid oxidation were increased in Tg-CA-RAC1 retinas and were reduced in mice treated with apocynin. Apocynin reduced the loss of photoreceptors and increased the rod ERG a- and b-wave amplitudes when compared with vehicle-injected transgenic controls. Photoreceptor loss was also observed in regions of adult WT retina transduced with AAV8-pOpsin-CA Rac1-GFP but not in neighboring regions that were not transduced or in AAV8-pOpsin-GFP–transduced retinas. Conclusions Constitutively active RAC1 promotes photoreceptor cell death by oxidative damage that occurs, at least partially, through NOX-induced ROS. Reactive oxygen species are likely involved in multiple forms of retinal degenerations, and our results support investigating RAC1 inhibition as a therapeutic approach that targets this disease pathway. PMID:27233035

  1. Technical assistance contractor management plan: Surface and ground water

    SciTech Connect

    Not Available

    1994-09-01

    This report presents the general management structure of the Technical Assistance Contractor (TAC) for the Uranium Mill Tailings Remedial Action (UMTRA) Project. This team is a partnership of four major private subcontractors, which teamed together, are striving to be the leader in environmental restoration of uranium mining and milling operations. It will provide a pool of experts in various aspects of the technologies necessary to accomplish this goal, available to DOE to deal with mission concerns. The report expands on goals from TAC`s mission statement, which include management concerns, environment, safety, and health, quality, technical support, communications, and personnel.

  2. Contingency Contractor Optimization Phase 3 Sustainment Software Design Document - Contingency Contractor Optimization Tool - Prototype

    SciTech Connect

    Durfee, Justin David; Frazier, Christopher Rawls; Bandlow, Alisa; Jones, Katherine A.

    2016-05-01

    This document describes the final software design of the Contingency Contractor Optimization Tool - Prototype. Its purpose is to provide the overall architecture of the software and the logic behind this architecture. Documentation for the individual classes is provided in the application Javadoc. The Contingency Contractor Optimization project is intended to address Department of Defense mandates by delivering a centralized strategic planning tool that allows senior decision makers to quickly and accurately assess the impacts, risks, and mitigation strategies associated with utilizing contract support. The Contingency Contractor Optimization Tool - Prototype was developed in Phase 3 of the OSD ATL Contingency Contractor Optimization project to support strategic planning for contingency contractors. The planning tool uses a model to optimize the Total Force mix by minimizing the combined total costs for selected mission scenarios. The model optimizes the match of personnel types (military, DoD civilian, and contractors) and capabilities to meet mission requirements as effectively as possible, based on risk, cost, and other requirements.

  3. Spatio-Temporal Regulation of Rac1 Mobility by Actin Islands.

    PubMed

    Lakhani, Vinal V; Hinde, Elizabeth; Gratton, Enrico; Elston, Timothy C

    2015-01-01

    Rho GTPases play important roles in many aspects of cell migration, including polarity establishment and organizing actin cytoskeleton. In particular, the Rho GTPase Rac1 has been associated with the generation of protrusions at leading edge of migrating cells. Previously we showed the mobility of Rac1 molecules is not uniform throughout a migrating cell (Hinde E et. al. PNAS 2013). Specifically, the closer a Rac1 molecule is to the leading edge, the slower the molecule diffuses. Because actin-bound Rac1 diffuses slower than unbound Rac1, we hypothesized that regions of high actin concentration, called "actin islands", act as diffusive traps and are responsible for the non-uniform diffusion observed in vivo. Here, in silico model simulations demonstrate that equally spaced actin islands can regulate the time scale for Rac1 diffusion in a manner consistent with data from live-cell imaging experiments. Additionally, we find this mechanism is robust; different patterns of Rac1 mobility can be achieved by changing the actin islands' positions or their affinity for Rac1.

  4. Spatio-Temporal Regulation of Rac1 Mobility by Actin Islands

    PubMed Central

    Lakhani, Vinal V.; Hinde, Elizabeth; Gratton, Enrico; Elston, Timothy C.

    2015-01-01

    Rho GTPases play important roles in many aspects of cell migration, including polarity establishment and organizing actin cytoskeleton. In particular, the Rho GTPase Rac1 has been associated with the generation of protrusions at leading edge of migrating cells. Previously we showed the mobility of Rac1 molecules is not uniform throughout a migrating cell (Hinde E et. al. PNAS 2013). Specifically, the closer a Rac1 molecule is to the leading edge, the slower the molecule diffuses. Because actin-bound Rac1 diffuses slower than unbound Rac1, we hypothesized that regions of high actin concentration, called “actin islands”, act as diffusive traps and are responsible for the non-uniform diffusion observed in vivo. Here, in silico model simulations demonstrate that equally spaced actin islands can regulate the time scale for Rac1 diffusion in a manner consistent with data from live-cell imaging experiments. Additionally, we find this mechanism is robust; different patterns of Rac1 mobility can be achieved by changing the actin islands’ positions or their affinity for Rac1. PMID:26606145

  5. Rac1 is a novel regulator of contraction-stimulated glucose uptake in skeletal muscle.

    PubMed

    Sylow, Lykke; Jensen, Thomas E; Kleinert, Maximilian; Mouatt, Joshua R; Maarbjerg, Stine J; Jeppesen, Jacob; Prats, Clara; Chiu, Tim T; Boguslavsky, Shlomit; Klip, Amira; Schjerling, Peter; Richter, Erik A

    2013-04-01

    In skeletal muscle, the actin cytoskeleton-regulating GTPase, Rac1, is necessary for insulin-dependent GLUT4 translocation. Muscle contraction increases glucose transport and represents an alternative signaling pathway to insulin. Whether Rac1 is activated by muscle contraction and regulates contraction-induced glucose uptake is unknown. Therefore, we studied the effects of in vivo exercise and ex vivo muscle contractions on Rac1 signaling and its regulatory role in glucose uptake in mice and humans. Muscle Rac1-GTP binding was increased after exercise in mice (~60-100%) and humans (~40%), and this activation was AMP-activated protein kinase independent. Rac1 inhibition reduced contraction-stimulated glucose uptake in mouse muscle by 55% in soleus and by 20-58% in extensor digitorum longus (EDL; P < 0.01). In agreement, the contraction-stimulated increment in glucose uptake was decreased by 27% (P = 0.1) and 40% (P < 0.05) in soleus and EDL muscles, respectively, of muscle-specific inducible Rac1 knockout mice. Furthermore, depolymerization of the actin cytoskeleton decreased contraction-stimulated glucose uptake by 100% and 62% (P < 0.01) in soleus and EDL muscles, respectively. These are the first data to show that Rac1 is activated during muscle contraction in murine and human skeletal muscle and suggest that Rac1 and possibly the actin cytoskeleton are novel regulators of contraction-stimulated glucose uptake.

  6. Mitochondrial Dysfunction in Human Leukemic Stem/Progenitor Cells upon Loss of RAC2

    PubMed Central

    Capala, Marta E.; Maat, Henny; Bonardi, Francesco; van den Boom, Vincent; Kuipers, Jeroen; Vellenga, Edo; Giepmans, Ben N. G.; Schuringa, Jan Jacob

    2015-01-01

    Leukemic stem cells (LSCs) reside within bone marrow niches that maintain their relatively quiescent state and convey resistance to conventional treatment. Many of the microenvironmental signals converge on RAC GTPases. Although it has become clear that RAC proteins fulfill important roles in the hematopoietic compartment, little has been revealed about the downstream effectors and molecular mechanisms. We observed that in BCR-ABL-transduced human hematopoietic stem/progenitor cells (HSPCs) depletion of RAC2 but not RAC1 induced a marked and immediate decrease in proliferation, progenitor frequency, cobblestone formation and replating capacity, indicative for reduced self-renewal. Cell cycle analyses showed reduced cell cycle activity in RAC2-depleted BCR-ABL leukemic cobblestones coinciding with an increased apoptosis. Moreover, a decrease in mitochondrial membrane potential was observed upon RAC2 downregulation, paralleled by severe mitochondrial ultrastructural malformations as determined by automated electron microscopy. Proteome analysis revealed that RAC2 specifically interacted with a set of mitochondrial proteins including mitochondrial transport proteins SAM50 and Metaxin 1, and interactions were confirmed in independent co-immunoprecipitation studies. Downregulation of SAM50 also impaired the proliferation and replating capacity of BCR-ABL-expressing cells, again associated with a decreased mitochondrial membrane potential. Taken together, these data suggest an important role for RAC2 in maintaining mitochondrial integrity. PMID:26016997

  7. Zinc-Catalyzed Highly Isoselective Ring Opening Polymerization of rac-Lactide

    PubMed Central

    2015-01-01

    A family of chiral zinc amido-oxazolinate complexes are shown to be highly active and isoselective initiators for the ring-opening polymerization (ROP) of rac-lactide, yielding isotactic stereoblock polylactides (PLA) with Pm up to 0.91. This represents the highest isoselectivity observed with zinc-based catalysts for ROP of rac-lactide. PMID:25068079

  8. The levels of RAC3 expression are up regulated by TNF in the inflammatory response.

    PubMed

    Alvarado, Cecilia Viviana; Rubio, María Fernanda; Fernández Larrosa, Pablo Nicolas; Panelo, Laura Carolina; Azurmendi, Pablo Javier; Ruiz Grecco, Marina; Martínez-Nöel, Giselle Astrid; Costas, Mónica Alejandra

    2014-01-01

    RAC3 is a coactivator of glucocorticoid receptor and nuclear factor-κB (NF-κB) that is usually over-expressed in tumors and which also has important functions in the immune system. We investigated the role of the inflammatory response in the control of RAC3 expression levels in vivo and in vitro. We found that inflammation regulates RAC3 levels. In mice, sub-lethal doses of lipopolysaccharide induce the increase of RAC3 in spleen and the administration of the synthetic anti-inflammatory glucocorticoid dexamethasone has a similar effect. However, the simultaneous treatment with both stimuli is mutually antagonistic. In vitro stimulation of the HEK293 cell line with tumor necrosis factor (TNF), one of the cytokines induced by lipopolysaccharide, also increases the levels of RAC3 mRNA and protein, which correlates with an enhanced transcription dependent on the RAC3 gene promoter. We found that binding of the transcription factor NF-κB to the RAC3 gene promoter could be responsible for these effects. Our results suggest that increase of RAC3 during the inflammatory response could be a molecular mechanism involved in the control of sensitivity to both pro- and anti-inflammatory stimuli in order to maintain the normal healthy course of the immune response.

  9. Synthesis and characterization of amine-bridged bis(phenolate)lanthanide alkoxides and their application in the controlled polymerization of rac-lactide and rac-β-butyrolactone.

    PubMed

    Nie, Kun; Fang, Lei; Yao, Yingming; Zhang, Yong; Shen, Qi; Wang, Yaorong

    2012-10-15

    A series of neutral lanthanide alkoxides supported by an amine-bridged bis(phenolate) ligand were synthesized, and their catalytic behaviors for the polymerization of rac-lactide (LA) and rac-β-butyrolactone (BBL) were explored. The reactions of (C(5)H(5))(3)Ln(THF) with amine-bridged bis(phenol) LH(2) [L = Me(2)NCH(2)CH(2)N{CH(2)-(2-OC(6)H(2)Bu(t)(2)-3,5)}(2)] in a 1:1 molar ratio in THF for 1 h and then with 1 equiv each of 2,2,2-trifluoroethanol, benzyl alcohol, and 2-propanol gave the neutral lanthanide alkoxides LLn(OCH(2)CF(3))(THF) [Ln = Y (1), Yb (2), Er (3), Sm (4)], LY(OCH(2)Ph)(THF) (5), and LY(OPr(i))(THF) (6), respectively. These lanthanide alkoxides are sensitive to moisture, and the yttrium complex [(LY)(2)(μ-OPr(i))(μ-OH)] (7) was also isolated as a byproduct during the synthesis of complex 6. Complexes 1-6 were well characterized by elemental analyses and IR and NMR spectroscopy in the cases of complexes 1 and 4-6. The definitive molecular structures of all of these complexes were determined by single-crystal X-ray analysis. It was found that complexes 1-6 can initiate efficiently the ring-opening polymerization of rac-LA and rac-BBL in a controlled manner. For rac-LA, polymerization gave polymers with very narrow molecular weight distributions (PDI ≤ 1.12) and very high heterotacticity (P(r) up to 0.99). The observed activity-increasing order is in agreement with the order of the ionic radii, whereas the order for stereoselectivity is in the reverse order. For rac-BBL polymerization, the resultant polymers have narrow molecular distributions (PDI ≤ 1.26) and high syndiotacticity (P(r) up to 0.83). It is worth noting that the activity-decreasing order Yb > Er > Y > Sm is observed for rac-BBL polymerization, which is opposite to the order of ionic radii and to the order of activity for rac-LA polymerization. The ionic radii of lanthanide metals have no obvious effect on the stereoselectivity for rac-BBL polymerization, which is quite

  10. List of Contractors to Support Anthrax Remediation

    SciTech Connect

    Judd, Kathleen S.; Lesperance, Ann M.

    2010-05-14

    This document responds to a need identified by private sector businesses for information on contractors that may be qualified to support building remediation efforts following a wide-area anthrax release.

  11. Contractor and government - Teamwork and commitment

    NASA Technical Reports Server (NTRS)

    Griffin, G. D.

    1985-01-01

    Procedures being implemented at NASA to improve cooperation with contractors and increase productivity are reviewed from the NASA point of view. The goals of the U.S. space program for the coming 25 years are listed, and the importance of the commercial utilization of space in these plans is stressed. Consideration is given to the ongoing American Productivity Center White-Collar Productivity-Improvement Project, the implementation of the recommendations of the 1984 NASA/Contractor Conferences in present and future contracts, and the use of incentive contracts to create situations in which both NASA and the contractor benefit from increased productivity. Future plans call for increased industry responsibility in managing and operating the STS; steamlining of Shuttle operations; advanced design-to-cost procedures, increased commonality, better NASA-contractor communications, and more use of CAD/CAM and robotics for the Space Station; and accommodation of greatly expanded private investment and exploitation of space.

  12. Assessing Contractor Capabilities for Streamlined Site Investigations

    EPA Pesticide Factsheets

    The purpose of this document is to familiarize and encourage brownfields decision makers to investigate and employ innovative methods for characterizing their sites, to assist brownfields decision makers in assessing contractors' capabilities.

  13. Analysis of Security Contractors in Deployed Environments

    DTIC Science & Technology

    2006-12-01

    of Security Contractors in Deployed Environments 6. AUTHOR(S) Herron, Jennifer F Santiago, Gregory 5 . FUNDING NUMBERS 7. PERFORMING ORGANIZATION... 5 II. DEFINITIONS AND BACKGROUND .....................................................................7 A. DEFINITIONS...Firms..................................35 5 . Legal Authority over Security Firms ...............................................35 C

  14. Audit of the Department of Energy`s management of field contractor employees assigned to headquarters and other federal agencies

    SciTech Connect

    1997-12-05

    The Department of Energy (Department) has spent at least $76 million annually for field contractor employee support in Headquarters and other Federal agencies. The employees were to provide technical expertise and experience critical to Department operations and programs. Overall, the audit was performed to determine if the Department was managing the use of field contractor employees assigned to Headquarters and other Federal agencies. Specifically, it was to determine whether the Department reviews and evaluates the costs for the use of contractor employees, is reimbursed for contractors working at other Federal agencies, and had implemented corrective actions proposed as the result of a prior audit report on this subject. The Department did not effectively manage the use of field contractor employees assigned to Headquarters and other Federal agencies. Specifically, the Department was unable to identify all contractor employees assigned to the Washington, DC area or determine the total cost of maintaining them; some employees were providing routine support and administrative services rather than unique program expertise; and several of the Department`s contractors had assigned their employees to work in other agencies without receiving full reimbursement for their services. In addition, the Department did not fully implement the corrective actions it agreed to in the prior audit report. Recommendations were made for the Deputy Secretary based on the audit findings. 3 tabs.

  15. 76 FR 57807 - Medicaid Program; Recovery Audit Contractors

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-16

    ... Medicare RAC contracts have an established period of performance of up to 5 years, beginning in calendar... Medicaid RAC contracts covering the period of performance beginning on July 1, 2014. The established rate... proposed elements included general program descriptors (for example, contract periods of...

  16. The Drosophila small GTPase Rac2 is required for normal feeding and mating behaviour.

    PubMed

    Goergen, Philip; Kasagiannis, Anna; Schiöth, Helgi B; Williams, Michael J

    2014-03-01

    All multicellular organisms require the ability to regulate bodily processes in order to maintain a stable condition, which necessitates fluctuations in internal metabolics, as well as modifications of outward behaviour. Understanding the genetics behind this modulation is important as a general model for the metabolic modification of behaviour. This study demonstrates that the activity of the small GTPase Rac2 is required in Drosophila for the proper regulation of lipid storage and feeding behaviour, as well as aggression and mating behaviours. Rac2 mutant males and females are susceptible to starvation and contain considerably less lipids than controls. Furthermore, Rac2 mutants also have disrupted feeding behaviour, eating fewer but larger meals than controls. Intriguingly, Rac2 mutant males rarely initiate aggressive behaviour and display significantly increased levels of courtship behaviour towards other males and mated females. From these results we conclude that Rac2 has a central role in regulating the Drosophila homeostatic system.

  17. [Toxicity effects of Rac- and S-metolachlor on two algaes].

    PubMed

    Cai, Wei-Dan; Liu, Hui-Jun; Fang, Zhi-Guo

    2012-02-01

    The enantioselective toxicity of the chiral herbicides Rac- and S-metolachlor to Scenedesmus obliquus and Chlorella vulgaris was determined, and the effect of humic acid was studied by using acute toxicity testing method. The results indicated that the toxicity of Rac- and S-metolachlor increased with increasing concentration and exposure time. The EC(50, 96 h) ratio of Rac-metolachlor to S-metolachlor was 2.25 for C. vulgaris and 1.81 for S. obliquus, indicating that S-metolachlor had higher effect on two algaes, and S. obliquus was more sensitive to Rac- and S-metolachlor. Linear correlation between toxicity on S. obliquus and C. vulgaris was observed. The toxicity of Rac- and S-metolachlor changed with humic acid, with more significant change was observed in S-metolachlor (P<0.05).

  18. 48 CFR 52.247-28 - Contractor's Invoices.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 2 2010-10-01 2010-10-01 false Contractor's Invoices. 52....247-28 Contractor's Invoices. As prescribed in 47.207-9(c), insert the following clause in... services: Contractor's Invoices (APR 1984) The Contractor shall submit itemized invoices as instructed...

  19. 48 CFR 1252.242-71 - Contractor testimony.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Contractor testimony. 1252... Contractor testimony. As prescribed in (TAR) 48 CFR 1242.7000(b), insert the following clause: Contractor Testimony (OCT 1994) All requests for the testimony of the Contractor or its employees, and any intention...

  20. 14 CFR 1245.108 - License to contractor.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false License to contractor. 1245.108 Section... INTELLECTUAL PROPERTY RIGHTS Patent Waiver Regulations § 1245.108 License to contractor. (a) Each contractor.... The license extends to the contractor's domestic subsidiaries and affiliates, if any, within...

  1. 48 CFR 52.241-5 - Contractor's Facilities.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 2 2010-10-01 2010-10-01 false Contractor's Facilities....241-5 Contractor's Facilities. As prescribed in 41.501(c)(4), insert a clause substantially the same as the following: Contractor's Facilities (FEB 1995) (a) The Contractor, at its expense,...

  2. 48 CFR 52.246-1 - Contractor Inspection Requirements.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 2 2010-10-01 2010-10-01 false Contractor Inspection....246-1 Contractor Inspection Requirements. As prescribed in 46.301, insert the following clause: Contractor Inspection Requirements (APR 1984) The Contractor is responsible for performing or...

  3. 41 CFR 60-1.31 - Reinstatement of ineligible contractors.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... ineligible contractors. 60-1.31 Section 60-1.31 Public Contracts and Property Management Other Provisions..., DEPARTMENT OF LABOR 1-OBLIGATIONS OF CONTRACTORS AND SUBCONTRACTORS General Enforcement; Compliance Review and Complaint Procedure § 60-1.31 Reinstatement of ineligible contractors. A contractor debarred...

  4. 48 CFR 51.104 - Furnishing assistance to contractors.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... contractors. 51.104 Section 51.104 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION CONTRACT MANAGEMENT USE OF GOVERNMENT SOURCES BY CONTRACTORS Contractor Use of Government Supply Sources 51.104 Furnishing assistance to contractors. After receiving an activity address code, the...

  5. 30 CFR 45.3 - Identification of independent contractors.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Identification of independent contractors. 45.3... ADMINISTRATIVE REQUIREMENTS INDEPENDENT CONTRACTORS § 45.3 Identification of independent contractors. (a) Any independent contractor may obtain a permanent MSHA identification number. To obtain an identification...

  6. 41 CFR 109-38.301-1 - Contractors' use.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 41 Public Contracts and Property Management 3 2010-07-01 2010-07-01 false Contractors' use. 109-38...-38.301-1 Contractors' use. Heads of field organizations shall ensure that provisions of the FPMR concerning contractor use of Government motor vehicles are complied with by their designated contractors....

  7. 48 CFR 3009.171-8 - Ineligible contractors.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 7 2010-10-01 2010-10-01 false Ineligible contractors..., HOMELAND SECURITY ACQUISITION REGULATION (HSAR) ACQUISITION PLANNING CONTRACTOR QUALIFICATIONS Responsible Prospective Contractors 3009.171-8 Ineligible contractors. Any business concern determined to be...

  8. 48 CFR 1852.209-72 - Composition of the contractor.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... contractor. 1852.209-72 Section 1852.209-72 Federal Acquisition Regulations System NATIONAL AERONAUTICS AND... and Clauses 1852.209-72 Composition of the contractor. As prescribed in 1809.670, insert the following clause: Composition of the Contractor (DEC 1988) If the Contractor is comprised of more than one...

  9. 30 CFR 45.4 - Independent contractor register.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Independent contractor register. 45.4 Section... ADMINISTRATIVE REQUIREMENTS INDEPENDENT CONTRACTORS § 45.4 Independent contractor register. (a) Each independent contractor shall provide the production-operator in writing the following information: (1) The...

  10. 48 CFR 1552.237-76 - Government-Contractor Relations.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 6 2011-10-01 2011-10-01 false Government-Contractor... 1552.237-76 Government-Contractor Relations. As prescribed in 1537.110(g), insert the following clause: Government-Contractor Relations (JUN 1999) (a) The Government and the Contractor understand and agree...

  11. 48 CFR 52.241-5 - Contractor's Facilities.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 2 2011-10-01 2011-10-01 false Contractor's Facilities....241-5 Contractor's Facilities. As prescribed in 41.501(c)(4), insert a clause substantially the same as the following: Contractor's Facilities (FEB 1995) (a) The Contractor, at its expense,...

  12. 48 CFR 52.247-28 - Contractor's Invoices.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 2 2011-10-01 2011-10-01 false Contractor's Invoices. 52....247-28 Contractor's Invoices. As prescribed in 47.207-9(c), insert the following clause in... services: Contractor's Invoices (APR 1984) The Contractor shall submit itemized invoices as instructed...

  13. 48 CFR 242.7000 - Contractor business system deficiencies.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 3 2011-10-01 2011-10-01 false Contractor business system... BUSINESS SYSTEMS 242.7000 Contractor business system deficiencies. (a) Definitions. As used in this subpart— Acceptable contractor business systems and contractor business systems are defined in the clause at...

  14. 48 CFR 242.7000 - Contractor business system deficiencies.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 3 2014-10-01 2014-10-01 false Contractor business system... Business Systems 242.7000 Contractor business system deficiencies. (a) Definitions. As used in this subpart— Acceptable contractor business systems and contractor business systems are defined in the clause at...

  15. 48 CFR 242.7000 - Contractor business system deficiencies.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 3 2013-10-01 2013-10-01 false Contractor business system... Business Systems 242.7000 Contractor business system deficiencies. (a) Definitions. As used in this subpart— Acceptable contractor business systems and contractor business systems are defined in the clause at...

  16. 48 CFR 242.7000 - Contractor business system deficiencies.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 3 2012-10-01 2012-10-01 false Contractor business system... BUSINESS SYSTEMS 242.7000 Contractor business system deficiencies. (a) Definitions. As used in this subpart— Acceptable contractor business systems and contractor business systems are defined in the clause at...

  17. 77 FR 65927 - 60-Day Notice of Proposed Information Collection: Office of Language Services Contractor...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-31

    ... Notice of Proposed Information Collection: Office of Language Services Contractor Application Form ACTION...: LSApplications@state.gov . Mail: Department of State, Office of Language Services SA- 1, Fourteenth Floor, 2401 E....gov . SUPPLEMENTARY INFORMATION: Title of Information Collection: Office of Language...

  18. 77 FR 52107 - Air Traffic Data in the Possession of Government Contractors

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-28

    ...: Federal Aviation Administration (FAA), DOT. ACTION: Notice. SUMMARY: The recently enacted Pilot's Bill of...: A. Background On August 3, 2012, the Pilot's Bill of Rights, Public Law 112-153, was enacted. The... Government Contractors Shortly, the FAA's Internet Web page ( www.faa.gov ) will have a ``Pilot's Bill...

  19. 77 FR 22312 - Access by EPA Contractors to Confidential Business Information Related to the Greenhouse Gas...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-13

    ... AGENCY Access by EPA Contractors to Confidential Business Information Related to the Greenhouse Gas Reporting Program AGENCY: Environmental Protection Agency (EPA). ACTION: Notice. SUMMARY: EPA's Office of... to EPA under the Greenhouse Gas Reporting ] Program that may be designated or claimed as...

  20. Rac Regulates Giardia lamblia Encystation by Coordinating Cyst Wall Protein Trafficking and Secretion

    PubMed Central

    Krtková, Jana; Thomas, Elizabeth B.; Alas, Germain C. M.; Schraner, Elisabeth M.; Behjatnia, Habib R.; Hehl, Adrian B.

    2016-01-01

    ABSTRACT Encystation of the common intestinal parasite Giardia lamblia involves the production, trafficking, and secretion of cyst wall material (CWM). However, the molecular mechanism responsible for the regulation of these sequential processes remains elusive. Here, we examined the role of GlRac, Giardia’s sole Rho family GTPase, in the regulation of endomembrane organization and cyst wall protein (CWP) trafficking. Localization studies indicated that GlRac is associated with the endoplasmic reticulum (ER) and the Golgi apparatus-like encystation-specific vesicles (ESVs). Constitutive GlRac signaling increased levels of the ER marker PDI2, induced ER swelling, reduced overall CWP1 production, and promoted the early maturation of ESVs. Quantitative analysis of cells expressing constitutively active hemagglutinin (HA)-tagged GlRac (HA-RacCA) revealed fewer but larger ESVs than control cells. Consistent with the phenotype of premature maturation of ESVs in HA-RacCA-expressing cells, constitutive GlRac signaling resulted in increased CWP1 secretion and, conversely, morpholino depletion of GlRac blocked CWP1 secretion. Wild-type cells unexpectedly secreted large quantities of CWP1 into the medium, and free CWP1 was used cooperatively during cyst formation. These results, in part, could account for the previously reported observation that G. lamblia encysts more efficiently at high cell densities. These studies of GlRac show that it regulates encystation at several levels, and our findings support its coordinating role as a regulator of CWP trafficking and secretion. The central role of GlRac in regulating membrane trafficking and the cytoskeleton, both of which are essential to Giardia parasitism, further suggests its potential as a novel target for drug development to treat giardiasis. PMID:27555307

  1. Hippocampal Activation of Rac1 Regulates the Forgetting of Object Recognition Memory.

    PubMed

    Liu, Yunlong; Du, Shuwen; Lv, Li; Lei, Bo; Shi, Wei; Tang, Yikai; Wang, Lianzhang; Zhong, Yi

    2016-09-12

    Forgetting is a universal feature for most types of memories. The best-defined and extensively characterized behaviors that depict forgetting are natural memory decay and interference-based forgetting [1, 2]. Molecular mechanisms underlying the active forgetting remain to be determined for memories in vertebrates. Recent progress has begun to unravel such mechanisms underlying the active forgetting [3-11] that is induced through the behavior-dependent activation of intracellular signaling pathways. In Drosophila, training-induced activation of the small G protein Rac1 mediates natural memory decay and interference-based forgetting of aversive conditioning memory [3]. In mice, the activation of photoactivable-Rac1 in recently potentiated spines in a motor learning task erases the motor memory [12]. These lines of evidence prompted us to investigate a role for Rac1 in time-based natural memory decay and interference-based forgetting in mice. The inhibition of Rac1 activity in hippocampal neurons through targeted expression of a dominant-negative Rac1 form extended object recognition memory from less than 72 hr to over 72 hr, whereas Rac1 activation accelerated memory decay within 24 hr. Interference-induced forgetting of this memory was correlated with Rac1 activation and was completely blocked by inhibition of Rac1 activity. Electrophysiological recordings of long-term potentiation provided independent evidence that further supported a role for Rac1 activation in forgetting. Thus, Rac1-dependent forgetting is evolutionarily conserved from invertebrates to vertebrates.

  2. A function for Rac1 in the terminal differentiation and pigmentation of hair.

    PubMed

    Behrendt, Kristina; Klatte, Jennifer; Pofahl, Ruth; Bloch, Wilhelm; Smyth, Neil; Tscharntke, Michael; Krieg, Thomas; Paus, Ralf; Niessen, Carien; Niemann, Catherin; Brakebusch, Cord; Haase, Ingo

    2012-02-15

    The small GTPase Rac1 is ubiquitously expressed in proliferating and differentiating layers of the epidermis and hair follicles. Previously, Rac1 was shown to regulate stem cell behaviour in these compartments. We have asked whether Rac1 has, in addition, a specific, stem-cell-independent function in the regulation of terminal hair follicle differentiation. To address this, we have expressed a constitutively active mutant of Rac1, L61Rac1, only in the basal epidermal layer and outer root sheath of mice possessing an epidermis-specific deletion of endogenous Rac1, which experience severe hair loss. The resulting 'rescue' mice exhibited a hair coat throughout their lives. Therefore, expression of Rac1 activity in the keratin-14-positive compartment of the skin is sufficient for the formation of hair follicles and hair in normal quantities. The quality of hair formed in rescue mice was, however, not normal. Rescue mice showed a grey, dull hair coat, whereas that of wild-type and L61Rac1-transgenic mice was black and shiny. Hair analysis in rescue mice revealed altered structures of the hair shaft and the cuticle and disturbed organization of medulla cells and pigment distribution. Disorganization of medulla cells correlates with the absence of cortical, keratin-filled spikes that normally protrude from the cortex into the medulla. The desmosomal cadherin Dsc2, which normally decorates these protrusions, was found to be reduced or absent in the hair of rescue mice. Our study demonstrates regulatory functions for Rac1 in the formation of hair structure and pigmentation and thereby identifies, for the first time, a role for Rac1 in terminal differentiation.

  3. Report on audit of management and operating contractor overtime costs

    SciTech Connect

    1995-10-01

    The Department of Energy (Department) uses contractors to operate its facilities. During Fiscal Year 1994, the Department`s management and operating contractors (contractors) had a total payroll of about $6.6 billion. Of this amount, about $251 million was compensation for overtime pay. The purpose of our audit was to evaluate contractor overtime payments for compliance with applicable regulations and contract provisions. Our objective was to determine whether the Department had controls in place to monitor and manage contractor overtime use.

  4. RotundRacGAP Functions with Ras during Spermatogenesis and Retinal Differentiation in Drosophila melanogaster

    PubMed Central

    Bergeret, Evelyne; Pignot-Paintrand, Isabelle; Guichard, Annabel; Raymond, Karine; Fauvarque, Marie-Odile; Cazemajor, Michel; Griffin-Shea, Ruth

    2001-01-01

    Our analysis of rotund (rn) null mutations in Drosophila melanogaster revealed that deletion of the rn locus affects both spermatid and retinal differentiation. In the male reproductive system, the absence of RnRacGAP induced small testes, empty seminal vesicles, short testicular cysts, reduced amounts of interspermatid membrane, the absence of individualization complexes, and incomplete mitochondrial condensation. Flagellar growth continued within the short rn null cysts to produce large bulbous terminations of intertwined mature flagella. Organization of the retina was also severely perturbed as evidenced by grossly misshapen ommatidia containing reduced numbers of photoreceptor and pigment cells. These morphological phenotypes were rescued by genomic rnRacGAP transgenes, demonstrating that RnRacGAP function is critical to spermatid and retinal differentiation. The testicular phenotypes were suppressed by heterozygous hypomorphic mutations in the Dras1 and drk genes, indicating cross talk between RacGAP-regulated signaling and that of the Ras pathway. The observed genetic interactions are consistent with a model in which Rac signaling is activated by Ras and negatively regulated by RnRacGAP during spermatid differentiation. RnRacGAP and Ras cross talk also operated during retinal differentiation; however, while the heterozygous hypomorphic drk mutation continued to act as a suppressor of the rn null mutation, the heterozygous hypomorphic Dras1 mutation induced novel retinal phenotypes. PMID:11509670

  5. The Role of Rac1 in the Growth Cone Dynamics and Force Generation of DRG Neurons

    PubMed Central

    Sayyad, Wasim A.; Fabris, Paolo; Torre, Vincent

    2016-01-01

    We used optical tweezers, video imaging, immunocytochemistry and a variety of inhibitors to analyze the role of Rac1 in the motility and force generation of lamellipodia and filopodia from developing growth cones of isolated Dorsal Root Ganglia neurons. When the activity of Rac1 was inhibited by the drug EHop-016, the period of lamellipodia protrusion/retraction cycles increased and the lamellipodia retrograde flow rate decreased; moreover, the axial force exerted by lamellipodia was reduced dramatically. Inhibition of Arp2/3 by a moderate amount of the drug CK-548 caused a transient retraction of lamellipodia followed by a complete recovery of their usual motility. This recovery was abolished by the concomitant inhibition of Rac1. The filopodia length increased upon inhibition of both Rac1 and Arp2/3, but the speed of filopodia protrusion increased when Rac1 was inhibited and decreased instead when Arp2/3 was inhibited. These results suggest that Rac1 acts as a switch that activates upon inhibition of Arp2/3. Rac1 also controls the filopodia dynamics necessary to explore the environment. PMID:26766136

  6. Role of the Rho GTPase Rac in the activation of the phagocyte NADPH oxidase

    PubMed Central

    Pick, Edgar

    2014-01-01

    The superoxide-generating NADPH oxidase of phagocytes consists of the membrane-associated cytochrome b558 (a heterodimer of Nox2 and p22phox) and 4 cytosolic components: p47phox, p67phox, p40phox, and the small GTPase, Rac, in complex with RhoGDI. Superoxide is produced by the NADPH-driven reduction of molecular oxygen, via a redox gradient located in Nox2. Electron flow in Nox2 is initiated by interaction with cytosolic components, which translocate to the membrane, p67phox playing the central role. The participation of Rac is expressed in the following sequence: (1) Translocation of the RacGDP-RhoGDI complex to the membrane; (2) Dissociation of RacGDP from RhoGDI; (3) GDP to GTP exchange on Rac, mediated by a guanine nucleotide exchange factor; (4) Binding of RacGTP to p67phox; (5) Induction of a conformational change in p67phox, promoting interaction with Nox2. The particular involvement of Rac in NADPH oxidase assembly serves as a paradigm for signaling by Rho GTPases, in general. PMID:24598074

  7. Rac-null leukocytes are associated with increased inflammation-mediated alveolar bone loss.

    PubMed

    Sima, Corneliu; Gastfreund, Shoshi; Sun, Chunxiang; Glogauer, Michael

    2014-02-01

    Periodontitis is characterized by altered host-biofilm interactions that result in irreversible inflammation-mediated alveolar bone loss. Genetic and epigenetic factors that predispose to ineffective control of biofilm composition and maintenance of tissue homeostasis are not fully understood. We elucidated how leukocytes affect the course of periodontitis in Rac-null mice. Mouse models of acute gingivitis and periodontitis were used to assess the early inflammatory response and patterns of chronicity leading to loss of alveolar bone due to inflammation in Rac-null mice. Leukocyte margination was differentially impaired in these mice during attachment in conditional Rac1-null (granulocyte/monocyte lineage) mice and during rolling and attachment in Rac2-null (all blood cells) mice. Inflammatory responses to subgingival ligatures, assessed by changes in peripheral blood differential leukocyte numbers, were altered in Rac-null compared with wild-type mice. In response to persistent subgingival ligature-mediated challenge, Rac-null mice had increased loss of alveolar bone with patterns of resorption characteristic of aggressive forms of periodontitis. These findings were partially explained by higher osteoclastic coverage of the bone-periodontal ligament interface in Rac-null compared with wild-type mice. In conclusion, this study demonstrates that leukocyte defects, such as decreased endothelial margination and tissue recruitment, are rate-limiting steps in the periodontal inflammatory process that lead to more aggressive forms of periodontitis.

  8. Rac signaling in breast cancer: a tale of GEFs and GAPs.

    PubMed

    Wertheimer, Eva; Gutierrez-Uzquiza, Alvaro; Rosemblit, Cinthia; Lopez-Haber, Cynthia; Sosa, Maria Soledad; Kazanietz, Marcelo G

    2012-02-01

    Rac GTPases, small G-proteins widely implicated in tumorigenesis and metastasis, transduce signals from tyrosine-kinase, G-protein-coupled receptors (GPCRs), and integrins, and control a number of essential cellular functions including motility, adhesion, and proliferation. Deregulation of Rac signaling in cancer is generally a consequence of enhanced upstream inputs from tyrosine-kinase receptors, PI3K or Guanine nucleotide Exchange Factors (GEFs), or reduced Rac inactivation by GTPase Activating Proteins (GAPs). In breast cancer cells Rac1 is a downstream effector of ErbB receptors and mediates migratory responses by ErbB1/EGFR ligands such as EGF or TGFα and ErbB3 ligands such as heregulins. Recent advances in the field led to the identification of the Rac-GEF P-Rex1 as an essential mediator of Rac1 responses in breast cancer cells. P-Rex1 is activated by the PI3K product PIP3 and Gβγ subunits, and integrates signals from ErbB receptors and GPCRs. Most notably, P-Rex1 is highly overexpressed in human luminal breast tumors, particularly those expressing ErbB2 and estrogen receptor (ER). The P-Rex1/Rac signaling pathway may represent an attractive target for breast cancer therapy.

  9. Two Rac paralogs regulate polarized growth in the human fungal pathogen Cryptococcus neoformans

    PubMed Central

    Ballou, Elizabeth Ripley; Selvig, Kyla; Narloch, Jessica L.; Nichols, Connie B.; Alspaugh, J. Andrew

    2013-01-01

    A genome wide analysis of the human fungal pathogen Cryptococcus neoformans var. grubii has revealed a number of duplications of highly conserved genes involved in morphogenesis. Previously, we reported that duplicate Cdc42 paralogs provide C. neoformans with niche-specific responses to environmental stresses: Cdc42 is required for thermotolerance, while Cdc420 supports the formation of titan cells. The related Rho-GTPase Rac1 has been shown in C. neoformans var. neoformans to play a major role in filamentation and to share Cdc42/Cdc420 binding partners. Here we report the characterization of a second Rac paralog in C. neoformans, Rac2, and describe its overlapping function with the previously described CnRac, Rac1. Further, we demonstrate that the Rac paralogs play a primary role in polarized growth via the organization of reactive oxygen species and play only a minor role in the organization of actin. Finally, we provide preliminary evidence that pharmacological inhibitors of Rac activity and actin stability have synergistic activity. PMID:23748012

  10. Nuclear expression of Rac1 in cervical premalignant lesions and cervical cancer cells

    PubMed Central

    2012-01-01

    Background Abnormal expression of Rho-GTPases has been reported in several human cancers. However, the expression of these proteins in cervical cancer has been poorly investigated. In this study we analyzed the expression of the GTPases Rac1, RhoA, Cdc42, and the Rho-GEFs, Tiam1 and beta-Pix, in cervical pre-malignant lesions and cervical cancer cell lines. Methods Protein expression was analyzed by immunochemistry on 102 cervical paraffin-embedded biopsies: 20 without Squamous Intraepithelial Lesions (SIL), 51 Low- grade SIL, and 31 High-grade SIL; and in cervical cancer cell lines C33A and SiHa, and non-tumorigenic HaCat cells. Nuclear localization of Rac1 in HaCat, C33A and SiHa cells was assessed by cellular fractionation and Western blotting, in the presence or not of a chemical Rac1 inhibitor (NSC23766). Results Immunoreacivity for Rac1, RhoA, Tiam1 and beta-Pix was stronger in L-SIL and H-SIL, compared to samples without SIL, and it was significantly associated with the histological diagnosis. Nuclear expression of Rac1 was observed in 52.9% L-SIL and 48.4% H-SIL, but not in samples without SIL. Rac1 was found in the nucleus of C33A and SiHa cells but not in HaCat cells. Chemical inhibition of Rac1 resulted in reduced cell proliferation in HaCat, C33A and SiHa cells. Conclusion Rac1 is expressed in the nucleus of epithelial cells in SILs and cervical cancer cell lines, and chemical inhibition of Rac1 reduces cellular proliferation. Further studies are needed to better understand the role of Rho-GTPases in cervical cancer progression. PMID:22443139

  11. RacGAP1-driven focal adhesion formation promotes melanoma transendothelial migration through mediating adherens junction disassembly.

    PubMed

    Zhang, Pu; Bai, Huiyuan; Fu, Changliang; Chen, Feng; Zeng, Panying; Wu, Chengxiang; Ye, Qichao; Dong, Cheng; Song, Yang; Song, Erqun

    2015-03-27

    Melanoma cell migration across vascular endothelial cells is an essential step of tumor metastasis. Here, we provide evidence that RacGAP1, a cytokinesis-related Rho GTPase-activating protein, contributed to this process. Depletion of RacGAP1 with RacGAP1-targeting siRNA or overexpression of RacGAP1 mutant (T249A) attenuated melanoma cell transendothelial migration and concomitant changes of adherens junctions. In addition, RacGAP1 promoted the activations of RhoA, FAK, paxillin and triggered focal adhesion formation and cytoskeletal rearrangement. By overexpressing FAK-related non-kinase (FRNK) in endothelium, we showed that RacGAP1 mediated endothelial barrier function loss and melanoma transmigration in a focal adhesion-dependent manner. These results suggest that endothelial RacGAP1 may play critical roles in pathogenic processes of cancer by regulating endothelial permeability.

  12. Photolysis of rac-leucine with circularly polarized synchrotron radiation.

    PubMed

    Meierhenrich, Uwe J; Filippi, Jean-Jacques; Meinert, Cornelia; Hoffmann, Søren V; Bredehöft, Jan Hendrik; Nahon, Laurent

    2010-06-01

    Amino acids that pass the RNA machinery in living organisms occur in L-configuration. The question on the evolutionary origin of this biomolecular asymmetry remains unanswered to this day. Amino acids were detected in artificially produced interstellar ices, and L-enantiomer-enriched amino acids were identified in CM-type meteorites. This hints at a possible interstellar/circumstellar origin of the amino acids themselves as well as their stereochemical asymmetry. Based upon the current knowledge about the occurrence of circularly-polarized electromagnetic radiation in interstellar environments, we subjected rac-leucine to far-UV circularly-polarized synchrotron radiation. Asymmetric photolysis was followed by an analysis in an enantioselective GC/MS system. Here, we report on an advanced photolysis rate of more than 99% for leucine. The results indicate that high photolysis rates can occur under the chosen conditions, favoring enantioselective photolysis. In 2014, the obtained results will be reexamined by cometary mission Rosetta.

  13. Final audit report of remedial action construction at the UMTRA Project Ambrosia Lake, New Mexico, site

    SciTech Connect

    1995-09-01

    The final audit report for remedial action at the Ambrosia Lake, New Mexico, Uranium Mill Tailings Remedial Action (UMTRA) Project site consists of a summary of the radiological surveillances/audits, quality assurance (QA) in-process surveillances, and a QA final closeout inspection performed by the US Department of Energy (DOE) and the Technical Assistance Contractor (TAC). One radiological surveillance and three radiological audits were performed at the Ambrosia Lake site. The surveillance was performed on 12--16 April 1993 (DOE, 1993d). The audits were performed on 26--29 July 1993 (DOE, 1993b); 21--23 March 1994 (DOE, 1994d); and 1--2 August 1994 (DOE, 1994d). The surveillance and audits resulted in 47 observations. Twelve of the observations raised DOE concerns that were resolved on site or through subsequent corrective action. All outstanding issues were satisfactorily closed out on 28 December 1994. The radiological surveillance and audits are discussed in this report. A total of seven QA in-process surveillances were performed at the Ambrosia Lake UMTRA site are discussed. The DOE/TAC Ambrosia Lake final remedial action close-out inspection was conducted on 26 July 1995 (DOE, 1995a). To summarize, a total of 155 observations were noted during DOE/TAC audit and surveillance activities. Follow-up to responses required from the RAC for the DOE/TAC surveillance and audit observations indicated that all issues related to the Ambrosia Lake site were resolved and closed to the satisfaction of the DOE.

  14. Ground-based plasma contractor characterization

    NASA Technical Reports Server (NTRS)

    Patterson, Michael J.; Aadland, Randall S.

    1987-01-01

    Presented are recent NASA Lewis Research Center (LeRC) plasma contractor experimental results, as well as a description of the plasma contractor test facility. The operation of a 24 cm diameter plasma source with hollow cathode was investigated in the lighted-mode regime of electron current collection from 0.1 to 7.0 A. These results are compared to those obtained with a 12 cm plasma source. Full two-dimensional plasma potential profiles were constructed from emissive probe traces of the contractor plume. The experimentally measured dimensions of the plume sheaths were then compared to those theoretically predicted using a model of a spherical double sheath. Results are consistent for currents up to approximately 1.0 A. For currents above 1.0 A, substantial deviations from theory occur. These deviations are due to sheath asphericity, and possibly volume ionization in the double-sheath region.

  15. RCP-driven α5β1 recycling suppresses Rac and promotes RhoA activity via the RacGAP1-IQGAP1 complex.

    PubMed

    Jacquemet, Guillaume; Green, David M; Bridgewater, Rebecca E; von Kriegsheim, Alexander; Humphries, Martin J; Norman, Jim C; Caswell, Patrick T

    2013-09-16

    Inhibition of αvβ3 or expression of mutant p53 promotes invasion into fibronectin (FN)-containing extracellular matrix (ECM) by enhancing Rab-coupling protein (RCP)-dependent recycling of α5β1 integrin. RCP and α5β1 cooperatively recruit receptor tyrosine kinases, including EGFR1, to regulate their trafficking and downstream signaling via protein kinase B (PKB)/Akt, which, in turn, promotes invasive migration. In this paper, we identify a novel PKB/Akt substrate, RacGAP1, which is phosphorylated as a consequence of RCP-dependent α5β1 trafficking. Phosphorylation of RacGAP1 promotes its recruitment to IQGAP1 at the tips of invasive pseudopods, and RacGAP1 then locally suppresses the activity of the cytoskeletal regulator Rac and promotes the activity of RhoA in this subcellular region. This Rac to RhoA switch promotes the extension of pseudopodial processes and invasive migration into FN-containing matrices, in a RhoA-dependent manner. Thus, the localized endocytic trafficking of α5β1 within the tips of invasive pseudopods elicits signals that promote the reorganization of the actin cytoskeleton, protrusion, and invasion into FN-rich ECM.

  16. ARF1 and ARF6 regulate recycling of GRASP/Tamalin and the Rac1-GEF Dock180 during HGF-induced Rac1 activation.

    PubMed

    Koubek, Emily J; Santy, Lorraine C

    2016-08-12

    Hepatocyte growth factor (HGF) is a potent signaling factor that acts on epithelial cells, causing them to dissociate and scatter. This migration is coordinated by a number of small GTPases, such as ARF6 and Rac1. Active ARF6 is required for HGF-stimulated migration and intracellular levels of ARF6-GTP and Rac1-GTP increase following HGF treatment. During migration, cross talk between ARF6 and Rac1 occurs through formation of a multi-protein complex containing the ARF-GEF cytohesin-2, the scaffolding protein GRASP/Tamalin, and the Rac1-GEF Dock180. Previously, the role of ARF6 in this process was unclear. We have now found that ARF6 and ARF1 regulate trafficking of GRASP and Dock180 to the plasma membrane following HGF treatment. Trafficking of GRASP and Dock180 is impaired by blocking ARF6-mediated recycling pathways and is required for HGF-stimulated Rac1 activation. Finally, HGF treatment stimulates association of GRASP and Dock180. Inhibition of ARF6 trafficking pathways traps GRASP and Dock180 as a complex in the cell.

  17. Management of government personal property in the hands of contractors. Handbook for contracting officers and staff

    SciTech Connect

    Not Available

    1982-04-01

    This manual is divided into three parts. Part One applies to the management of Government personal property within the Department of Energy in general terms. Part Two describes the specifics of the application of personal property management techniques to On-Site Contractors. Part three applies to Off-Site Contractors. Part One introduces the field of property management. It discusses: the legal basis and requirements established by Federal Statutes and the parallel authorities and responsibilities; the related evolution of the Department of Energy; the regulation system within the Federal Government and its implementation by the Department for personal property management. The life cycle of equipment is presented and how control over personal property is maintained through an accountability system. Classifications of property and contract clauses are discussed. The relationships of contracting officers and property administrators with contractors are presented in each of the discussions as appropriate. Part One consists of only one chapter and is applicable to the management of property utilized by all types of contractors. It provides the foundation to explore in some detail the actions and interactions that occur between the Department's procurement and property personnel and those of the contractor. This exploration in depth is made in Parts Two and Three.

  18. Rac1 Is a Critical Mediator of Endothelium-Derived Neurotrophic Activity

    PubMed Central

    Sawada, Naoki; Kim, Hyung-Hwan; Moskowitz, Michael A.; Liao, James K.

    2009-01-01

    The therapeutic potential of neurotrophic factors has been hampered by their inability to achieve adequate tissue penetration. Brain blood vessels, however, could be an alternative target for neuro-salvage therapies by virtue of their close proximity to neurons. Here we show that hemizygous deletion of Rac1 in mouse endothelial cells (ECs) attenuates brain injury and edema after focal cerebral ischemia. Microarray analysis of Rac1+/− ECs revealed enrichment of stress response genes, basement membrane components, and neurotrophic factors that could affect neuronal survival. Consistent with these expression profiles, endothelial Rac1 hemizygosity enhanced antioxidative and endothelial barrier capacities and potentiated paracrine neuroprotective activities through the up-regulation of the neurotrophic factor, artemin. Endothelial Rac1, therefore, could be an important therapeutic target for promoting endothelial barrier integrity and neurotrophic activity. PMID:19278959

  19. Regulation of lymphatic-blood vessel separation by endothelial Rac1

    PubMed Central

    D'Amico, Gabriela; Jones, Dylan T.; Nye, Emma; Sapienza, Karen; Ramjuan, Antoine R.; Reynolds, Louise E.; Robinson, Stephen D.; Kostourou, Vassiliki; Martinez, Dolores; Aubyn, Deborah; Grose, Richard; Thomas, Gareth J.; Spencer-Dene, Bradley; Zicha, Daniel; Davies, Derek; Tybulewicz, Victor; Hodivala-Dilke, Kairbaan M.

    2009-01-01

    Sprouting angiogenesis and lymphatic-blood vessel segregation both involve the migration of endothelial cells, but the precise migratory molecules that govern the decision of blood vascular endothelial cells to segregate into lymphatic vasculature are unknown. Here, we deleted endothelial Rac1 in mice (Tie1-Cre+;Rac1fl/fl) and revealed, unexpectedly, that whereas blood vessel morphology appeared normal, lymphatic-blood vessel separation was impaired, with corresponding edema, haemorrhage and embryonic lethality. Importantly, normal levels of Rac1 were essential for directed endothelial cell migratory responses to lymphatic-inductive signals. Our studies identify Rac1 as a crucial part of the migratory machinery required for endothelial cells to separate and form lymphatic vasculature. PMID:19906871

  20. Novel aspects of the roles of Rac1 GTPase in the cardiovascular system.

    PubMed

    Sawada, Naoki; Li, Yuxin; Liao, James K

    2010-04-01

    Rac1 GTPase is an established master regulator of cell motility through cortical actin re-organization and of reactive oxygen species generation through regulation of NADPH oxidase activity. Numerous molecular and cellular studies have implicated Rac1 in various cardiovascular pathologies: vascular smooth muscle proliferation, cardiomyocyte hypertrophy, and endothelial cell shape change. The physiological relevance of these in vitro findings, however, is just beginning to be reassessed with the newly developed, conditional mouse mutagenesis technology. Conditional gene targeting has also revealed unexpected, cell type-specific roles of Rac1. The aim of this review is to summarize the recent advance made in Rac1 research in the cardiovascular system, with special focus on its novel roles in the regulation of endothelial function, angiogenesis, and endothelium-mediated neuroprotection.

  1. 75 FR 69037 - Medicaid Program; Recovery Audit Contractors

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-10

    ... participate in the Medicaid program, all States, the District of Columbia, and the territories do participate... RAC to hire a physician Medical Director to oversee the medical record review process; assist...

  2. RAC1b overexpression stimulates proliferation and NF-kB-mediated anti-apoptotic signaling in thyroid cancer cells.

    PubMed

    Faria, Márcia; Matos, Paulo; Pereira, Teresa; Cabrera, Rafael; Cardoso, Bruno A; Bugalho, Maria João; Silva, Ana Luísa

    2017-01-01

    Overexpression of tumor-associated RAC1b has been recently highlighted as one of the most promising targets for therapeutic intervention in colon, breast, lung and pancreatic cancer. RAC1b is a hyperactive variant of the small GTPase RAC1 and has been recently shown to be overexpressed in a subset of papillary thyroid carcinomas associated with unfavorable outcome. Using the K1 PTC derived cell line as an in vitro model, we observed that both RAC1 and RAC1b were able to induce a significant increase on NF-kB and cyclin D1 reporter activity. A clear p65 nuclear localization was found in cells transfected with RAC1b-WT, confirming NF-kB canonical pathway activation. Consistently, we observed a RAC1b-mediated decrease in IκBα (NF-kB inhibitor) protein levels. Moreover, we show that RAC1b overexpression stimulates G1/S progression and protects thyroid cells against induced apoptosis, the latter through a process involving the NF-kB pathway. Present data support previous findings suggesting an important role for RAC1b in the development of follicular cell-derived thyroid malignancies and point out NF-kB activation as one of the molecular mechanisms associated with the pro-tumorigenic advantage of RAC1b overexpression in thyroid carcinomas.

  3. Epidermal growth factor stimulates Rac activation through Src and phosphatidylinositol 3-kinase to promote colonic epithelial cell migration.

    PubMed

    Dise, Rebecca S; Frey, Mark R; Whitehead, Robert H; Polk, D Brent

    2008-01-01

    Regulated intestinal epithelial cell migration plays a key role in wound healing and maintenance of a healthy gastrointestinal tract. Epidermal growth factor (EGF) stimulates cell migration and wound closure in intestinal epithelial cells through incompletely understood mechanisms. In this study we investigated the role of the small GTPase Rac in EGF-induced cell migration using an in vitro wound-healing assay. In mouse colonic epithelial (MCE) cell lines, EGF-stimulated wound closure was accompanied by a doubling of the number of cells containing lamellipodial extensions at the wound margin, increased Rac membrane translocation in cells at the wound margin, and rapid Rac activation. Either Rac1 small interfering (si)RNA or a Rac1 inhibitor completely blocked EGF-stimulated wound closure. Whereas EGF failed to activate Rac in colon cells from EGF receptor (EGFR) knockout mice, stable expression of wild-type EGFR restored EGF-stimulated Rac activation and migration. Pharmacological inhibition of either phosphatidylinositol 3-kinase (PI3K) or Src family kinases reduced EGF-stimulated Rac activation. Cotreatment of cells with both inhibitors completely blocked EGF-stimulated Rac activation and localization to the leading edge of cells and lamellipodial extension. Our results present a novel mechanism by which the PI3K and Src signaling cascades cooperate to activate Rac and promote intestinal epithelial cell migration downstream of EGFR.

  4. RAC1b overexpression stimulates proliferation and NF-kB-mediated anti-apoptotic signaling in thyroid cancer cells

    PubMed Central

    Faria, Márcia; Matos, Paulo; Pereira, Teresa; Cabrera, Rafael; Cardoso, Bruno A.; Bugalho, Maria João

    2017-01-01

    Overexpression of tumor-associated RAC1b has been recently highlighted as one of the most promising targets for therapeutic intervention in colon, breast, lung and pancreatic cancer. RAC1b is a hyperactive variant of the small GTPase RAC1 and has been recently shown to be overexpressed in a subset of papillary thyroid carcinomas associated with unfavorable outcome. Using the K1 PTC derived cell line as an in vitro model, we observed that both RAC1 and RAC1b were able to induce a significant increase on NF-kB and cyclin D1 reporter activity. A clear p65 nuclear localization was found in cells transfected with RAC1b-WT, confirming NF-kB canonical pathway activation. Consistently, we observed a RAC1b-mediated decrease in IκBα (NF-kB inhibitor) protein levels. Moreover, we show that RAC1b overexpression stimulates G1/S progression and protects thyroid cells against induced apoptosis, the latter through a process involving the NF-kB pathway. Present data support previous findings suggesting an important role for RAC1b in the development of follicular cell-derived thyroid malignancies and point out NF-kB activation as one of the molecular mechanisms associated with the pro-tumorigenic advantage of RAC1b overexpression in thyroid carcinomas. PMID:28234980

  5. Regulation of Rac1 and Reactive Oxygen Species Production in Response to Infection of Gastrointestinal Epithelia.

    PubMed

    den Hartog, Gerco; Chattopadhyay, Ranajoy; Ablack, Amber; Hall, Emily H; Butcher, Lindsay D; Bhattacharyya, Asima; Eckmann, Lars; Harris, Paul R; Das, Soumita; Ernst, Peter B; Crowe, Sheila E

    2016-01-01

    Generation of reactive oxygen species (ROS) during infection is an immediate host defense leading to microbial killing. APE1 is a multifunctional protein induced by ROS and after induction, protects against ROS-mediated DNA damage. Rac1 and NAPDH oxidase (Nox1) are important contributors of ROS generation following infection and associated with gastrointestinal epithelial injury. The purpose of this study was to determine if APE1 regulates the function of Rac1 and Nox1 during oxidative stress. Gastric or colonic epithelial cells (wild-type or with suppressed APE1) were infected with Helicobacter pylori or Salmonella enterica and assessed for Rac1 and NADPH oxidase-dependent superoxide production. Rac1 and APE1 interactions were measured by co-immunoprecipitation, confocal microscopy and proximity ligation assay (PLA) in cell lines or in biopsy specimens. Significantly greater levels of ROS were produced by APE1-deficient human gastric and colonic cell lines and primary gastric epithelial cells compared to control cells after infection with either gastric or enteric pathogens. H. pylori activated Rac1 and Nox1 in all cell types, but activation was higher in APE1 suppressed cells. APE1 overexpression decreased H. pylori-induced ROS generation, Rac1 activation, and Nox1 expression. We determined that the effects of APE1 were mediated through its N-terminal lysine residues interacting with Rac1, leading to inhibition of Nox1 expression and ROS generation. APE1 is a negative regulator of oxidative stress in the gastrointestinal epithelium during bacterial infection by modulating Rac1 and Nox1. Our results implicate APE1 in novel molecular interactions that regulate early stress responses elicited by microbial infections.

  6. Distinct Effects of Rac1 on Differentiation of Primary Avian Myoblasts

    PubMed Central

    Gallo, Rita; Serafini, Marco; Castellani, Loriana; Falcone, Germana; Alemà, Stefano

    1999-01-01

    Rho family GTPases have been implicated in the regulation of the actin cytoskeleton in response to extracellular cues and in the transduction of signals from the membrane to the nucleus. Their role in development and cell differentiation, however, is little understood. Here we show that the transient expression of constitutively active Rac1 and Cdc42 in unestablished avian myoblasts is sufficient to cause inhibition of myogenin expression and block of the transition to the myocyte compartment, whereas activated RhoA affects myogenic differentiation only marginally. Activation of c-Jun N-terminal kinase (JNK) appears not to be essential for block of differentiation because, although Rac1 and Cdc42 GTPases modestly activate JNK in quail myoblasts, a Rac1 mutant defective for JNK activation can still inhibit myogenic differentiation. Stable expression of active Rac1, attained by infection with a recombinant retrovirus, is permissive for terminal differentiation, but the resulting myotubes accumulate severely reduced levels of muscle-specific proteins. This inhibition is the consequence of posttranscriptional events and suggests the presence of a novel level of regulation of myogenesis. We also show that myotubes expressing constitutively active Rac1 fail to assemble ordered sarcomeres. Conversely, a dominant-negative Rac1 variant accelerates sarcomere maturation and inhibits v-Src–induced selective disassembly of I-Z-I complexes. Collectively, our findings provide a role for Rac1 during skeletal muscle differentiation and strongly suggest that Rac1 is required downstream of v-Src in the signaling pathways responsible for the dismantling of tissue-specific supramolecular structures. PMID:10512856

  7. A Minimal Rac Activation Domain in the Unconventional Guanine Nucleotide Exchange Factor Dock180†

    PubMed Central

    Wu, Xin; Ramachandran, Sekar; Cerione, Richard A.; Erickson, Jon W.

    2011-01-01

    Guanine nucleotide exchange factors (GEFs) activate Rho GTPases by catalyzing the exchange of bound GDP for GTP, thereby resulting in downstream effector recognition. Two metazoan families of GEFs have been described: Dbl-GEF family members that share conserved Dbl homology (DH) and Pleckstrin homology (PH) domains and the more recently described Dock180 family members that share little sequence homology with the Dbl family and are characterized by conserved Dock homology regions 1 and 2 (DHR-1 and -2). While extensive characterization of the Dbl family has been performed, less is known about how Dock180 family members act as GEFs, with only a single x-ray structure having recently been reported for the Dock9-Cdc42 complex. In order to learn more about the mechanisms used by the founding member of the family, Dock180, to act as a Rac-specific GEF, we set out to identify and characterize its limit functional GEF domain. A C-terminal portion of the DHR-2 domain, composed of approximately 300 residues (designated as Dock180DHR-2c), is shown to be necessary and sufficient for robust Rac-specific GEF activity both in vitro and in vivo. We further show that Dock180DHR-2c binds to Rac in a manner distinct from Rac-GEFs of the Dbl family. Specifically, Ala27 and Trp56 of Rac appear to provide a bipartite binding site for the specific recognition of Dock180DHR-2c, whereas, for Dbl family Rac-GEFs, Trp56 of Rac is the sole primary determinant of GEF specificity. Based on our findings, we are able to define the core of Dock180 responsible for its Rac-GEF activity as well as highlight key recognition sites that distinguish different Dock180 family members and determine their corresponding GTPase specificities. PMID:21033699

  8. Inhibition of Rac GTPases in the Therapy of Chronic Myelogenous Leukemia

    DTIC Science & Technology

    2008-04-01

    subcellular localization of the GTPase Rac3. In ‘‘Proceedings of the Small GTPase Meeting Snowmass’’ (T. S. R. Institute, ed.). La Jolla, CA. Burridge...cell localization . Methods Enzymol 2008;439:365-93. 3. Thomas EK*, Cancelas JA*, Chae H-D, Cox AD, Keller PJ, Perrotti D, Neviani, Druker BJ...302(5644): p. 445-9. 33. Cancelas, J.A., et al., Rac GTPases differentially integrate signals regulating hematopoietic stem cell localization . Nat

  9. Remedial Strategies in Structural Proteomics: Expression, Purification and Crystallization of the Vav1/Rac1 Complex

    PubMed Central

    Brooun, Alexei; Foster, Scott A.; Chrencik, Jill E.; Chien, Ellen Y.T.; Kolatkar, Anand R.; Streiff, Markus; Ramage, Paul; Widmer, Hans; Weckbecker, Gisbert; Kuhn, Peter

    2007-01-01

    The signal transduction pathway involving the Vav1 guanine nucleotide exchange factor (GEF) and the Rac1 GTPase plays several key roles in the immune response mediated by the T cell receptor. Vav1 is also a unique member of the GEF family in that it contains a cysteine-rich domain (CRD) that is critical for Rac1 binding and maximal guanine nucleotide exchange activity, and thus may provide a unique protein-protein interface compared to other GEF/GTPase pairs. Here we have applied a number of remedial structural proteomics strategies, such as construct and expression optimization, surface mutagenesis, limited proteolysis, and protein formulation to successfully express, purify, and crystallize the Vav1-DH-PH-CRD/Rac1 complex in an active conformation. We have also systematically characterized various Vav1 domains in a GEF assay, and Rac1 in vitro binding experiments. In the context of Vav1-DH-PH-CRD, the zinc finger motif of the CRD is required for the expression of stable Vav1, as well as for activity in both a GEF assay and in vitro formation of a Vav1/Rac1 complex suitable for biophysical and structural characterization. Our data also indicate that the isolated CRD maintains a low level of specific binding to Rac1, appears to be folded based on 1D-NMR analysis and coordinates two zinc ions based on ICP-MS analysis. The protein reagents generated here are essential tools for the determination of a three dimensional Vav1/Rac1 complex crystal structure and possibly for the identification of inhibitors of the Vav1/Rac1 protein-protein interaction with potential to inhibit lymphocyte activation. PMID:17275330

  10. Regulation of Rac1 and Reactive Oxygen Species Production in Response to Infection of Gastrointestinal Epithelia

    PubMed Central

    Ablack, Amber; Hall, Emily H.; Butcher, Lindsay D.; Bhattacharyya, Asima; Eckmann, Lars; Harris, Paul R.; Das, Soumita; Ernst, Peter B.; Crowe, Sheila E.

    2016-01-01

    Generation of reactive oxygen species (ROS) during infection is an immediate host defense leading to microbial killing. APE1 is a multifunctional protein induced by ROS and after induction, protects against ROS-mediated DNA damage. Rac1 and NAPDH oxidase (Nox1) are important contributors of ROS generation following infection and associated with gastrointestinal epithelial injury. The purpose of this study was to determine if APE1 regulates the function of Rac1 and Nox1 during oxidative stress. Gastric or colonic epithelial cells (wild-type or with suppressed APE1) were infected with Helicobacter pylori or Salmonella enterica and assessed for Rac1 and NADPH oxidase-dependent superoxide production. Rac1 and APE1 interactions were measured by co-immunoprecipitation, confocal microscopy and proximity ligation assay (PLA) in cell lines or in biopsy specimens. Significantly greater levels of ROS were produced by APE1-deficient human gastric and colonic cell lines and primary gastric epithelial cells compared to control cells after infection with either gastric or enteric pathogens. H. pylori activated Rac1 and Nox1 in all cell types, but activation was higher in APE1 suppressed cells. APE1 overexpression decreased H. pylori-induced ROS generation, Rac1 activation, and Nox1 expression. We determined that the effects of APE1 were mediated through its N-terminal lysine residues interacting with Rac1, leading to inhibition of Nox1 expression and ROS generation. APE1 is a negative regulator of oxidative stress in the gastrointestinal epithelium during bacterial infection by modulating Rac1 and Nox1. Our results implicate APE1 in novel molecular interactions that regulate early stress responses elicited by microbial infections. PMID:26761793

  11. Epidermal Rac1 regulates the DNA damage response and protects from UV-light-induced keratinocyte apoptosis and skin carcinogenesis.

    PubMed

    Deshmukh, Jayesh; Pofahl, Ruth; Haase, Ingo

    2017-03-09

    Non-melanoma skin cancer (NMSC) is the most common type of cancer. Increased expression and activity of Rac1, a small Rho GTPase, has been shown previously in NMSC and other human cancers; suggesting that Rac1 may function as an oncogene in skin. DMBA/TPA skin carcinogenesis studies in mice have shown that Rac1 is required for chemically induced skin papilloma formation. However, UVB radiation by the sun, which causes DNA damage, is the most relevant cause for NMSC. A potential role of Rac1 in UV-light-induced skin carcinogenesis has not been investigated so far. To investigate this, we irradiated mice with epidermal Rac1 deficiency (Rac1-EKO) and their controls using a well-established protocol for long-term UV-irradiation. Most of the Rac1-EKO mice developed severe skin erosions upon long-term UV-irradiation, unlike their controls. These skin erosions in Rac1-EKO mice healed subsequently. Surprisingly, we observed development of squamous cell carcinomas (SCCs) within the UV-irradiation fields. This shows that the presence of Rac1 in the epidermis protects from UV-light-induced skin carcinogenesis. Short-term UV-irradiation experiments revealed increased UV-light-induced apoptosis of Rac1-deficient epidermal keratinocytes in vitro as well as in vivo. Further investigations using cyclobutane pyrimidine dimer photolyase transgenic mice revealed that the observed increase in UV-light-induced keratinocyte apoptosis in Rac1-EKO mice is DNA damage dependent and correlates with caspase-8 activation. Furthermore, Rac1-deficient keratinocytes showed reduced levels of p53, γ-H2AX and p-Chk1 suggesting an attenuated DNA damage response upon UV-irradiation. Taken together, our data provide direct evidence for a protective role of Rac1 in UV-light-induced skin carcinogenesis and keratinocyte apoptosis probably through regulating mechanisms of the DNA damage response and repair pathways.

  12. Environmental Cleanup: Defense Indemnification for Contractor Operations.

    DTIC Science & Technology

    1994-11-25

    The Comprehensive Environmental Response and Liability Act ( CERCLA ) as amended, commonly known as Superfund (42 U.S.C. 9601-75), imposes liability... CERCLA , DoD is included among parties responsible for environmental cleanup of its facilities. If DoD pays cleaup costs related to a contractor’s

  13. 24 CFR 242.53 - Excluded contractors.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... construction of the project shall not be made with any person or entity that has been excluded from... construction manager (or any firm, corporation, partnership, or association in which such contractor... excluded parties maintained by HUD. (b) Contracts relating to the construction of the project shall not...

  14. 28 CFR 513.36 - Government contractors.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 28 Judicial Administration 2 2012-07-01 2012-07-01 false Government contractors. 513.36 Section 513.36 Judicial Administration BUREAU OF PRISONS, DEPARTMENT OF JUSTICE GENERAL MANAGEMENT AND ADMINISTRATION ACCESS TO RECORDS Release of Information General Provisions and Procedures § 513.36...

  15. 28 CFR 513.36 - Government contractors.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 28 Judicial Administration 2 2013-07-01 2013-07-01 false Government contractors. 513.36 Section 513.36 Judicial Administration BUREAU OF PRISONS, DEPARTMENT OF JUSTICE GENERAL MANAGEMENT AND ADMINISTRATION ACCESS TO RECORDS Release of Information General Provisions and Procedures § 513.36...

  16. 28 CFR 513.36 - Government contractors.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 28 Judicial Administration 2 2014-07-01 2014-07-01 false Government contractors. 513.36 Section 513.36 Judicial Administration BUREAU OF PRISONS, DEPARTMENT OF JUSTICE GENERAL MANAGEMENT AND ADMINISTRATION ACCESS TO RECORDS Release of Information General Provisions and Procedures § 513.36...

  17. 28 CFR 513.36 - Government contractors.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 28 Judicial Administration 2 2011-07-01 2011-07-01 false Government contractors. 513.36 Section 513.36 Judicial Administration BUREAU OF PRISONS, DEPARTMENT OF JUSTICE GENERAL MANAGEMENT AND ADMINISTRATION ACCESS TO RECORDS Release of Information General Provisions and Procedures § 513.36...

  18. 48 CFR 1602.170-4 - Contractor.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 6 2010-10-01 2010-10-01 true Contractor. 1602.170-4 Section 1602.170-4 Federal Acquisition Regulations System OFFICE OF PERSONNEL MANAGEMENT FEDERAL EMPLOYEES HEALTH BENEFITS ACQUISITION REGULATION GENERAL DEFINITIONS OF WORDS AND TERMS Definitions of FEHBP...

  19. 78 FR 29247 - Contractor Legal Management Requirements; Acquisition Regulations; Correction

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-20

    ..., on May 14, 2013. Paul Bosco, Director, Office of Acquisition and Project Management. BILLING CODE... Part 952 RIN 1990-AA37 Contractor Legal Management Requirements; Acquisition Regulations; Correction..., DOE revised existing regulations covering contractor legal management requirements....

  20. 48 CFR 1004.470 - Investigative Requirements for Contractors.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Investigative Requirements for Contractors. 1004.470 Section 1004.470 Federal Acquisition Regulations System DEPARTMENT OF THE... Investigative Requirements for Contractors....

  1. 78 FR 1256 - Guam Military Base Realignment Contractor Recruitment Standards

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-01-08

    ... Employment and Training Administration Guam Military Base Realignment Contractor Recruitment Standards AGENCY... for Guam military base realignment projects funded through the National Defense Authorization Act... end of this Federal Register Notice). I. Guam Military Base Realignment Contractor...

  2. 48 CFR 1845.7210 - Contractor utilization of Government property.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 6 2010-10-01 2010-10-01 true Contractor utilization of Government property. 1845.7210 Section 1845.7210 Federal Acquisition Regulations System NATIONAL AERONAUTICS....7210 Contractor utilization of Government property....

  3. 48 CFR 645.608 - Screening of contractor inventory.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... inventory. 645.608 Section 645.608 Federal Acquisition Regulations System DEPARTMENT OF STATE CONTRACT MANAGEMENT GOVERNMENT PROPERTY Reporting, Redistribution, and Disposal of Contractor Inventory 645.608 Screening of contractor inventory....

  4. 48 CFR 645.608 - Screening of contractor inventory.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... inventory. 645.608 Section 645.608 Federal Acquisition Regulations System DEPARTMENT OF STATE CONTRACT MANAGEMENT GOVERNMENT PROPERTY Reporting, Redistribution, and Disposal of Contractor Inventory 645.608 Screening of contractor inventory....

  5. Adenylyl cyclase localization to the uropod of aggregating Dictyostelium cells requires RacC

    PubMed Central

    Wang, C.; Jung, D.; Cao, Z.; Chung, C. Y.

    2015-01-01

    The localization of adenylyl cyclase A (ACA) to uropod of cells is required for the stream formation during Dictyostelium development. RacC is a Dictyostelium orthologue of Cdc42. We identified a streaming defect of racC− cells as they are clearly less polarized and form smaller and fragmented streams. ACA-YFP is mainly associated with intracellular vesicular structures, but not with the plasma membrane in racC− cells. racC− cells have a slightly higher number of vesicles than Ax3 cells, suggesting that the defect of ACA trafficking is not simply due to the lack of vesicle formation. While the ACA-YFP vesicles traveled with an average velocity of 9.1 µm/min in Ax3 cells, a slow and diffusional movement without direction with an average velocity of 4 µm/min was maintained in racC− cells. Images acquired by using total internal reflection fluorescence (TIRF) microscopy and fluorescence recovery after photobleaching (FRAP) analysis revealed that a significantly decreased number of ACA-YFP vesicles appeared near the cell membrane, indicating a defect in ACA-YFP vesicle trafficking. These results suggest an important role of RacC in the rapid and directional movements of ACA vesicles on microtubules to the plasma membrane, especially to the back of polarized cell. PMID:26315268

  6. Adenylyl cyclase localization to the uropod of aggregating Dictyostelium cells requires RacC.

    PubMed

    Wang, C; Jung, D; Cao, Z; Chung, C Y

    2015-09-25

    The localization of adenylyl cyclase A (ACA) to uropod of cells is required for the stream formation during Dictyostelium development. RacC is a Dictyostelium orthologue of Cdc42. We identified a streaming defect of racC(-) cells as they are clearly less polarized and form smaller and fragmented streams. ACA-YFP is mainly associated with intracellular vesicular structures, but not with the plasma membrane in racC(-) cells. racC(-) cells have a slightly higher number of vesicles than Ax3 cells, suggesting that the defect of ACA trafficking is not simply due to the lack of vesicle formation. While the ACA-YFP vesicles traveled with an average velocity of 9.1 μm/min in Ax3 cells, a slow and diffusional movement without direction with an average velocity of 4 μm/min was maintained in racC(-) cells. Images acquired by using total internal reflection fluorescence (TIRF) microscopy and fluorescence recovery after photobleaching (FRAP) analysis revealed that a significantly decreased number of ACA-YFP vesicles appeared near the cell membrane, indicating a defect in ACA-YFP vesicle trafficking. These results suggest an important role of RacC in the rapid and directional movements of ACA vesicles on microtubules to the plasma membrane, especially to the back of polarized cell.

  7. Fluctuation-based imaging of nuclear Rac1 activation by protein oligomerisation

    PubMed Central

    Hinde, Elizabeth; Yokomori, Kyoko; Gaus, Katharina; Hahn, Klaus M.; Gratton, Enrico

    2014-01-01

    Here we describe a fluctuation-based method to quantify how protein oligomerisation modulates signalling activity of a multifunctional protein. By recording fluorescence lifetime imaging microscopy (FLIM) data of a FRET biosensor in a format that enables concomitant phasor and cross Number and Brightness (cN&B) analysis, we measure the nuclear dynamics of a Rac1 FRET biosensor and assess how Rac1 homo-oligomers (N&B) regulate Rac1 activity (hetero-oligomerisation with the biosensor affinity reagent, PBD, by FLIM-FRET) or interaction with an unknown binding partner (cN&B). The high spatiotemporal resolution of this method allowed us to discover that upon DNA damage monomeric and active Rac1 in the nucleus is segregated from dimeric and inactive Rac1 in the cytoplasm. This reorganisation requires Rac1 GTPase activity and is associated with an importin-α2 redistribution. Only with this multiplexed approach can we assess the oligomeric state a molecular complex must form in order to regulate a complex signalling network. PMID:24573109

  8. PLC-gamma1 and Rac1 coregulate EGF-induced cytoskeleton remodeling and cell migration.

    PubMed

    Li, Siwei; Wang, Qian; Wang, Yi; Chen, Xinmei; Wang, Zhixiang

    2009-06-01

    It is well established that epidermal growth factor (EGF) induces the cytoskeleton reorganization and cell migration through two major signaling cascades: phospholipase C-gamma1 (PLC-gamma1) and Rho GTPases. However, little is known about the cross talk between PLC-gamma1 and Rho GTPases. Here we showed that PLC-gamma1 forms a complex with Rac1 in response to EGF. This interaction is direct and mediated by PLC-gamma1 Src homology 3 (SH3) domain and Rac1 (106)PNTP(109) motif. This interaction is critical for EGF-induced Rac1 activation in vivo, and PLC-gamma1 SH3 domain is actually a potent and specific Rac1 guanine nucleotide exchange factor in vitro. We have also demonstrated that the interaction between PLC-gamma1 SH3 domain and Rac1 play a significant role in EGF-induced F-actin formation and cell migration. We conclude that PLC-gamma1 and Rac1 coregulate EGF-induced cell cytoskeleton remodeling and cell migration by a direct functional interaction.

  9. Rac1 functions as a reversible tension modulator to stabilize VE-cadherin trans-interaction

    PubMed Central

    Daneshjou, Nazila; Sieracki, Nathan; van Nieuw Amerongen, Geerten P.; Conway, Daniel E.; Schwartz, Martin A.

    2015-01-01

    The role of the RhoGTPase Rac1 in stabilizing mature endothelial adherens junctions (AJs) is not well understood. In this paper, using a photoactivatable probe to control Rac1 activity at AJs, we addressed the relationship between Rac1 and the dynamics of vascular endothelial cadherin (VE-cadherin). We demonstrated that Rac1 activation reduced the rate of VE-cadherin dissociation, leading to increased density of VE-cadherin at AJs. This response was coupled to a reduction in actomyosin-dependent tension across VE-cadherin adhesion sites. We observed that inhibiting myosin II directly or through photo-release of the caged Rho kinase inhibitor also reduced the rate of VE-cadherin dissociation. Thus, Rac1 functions by stabilizing VE-cadherin trans-dimers in mature AJs by counteracting the actomyosin tension. The results suggest a new model of VE-cadherin adhesive interaction mediated by Rac1-induced reduction of mechanical tension at AJs, resulting in the stabilization of VE-cadherin adhesions. PMID:25559184

  10. Proapoptotic and antiinvasive activity of Rac1 small molecule inhibitors on malignant glioma cells

    PubMed Central

    Cardama, Georgina A; Gonzalez, Nazareno; Ciarlantini, Matias; Gandolfi Donadío, Lucia; Comin, María Julieta; Alonso, Daniel F; Menna, Pablo Lorenzano; Gomez, Daniel E

    2014-01-01

    Malignant gliomas are characterized by an intrinsic ability to invade diffusely throughout the normal brain tissue. This feature contributes mainly to the failure of existing therapies. Deregulation of small GTPases signaling, in particular Rac1 activity, plays a key role in the invasive phenotype of gliomas. Here we report the effect of ZINC69391, a specific Rac1 inhibitor developed by our group, on human glioma cell lines LN229 and U-87 MG. ZINC69391 is able to interfere with the interaction of Rac1 with Dock180, a relevant Rac1 activator in glioma invasion, and to reduce Rac1-GTP levels. The kinase Pak1, a downstream effector of Dock180–Rac1 signaling, was also downregulated upon ZINC69391 treatment. ZINC69391 reduced cell proliferation, arrested cells in G1 phase, and triggered apoptosis in glioma cells. Importantly, ZINC69391 dramatically affected cell migration and invasion in vitro, interfering with actin cytoskeleton dynamics. We also evaluated the effect of analog 1A-116, a compound derived from ZINC69391 structure. 1A-116 showed an improved antiproliferative and antiinvasive activity on glioma cells. These findings encourage further preclinical testing in clinically relevant animal models. PMID:25378937

  11. Coronin1 Proteins Dictate Rac1 Intracellular Dynamics and Cytoskeletal Output

    PubMed Central

    Ojeda, Virginia; Castro-Castro, Antonio

    2014-01-01

    Rac1 regulates lamellipodium formation, myosin II-dependent contractility, and focal adhesions during cell migration. While the spatiotemporal assembly of those processes is well characterized, the signaling mechanisms involved remain obscure. We report here that the cytoskeleton-related Coronin1A and -1B proteins control a myosin II inactivation-dependent step that dictates the intracellular dynamics and cytoskeletal output of active Rac1. This step is signaling-branch specific, since it affects the functional competence of active Rac1 only when forming complexes with downstream ArhGEF7 and Pak proteins in actomyosin-rich structures. The pathway is used by default unless Rac1 is actively rerouted away from the structures by upstream activators and signals from other Rho GTPases. These results indicate that Coronin1 proteins are at the center of a regulatory hub that coordinates Rac1 activation, effector exchange, and the F-actin organization state during cell signaling. Targeting this route could be useful to hamper migration of cancer cells harboring oncogenic RAC1 mutations. PMID:24980436

  12. Regulation of cell-matrix adhesion dynamics and Rac-1 by integrin linked kinase.

    PubMed

    Boulter, Etienne; Grall, Dominique; Cagnol, Sébastien; Van Obberghen-Schilling, Ellen

    2006-07-01

    Extracellular matrix (ECM) receptors of the integrin family initiate changes in cell shape and motility by recruiting signaling components that coordinate these events. Integrin-linked kinase (ILK) is one such partner of beta1 integrins that participates in dynamic rearrangement of cell-matrix adhesions and cell spreading by mechanisms that are not well understood. To further elucidate the role of ILK in these events, we engineered a chimeric molecule comprising ILK fused to a membrane-targeted green fluorescent protein (ILK-GFP-F). ILK-GFP-F is highly enriched in cell-matrix adhesions, and its expression in fibroblasts leads to an accumulation of focal adhesions (2-5 microm) and elongated adhesions (>5 microm). ILK-GFP-F enhances cell spreading on fibronectin and induces a constitutive increase in the levels of GTP-bound Rac-1. Conversely, ILK knock-down by siRNA transfection decreases active Rac-1. Endogenous ILK was found to associate with PKL (paxillin kinase linker) and the Rac/Cdc42 guanine nucleotide exchange factor betaPIX. Further, expression of a dominant negative betaPIX mutant reversed the increase in active Rac-1 levels of ILK-GFP-F-expressing cells, thus placing betaPIX in the pathway leading from ILK to Rac-1 activation. However, expression of constitutively active Rac only partially restores the spreading defects of ILK-depleted cells, suggesting that an additional ILK-dependent signal is required for cell spreading.

  13. Enucleation of cultured mouse fetal erythroblasts requires Rac GTPases and mDia2.

    PubMed

    Ji, Peng; Jayapal, Senthil Raja; Lodish, Harvey F

    2008-03-01

    Mammalian erythroid cells undergo enucleation, an asymmetric cell division involving extrusion of a pycnotic nucleus enveloped by the plasma membrane. The mechanisms that power and regulate the enucleation process have remained obscure. Here, we show that deregulation of Rac GTPase during a late stage of erythropoiesis completely blocks enucleation of cultured mouse fetal erythroblasts without affecting their proliferation or differentiation. Formation of the contractile actin ring (CAR) on the plasma membrane of enucleating erythroblasts was disrupted by inhibition of Rac GTPases. Furthermore, we demonstrate that mDia2, a downstream effector of Rho GTPases and a formin protein required for nucleation of unbranched actin filaments, is also required for enucleation of mouse fetal erythroblasts. We show that Rac1 and Rac2 bind to mDia2 in a GTP-dependent manner and that downregulation of mDia2, but not mDia1, by small interfering RNA (siRNA) during the late stages of erythropoiesis blocked both CAR formation and erythroblast enucleation. Additionally, overexpression of a constitutively active mutant of mDia2 rescued the enucleation defects induced by the inhibition of Rac GTPases. These results reveal important roles for Rac GTPases and their effector mDia2 in enucleation of mammalian erythroblasts.

  14. Contingency Contractor Optimization Phase 3 Sustainment Third-Party Software List - Contingency Contractor Optimization Tool - Prototype

    SciTech Connect

    Durfee, Justin David; Frazier, Christopher Rawls; Bandlow, Alisa

    2016-05-01

    The Contingency Contractor Optimization Tool - Prototype (CCOT-P) requires several third-party software packages. These are documented below for each of the CCOT-P elements: client, web server, database server, solver, web application and polling application.

  15. Building America Expert Meeting Report. Transitioning Traditional HVAC Contractors to Whole House Performance Contractors

    SciTech Connect

    Burdick, Arlan

    2011-10-01

    This expert meeting was hosted by the IBACOS Building America research team to determine how HVAC companies can transition from a traditional contractor status to a service provider for whole house energy upgrade contracting.

  16. National radon contractor proficiency (RCP) program. Proficiency report, July 1993

    SciTech Connect

    Not Available

    1993-07-01

    The report will assist State, EPA Regions, and local government officials in providing advice to the public on the selection of proficient radon mitigation contractors. The Report is a listing of 853 contractors who have met the requirements of EPA's National Radon Contractor Proficiency (RCP) Program as of July 15, 1993. Each contractor is listed by name, RCP identification number, company name, address, phone number, and geographic service area.

  17. Defense Contractor Recovery of Cleanup Costs at Contractor Owned and Operated Facilitie

    DTIC Science & Technology

    1993-09-30

    COCO ) facilities’ or disposal sites for which the contractor is held responsible as a "Potentially Responsible Party".2 Its primary focus is on...ground water. A recent GAO study on COCO liability noted: "aggregate projections range from $0.9 billion to $1.1 billion...one contractor, spending $9...for transport".3 The focus of this chapter is whether a company owned and operated facility ( COCO ) which performed government contracts can shift

  18. Deletion of Rac1GTPase in the Myeloid Lineage Protects against Inflammation-Mediated Kidney Injury in Mice

    PubMed Central

    Nagase, Miki; Kurihara, Hidetake; Aiba, Atsu; Young, Morag J.; Sakai, Tatsuo

    2016-01-01

    Macrophage-mediated inflammation has been implicated in various kidney diseases. We previously reported that Rac1, a Rho family small GTP-binding protein, was overactivated in several chronic kidney disease models, and that Rac1 inhibitors ameliorated renal injury, in part via inhibition of inflammation, but the detailed mechanisms have not been clarified. In the present study, we examined whether Rac1 in macrophages effects cytokine production and the inflammatory mechanisms contributing to kidney derangement. Myeloid-selective Rac1 flox control (M-Rac1 FC) and knockout (M-Rac1 KO) mice were generated using the cre-loxP system. Renal function under basal conditions did not differ between M-Rac1 FC and KO mice. Accordingly, lipopolysaccharide (LPS)-evoked kidney injury model was created. LPS elevated blood urea nitrogen and serum creatinine, enhanced expressions of kidney injury biomarkers, Kim-1 and Ngal, and promoted tubular injury in M-Rac1 FC mice. By contrast, deletion of myeloid Rac1 almost completely prevented the LPS-mediated renal impairment. LPS triggered a marked induction of macrophage-derived inflammatory cytokines, IL-6 and TNFα, in M-Rac1 FC mice, which was accompanied by Rac1 activation, stimulation of reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase, and reactive oxygen species overproduction. These changes were inhibited in M-Rac1 KO mice. LPS evoked F4/80-positive macrophages accumulation in the kidney, which was not affected by myeloid Rac1 deficiency. We further tested the role of Rac1 signaling in cytokine production using macrophage cell line, RAW264.7. Exposure to LPS increased IL-6 and TNFα mRNA expression. The LPS-driven cytokine induction was dose-dependently blocked by the Rac1 inhibitor EHT1864, NADPH oxidase inhibitor diphenyleneiodonium, and NF-κB inhibitor BAY11-7082. In conclusion, genetic ablation of Rac1 in the myeloid lineage protected against LPS-induced renal inflammation and injury, by suppressing

  19. 20 CFR 655.19 - Job contractor filing requirements.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 20 Employees' Benefits 3 2012-04-01 2012-04-01 false Job contractor filing requirements. 655.19... States (H-2B Workers) Application for Temporary Employment Certification Filing Procedures § 655.19 Job contractor filing requirements. (a) Provided that a job contractor and any employer-client are...

  20. 20 CFR 655.19 - Job contractor filing requirements.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 20 Employees' Benefits 3 2013-04-01 2013-04-01 false Job contractor filing requirements. 655.19... States (H-2B Workers) Application for Temporary Employment Certification Filing Procedures § 655.19 Job contractor filing requirements. (a) Provided that a job contractor and any employer-client are...

  1. 20 CFR 655.19 - Job contractor filing requirements.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 20 Employees' Benefits 3 2014-04-01 2014-04-01 false Job contractor filing requirements. 655.19... States (H-2B Workers) Application for Temporary Employment Certification Filing Procedures § 655.19 Job contractor filing requirements. (a) Provided that a job contractor and any employer-client are...

  2. 48 CFR 852.237-70 - Contractor responsibilities.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... responsibilities. 852.237-70 Section 852.237-70 Federal Acquisition Regulations System DEPARTMENT OF VETERANS....237-70 Contractor responsibilities. As prescribed in 837.110, insert the following clause: Contractor Responsibilities (APR 1984) The contractor shall obtain all necessary licenses and/or permits required to...

  3. 48 CFR 852.237-70 - Contractor responsibilities.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... responsibilities. 852.237-70 Section 852.237-70 Federal Acquisition Regulations System DEPARTMENT OF VETERANS....237-70 Contractor responsibilities. As prescribed in 837.110, insert the following clause: Contractor Responsibilities (APR 1984) The contractor shall obtain all necessary licenses and/or permits required to...

  4. 29 CFR 780.331 - Crew leaders and labor contractors.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 3 2010-07-01 2010-07-01 false Crew leaders and labor contractors. 780.331 Section 780.331... 13(a)(6) Statutory Provisions § 780.331 Crew leaders and labor contractors. (a) Whether a crew leader... contractor. A crew leader who merely assembles a crew and brings them to the farm to be supervised and...

  5. 14 CFR 1245.108 - License to contractor.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 5 2011-01-01 2010-01-01 true License to contractor. 1245.108 Section 1245.108 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION PATENTS AND OTHER INTELLECTUAL PROPERTY RIGHTS Patent Waiver Regulations § 1245.108 License to contractor. (a) Each contractor...

  6. 48 CFR 2452.251-70 - Contractor employee travel.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 6 2011-10-01 2011-10-01 false Contractor employee travel... 2452.251-70 Contractor employee travel. As prescribed in 2451.7001, insert the following clause in all cost-reimbursement solicitations and contracts involving travel: Contractor Employee Travel (OCT...

  7. 6 CFR 25.8 - Government contractor Defense.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 6 Domestic Security 1 2014-01-01 2014-01-01 false Government contractor Defense. 25.8 Section 25.8...-TERRORISM BY FOSTERING EFFECTIVE TECHNOLOGIES § 25.8 Government contractor Defense. (a) Criteria for... applicability of the government contractor defense. In determining whether to issue such Certification,...

  8. 6 CFR 25.8 - Government contractor Defense.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 6 Domestic Security 1 2013-01-01 2013-01-01 false Government contractor Defense. 25.8 Section 25.8...-TERRORISM BY FOSTERING EFFECTIVE TECHNOLOGIES § 25.8 Government contractor Defense. (a) Criteria for... applicability of the government contractor defense. In determining whether to issue such Certification,...

  9. 6 CFR 25.8 - Government contractor Defense.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 6 Domestic Security 1 2011-01-01 2011-01-01 false Government contractor Defense. 25.8 Section 25.8...-TERRORISM BY FOSTERING EFFECTIVE TECHNOLOGIES § 25.8 Government contractor Defense. (a) Criteria for... applicability of the government contractor defense. In determining whether to issue such Certification,...

  10. 48 CFR 2936.201 - Evaluation of contractor performance.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 7 2010-10-01 2010-10-01 false Evaluation of contractor... Construction 2936.201 Evaluation of contractor performance. The HCA must establish procedures to evaluate construction contractor performance and prepare performance reports as required by FAR 36.201....

  11. 6 CFR 25.8 - Government contractor Defense.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 6 Domestic Security 1 2010-01-01 2010-01-01 false Government contractor Defense. 25.8 Section 25.8...-TERRORISM BY FOSTERING EFFECTIVE TECHNOLOGIES § 25.8 Government contractor Defense. (a) Criteria for... applicability of the government contractor defense. In determining whether to issue such Certification,...

  12. 48 CFR 53.209-1 - Responsible prospective contractors.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... contractors. 53.209-1 Section 53.209-1 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION (CONTINUED) CLAUSES AND FORMS FORMS Prescription of Forms 53.209-1 Responsible prospective contractors. (a) SF 1403 (Rev. 9/88), Preaward Survey of Prospective Contractor (General). SF 1403 is authorized...

  13. 40 CFR 35.938-6 - Progress payments to contractors.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Progress payments to contractors. 35... § 35.938-6 Progress payments to contractors. (a) Policy. EPA policy is that, except as State law otherwise provides, grantees should make prompt progress payments to prime contractors and prime...

  14. 32 CFR 989.23 - Contractor prepared documents.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 6 2010-07-01 2010-07-01 false Contractor prepared documents. 989.23 Section... PROTECTION ENVIRONMENTAL IMPACT ANALYSIS PROCESS (EIAP) § 989.23 Contractor prepared documents. All Air Force... should reflect on the cover sheet they are an Air Force document. Contractor preparation...

  15. 48 CFR 970.5203-3 - Contractor's organization.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Contractor's organization... for Management and Operating Contracts 970.5203-3 Contractor's organization. As prescribed in 970.0371-9, insert the following clause: Contractor's Organization (DEC 2000) (a) Organization chart....

  16. 48 CFR 2452.237-75 - Clearance of contractor personnel.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 6 2010-10-01 2010-10-01 true Clearance of contractor... Clauses 2452.237-75 Clearance of contractor personnel. As prescribed in 2437.110(e), insert the following clause in solicitations and contracts. Clearance of Contractor Personnel (OCT 1999) (a) General....

  17. 76 FR 60838 - Debarment, Suspension, and Ineligibility of Contractors

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-30

    ... OFFICE Debarment, Suspension, and Ineligibility of Contractors AGENCY: Government Accountability Office... contractors. As a legislative branch agency, GAO is not subject to the requirements of the FAR. However, it is..., contractors) who are responsible. However, GAO's Procurement Order has not explicitly referenced the...

  18. 48 CFR 923.102 - Applicability to contractors.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... contractors. 923.102 Section 923.102 Federal Acquisition Regulations System DEPARTMENT OF ENERGY SOCIOECONOMIC... 923.102 Applicability to contractors. Many of the Department's major facilities are operated by contractors. Provisions regarding those contracts may be found at Part 970 of this chapter. At other...

  19. 21 CFR 21.30 - Records of contractors.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 1 2010-04-01 2010-04-01 false Records of contractors. 21.30 Section 21.30 Food... PRIVACY Requirements for Specific Categories of Records § 21.30 Records of contractors. (a) Systems of... contractors to accomplish Food and Drug Administration functions, from which information is retrieved...

  20. 48 CFR 36.506 - Superintendence by the contractor.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... contractor. 36.506 Section 36.506 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION... Superintendence by the contractor. The contracting officer shall insert the clause at 52.236-6, Superintendence by the Contractor, in solicitations and contracts when a fixed-price construction contract or a...

  1. 48 CFR 1652.204-70 - Contractor records retention.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 6 2010-10-01 2010-10-01 true Contractor records... of FEHBP Clauses 1652.204-70 Contractor records retention. As prescribed in 1604.705 the following clause will be inserted in all FEHB Program contracts. Contractor Records Retention (JUL...

  2. 48 CFR 8.406-7 - Contractor Performance Evaluation.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Contractor Performance... ACQUISITION PLANNING REQUIRED SOURCES OF SUPPLIES AND SERVICES Federal Supply Schedules 8.406-7 Contractor Performance Evaluation. Ordering activities must prepare an evaluation of contractor performance for...

  3. 4 CFR 75.1 - Contractors' and vendors' certificates.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 4 Accounts 1 2010-01-01 2010-01-01 false Contractors' and vendors' certificates. 75.1 Section 75.1... BASIC VOUCHERS AND INVOICES § 75.1 Contractors' and vendors' certificates. (a) The Government... bills and invoices of contractors and vendors, with the exception that carriers, or other...

  4. 48 CFR 47.305-15 - Loading responsibilities of contractors.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Loading responsibilities of contractors. 47.305-15 Section 47.305-15 Federal Acquisition Regulations System FEDERAL... responsibilities of contractors. (a)(1) Contractors are responsible for loading, blocking, and bracing...

  5. 75 FR 3977 - Addressing Tax Delinquency by Government Contractors

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-25

    ... Memorandum of January 20, 2010--Addressing Tax Delinquency by Government Contractors #0; #0; #0; Presidential... Delinquency by Government Contractors Memorandum for the Heads of Executive Departments and Agencies The Federal Government pays more than half a trillion dollars a year to contractors and has an...

  6. 77 FR 12754 - Contractor Legal Management Requirements; Acquisition Regulations

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-03-02

    ... Part 719 48 Parts 931, 952 and 970 RIN 1990-AA37 Contractor Legal Management Requirements; Acquisition... covering contractor legal management requirements and make conforming amendments to the Department of... rulemaking to revise existing regulations covering contractor legal management requirements and...

  7. 48 CFR 46.301 - Contractor inspection requirements.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Contractor inspection... CONTRACT MANAGEMENT QUALITY ASSURANCE Contract Clauses 46.301 Contractor inspection requirements. The contracting officer shall insert the clause at 52.246-1, Contractor Inspection Requirements, in...

  8. 48 CFR 52.236-6 - Superintendence by the Contractor.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Contractor. 52.236-6 Section 52.236-6 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION....236-6 Superintendence by the Contractor. As prescribed in 36.506, insert the following clause: Superintendence by the Contractor (APR 1984) At all times during performance of this contract and until the...

  9. 41 CFR 109-40.000-50 - Applicability to contractors.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... contractors. 109-40.000-50 Section 109-40.000-50 Public Contracts and Property Management Federal Property...-50 Applicability to contractors. DOE-PMR 109-40, Transportation and Traffic Management, should be applied to cost-type contractors' transportation and traffic management activities. Departure by...

  10. 7 CFR 3015.183 - Access to contractor records.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 15 2010-01-01 2010-01-01 false Access to contractor records. 3015.183 Section 3015... contractor records. The Attachment 0 requires recipients to include in specified kinds of contracts a provision for access to the contractor's records by the recipient and the Federal government. The...

  11. 48 CFR 2152.215-70 - Contractor records retention.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 6 2010-10-01 2010-10-01 true Contractor records... PRECONTRACT PROVISIONS AND CONTRACT CLAUSES Text of Provisions and Clauses 2152.215-70 Contractor records retention. As prescribed in 2115.071, insert the following clause: Contractor Records Retention (OCT...

  12. 30 CFR 45.4 - Independent contractor register.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Independent contractor register. 45.4 Section 45.4 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR FILING AND OTHER ADMINISTRATIVE REQUIREMENTS INDEPENDENT CONTRACTORS § 45.4 Independent contractor register. (a) Each...

  13. 30 CFR 45.4 - Independent contractor register.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Independent contractor register. 45.4 Section 45.4 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR FILING AND OTHER ADMINISTRATIVE REQUIREMENTS INDEPENDENT CONTRACTORS § 45.4 Independent contractor register. (a) Each...

  14. 30 CFR 45.4 - Independent contractor register.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Independent contractor register. 45.4 Section 45.4 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR FILING AND OTHER ADMINISTRATIVE REQUIREMENTS INDEPENDENT CONTRACTORS § 45.4 Independent contractor register. (a) Each...

  15. 30 CFR 45.4 - Independent contractor register.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Independent contractor register. 45.4 Section 45.4 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR FILING AND OTHER ADMINISTRATIVE REQUIREMENTS INDEPENDENT CONTRACTORS § 45.4 Independent contractor register. (a) Each...

  16. 48 CFR 252.242-7005 - Contractor business systems.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 3 2011-10-01 2011-10-01 false Contractor business... of Provisions And Clauses 252.242-7005 Contractor business systems. As prescribed in 242.7001, use the following clause: CONTRACTOR BUSINESS SYSTEMS (MAY 2011) (a) Definitions. As used in this...

  17. 48 CFR 252.242-7005 - Contractor business systems.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 3 2014-10-01 2014-10-01 false Contractor business... of Provisions And Clauses 252.242-7005 Contractor business systems. As prescribed in 242.7001, use the following clause: Contractor Business Systems (FEB 2012) (a) This clause only applies to...

  18. 48 CFR 252.242-7005 - Contractor business systems.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 3 2012-10-01 2012-10-01 false Contractor business... of Provisions And Clauses 252.242-7005 Contractor business systems. As prescribed in 242.7001, use the following clause: Contractor Business Systems (FEB 2012) (a) This clause only applies to...

  19. 48 CFR 252.242-7005 - Contractor business systems.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 3 2013-10-01 2013-10-01 false Contractor business... of Provisions And Clauses 252.242-7005 Contractor business systems. As prescribed in 242.7001, use the following clause: Contractor Business Systems (FEB 2012) (a) This clause only applies to...

  20. 48 CFR 245.608 - Screening of contractor inventory.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 3 2010-10-01 2010-10-01 false Screening of contractor inventory. 245.608 Section 245.608 Federal Acquisition Regulations System DEFENSE ACQUISITION REGULATIONS... Disposal of Contractor Inventory 245.608 Screening of contractor inventory....

  1. 48 CFR 227.7108 - Contractor data repositories.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... require, as a minimum, the data repository management contractor to— (1) Establish and maintain adequate... contractor's data management and distribution responsibilities must be identified in the contract or the... 48 Federal Acquisition Regulations System 3 2012-10-01 2012-10-01 false Contractor...

  2. 48 CFR 227.7108 - Contractor data repositories.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... require, as a minimum, the data repository management contractor to— (1) Establish and maintain adequate... contractor's data management and distribution responsibilities must be identified in the contract or the... 48 Federal Acquisition Regulations System 3 2011-10-01 2011-10-01 false Contractor...

  3. 48 CFR 227.7108 - Contractor data repositories.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... require, as a minimum, the data repository management contractor to— (1) Establish and maintain adequate... contractor's data management and distribution responsibilities must be identified in the contract or the... 48 Federal Acquisition Regulations System 3 2013-10-01 2013-10-01 false Contractor...

  4. 48 CFR 227.7108 - Contractor data repositories.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... require, as a minimum, the data repository management contractor to— (1) Establish and maintain adequate... contractor's data management and distribution responsibilities must be identified in the contract or the... 48 Federal Acquisition Regulations System 3 2014-10-01 2014-10-01 false Contractor...

  5. 48 CFR 227.7108 - Contractor data repositories.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... require, as a minimum, the data repository management contractor to— (1) Establish and maintain adequate... contractor's data management and distribution responsibilities must be identified in the contract or the... 48 Federal Acquisition Regulations System 3 2010-10-01 2010-10-01 false Contractor...

  6. 48 CFR 1552.237-76 - Government-Contractor Relations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... the services to be delivered under this contract by the contractor to the Government are non-personal... under this contract do not require the Contractor or his/her personnel to exercise personal judgment and discretion on behalf of the Government. Rather the Contractor's personnel will act and exercise...

  7. 48 CFR 952.251-70 - Contractor employee travel discounts.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... Employee Travel Discounts (AUG 2009) (a) The Contractor shall take advantage of travel discounts offered to Federal Contractor employee travelers by AMTRAK, hotels, motels, or car rental companies, when use of such... Federal contractor employees. (e) Car rentals. The Surface Deployment and Distribution Command (SDDC)...

  8. 48 CFR 952.251-70 - Contractor employee travel discounts.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... Employee Travel Discounts (AUG 2009) (a) The Contractor shall take advantage of travel discounts offered to Federal Contractor employee travelers by AMTRAK, hotels, motels, or car rental companies, when use of such... Federal contractor employees. (e) Car rentals. The Surface Deployment and Distribution Command (SDDC)...

  9. 48 CFR 952.251-70 - Contractor employee travel discounts.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... Employee Travel Discounts (AUG 2009) (a) The Contractor shall take advantage of travel discounts offered to Federal Contractor employee travelers by AMTRAK, hotels, motels, or car rental companies, when use of such... Federal contractor employees. (e) Car rentals. The Surface Deployment and Distribution Command (SDDC)...

  10. 48 CFR 952.251-70 - Contractor employee travel discounts.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... Employee Travel Discounts (AUG 2009) (a) The Contractor shall take advantage of travel discounts offered to Federal Contractor employee travelers by AMTRAK, hotels, motels, or car rental companies, when use of such... Federal contractor employees. (e) Car rentals. The Surface Deployment and Distribution Command (SDDC)...

  11. p21-activated Kinases (PAKs) Mediate the Phosphorylation of PREX2 Protein to Initiate Feedback Inhibition of Rac1 GTPase.

    PubMed

    Barrows, Douglas; Schoenfeld, Sarah M; Hodakoski, Cindy; Silkov, Antonina; Honig, Barry; Couvillon, Anthony; Shymanets, Aliaksei; Nürnberg, Bernd; Asara, John M; Parsons, Ramon

    2015-11-27

    Phosphatidylinositol 3,4,5-trisphosphate (PIP3)-dependent Rac exchanger 2 (PREX2) is a guanine nucleotide exchange factor (GEF) for the Ras-related C3 botulinum toxin substrate 1 (Rac1) GTPase, facilitating the exchange of GDP for GTP on Rac1. GTP-bound Rac1 then activates its downstream effectors, including p21-activated kinases (PAKs). PREX2 and Rac1 are frequently mutated in cancer and have key roles within the insulin-signaling pathway. Rac1 can be inactivated by multiple mechanisms; however, negative regulation by insulin is not well understood. Here, we show that in response to being activated after insulin stimulation, Rac1 initiates its own inactivation by decreasing PREX2 GEF activity. Following PREX2-mediated activation of Rac1 by the second messengers PIP3 or Gβγ, we found that PREX2 was phosphorylated through a PAK-dependent mechanism. PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ. Cell fractionation experiments also revealed that phosphorylation prevented PREX2 from localizing to the cellular membrane. Furthermore, the onset of insulin-induced phosphorylation of PREX2 was delayed compared with AKT. Altogether, we propose that second messengers activate the Rac1 signal, which sets in motion a cascade whereby PAKs phosphorylate and negatively regulate PREX2 to decrease Rac1 activation. This type of regulation would allow for transient activation of the PREX2-Rac1 signal and may be relevant in multiple physiological processes, including diseases such as diabetes and cancer when insulin signaling is chronically activated.

  12. p21-activated Kinases (PAKs) Mediate the Phosphorylation of PREX2 Protein to Initiate Feedback Inhibition of Rac1 GTPase*

    PubMed Central

    Barrows, Douglas; Schoenfeld, Sarah M.; Hodakoski, Cindy; Silkov, Antonina; Honig, Barry; Couvillon, Anthony; Shymanets, Aliaksei; Nürnberg, Bernd; Asara, John M.; Parsons, Ramon

    2015-01-01

    Phosphatidylinositol 3,4,5-trisphosphate (PIP3)-dependent Rac exchanger 2 (PREX2) is a guanine nucleotide exchange factor (GEF) for the Ras-related C3 botulinum toxin substrate 1 (Rac1) GTPase, facilitating the exchange of GDP for GTP on Rac1. GTP-bound Rac1 then activates its downstream effectors, including p21-activated kinases (PAKs). PREX2 and Rac1 are frequently mutated in cancer and have key roles within the insulin-signaling pathway. Rac1 can be inactivated by multiple mechanisms; however, negative regulation by insulin is not well understood. Here, we show that in response to being activated after insulin stimulation, Rac1 initiates its own inactivation by decreasing PREX2 GEF activity. Following PREX2-mediated activation of Rac1 by the second messengers PIP3 or Gβγ, we found that PREX2 was phosphorylated through a PAK-dependent mechanism. PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ. Cell fractionation experiments also revealed that phosphorylation prevented PREX2 from localizing to the cellular membrane. Furthermore, the onset of insulin-induced phosphorylation of PREX2 was delayed compared with AKT. Altogether, we propose that second messengers activate the Rac1 signal, which sets in motion a cascade whereby PAKs phosphorylate and negatively regulate PREX2 to decrease Rac1 activation. This type of regulation would allow for transient activation of the PREX2-Rac1 signal and may be relevant in multiple physiological processes, including diseases such as diabetes and cancer when insulin signaling is chronically activated. PMID:26438819

  13. The interferon-gamma-induced GTPase, mGBP-2, inhibits tumor necrosis factor alpha (TNF-alpha) induction of matrix metalloproteinase-9 (MMP-9) by inhibiting NF-kappaB and Rac protein.

    PubMed

    Balasubramanian, Sujata; Fan, Meiyun; Messmer-Blust, Angela F; Yang, Chuan H; Trendel, Jill A; Jeyaratnam, Jonathan A; Pfeffer, Lawrence M; Vestal, Deborah J

    2011-06-03

    Matrix metalloproteinase-9 (MMP-9) is important in numerous normal and pathological processes, including the angiogenic switch during tumor development and tumor metastasis. Whereas TNF-α and other cytokines up-regulate MMP-9 expression, interferons (IFNs) inhibit MMP-9 expression. We found that IFN-γ treatment or forced expression of the IFN-induced GTPase, mGBP-2, inhibit TNF-α-induced MMP-9 expression in NIH 3T3 fibroblasts, by inhibiting MMP-9 transcription. The NF-κB transcription factor is required for full induction of MMP-9 by TNF-α. Both IFN-γ and mGBP-2 inhibit the transcription of a NF-κB-dependent reporter construct, suggesting that mGBP-2 inhibits MMP-9 induction via inhibition of NF-κB-mediated transcription. Interestingly, mGBP-2 does not inhibit TNF-α-induced degradation of IκBα or p65/RelA translocation into the nucleus. However, mGBP-2 inhibits p65 binding to a κB oligonucleotide probe in gel shift assays and to the MMP-9 promoter in chromatin immunoprecipitation assays. In addition, TNF-α activation of NF-κB in NIH 3T3 cells is dependent on Rac activation, as evidenced by the inhibition of TNF-α induction of NF-κB-mediated transcription by a dominant inhibitory form of Rac1. A role for Rac in the inhibitory action of mGBP-2 on NF-κB is further shown by the findings that mGBP-2 inhibits TNF-α activation of endogenous Rac and constitutively activate Rac can restore NF-κB transcription in the presence of mGBP-2. This is a novel mechanism by which IFNs can inhibit the cytokine induction of MMP-9 expression.

  14. Tiam1 Regulates the Wnt/Dvl/Rac1 Signaling Pathway and the Differentiation of Midbrain Dopaminergic Neurons

    PubMed Central

    Čajánek, Lukáš; Ganji, Ranjani Sri; Henriques-Oliveira, Catarina; Theofilopoulos, Spyridon; Koník, Peter

    2013-01-01

    Understanding the mechanisms that drive the differentiation of dopaminergic (DA) neurons is crucial for successful development of novel therapies for Parkinson's disease, in which DA neurons progressively degenerate. However, the mechanisms underlying the differentiation-promoting effects of Wnt5a on DA precursors are poorly understood. Here, we present the molecular and functional characterization of a signaling pathway downstream of Wnt5a, the Wnt/Dvl/Rac1 pathway. First, we characterize the interaction between Rac1 and Dvl and identify the N-terminal part of Dvl3 as necessary for Rac1 binding. Next, we show that Tiam1, a Rac1 guanosine exchange factor (GEF), is expressed in the ventral midbrain, interacts with Dvl, facilitates Dvl-Rac1 interaction, and is required for Dvl- or Wnt5a-induced activation of Rac1. Moreover, we show that Wnt5a promotes whereas casein kinase 1 (CK1), a negative regulator of the Wnt/Dvl/Rac1 pathway, abolishes the interactions between Dvl and Tiam1. Finally, using ventral midbrain neurosphere cultures, we demonstrate that the generation of DA neurons in culture is impaired after Tiam1 knockdown, indicating that Tiam1 is required for midbrain DA differentiation. In summary, our data identify Tiam1 as a novel regulator of DA neuron development and as a Dvl-associated and Rac1-specific GEF acting in the Wnt/Dvl/Rac1 pathway. PMID:23109420

  15. The eighteenth-century vagrant contractor.

    PubMed

    Eccles, Audrey

    2010-01-01

    This article traces the salient developments in poor law and vagrancy law that led to the counties of England and Wales being obliged to shoulder the financial burden of the mobile poor throughout the eighteenth century. It shows that despite the lack of statutory authority many, probably most, counties contracted with a new type of official to implement the conveyance of vagrants under vagrancy legislation in an attempt to counter suspected negligence and profiteering by constables. It shows, with particular reference to Middlesex and the West Riding, that the terms and conditions of these contracts varied considerably, and describes arrangements for the vagrants. The article also suggests reasons why the mobile poor formed an increasing segment of the population well into the nineteenth century and finds that by then the contractors were suspected of the same faults as the constables before them, leading to the abandonment of the contractor system.

  16. A model of electron collecting plasma contractors

    NASA Technical Reports Server (NTRS)

    Davis, V. A.; Katz, I.; Mandell, M. J.; Parks, D. E.

    1989-01-01

    A model of plasma contractors is being developed, which can be used to describe electron collection in a laboratory test tank and in the space environment. To validate the model development, laboratory experiments are conducted in which the source plasma is separated from the background plasma by a double layer. Model calculations show that an increase in ionization rate with potential produces a steep rise in collected current with increasing potential.

  17. Needs of Non-Energy Focused Contractors

    SciTech Connect

    Liakus, C.

    2012-12-01

    To better understand the informational needs of non-energy focused contractors, including what information they need to motivate them to become energy-focused, the BARA team studied the type of information provided by the national programs, trade associations, and manufacturers that were researched for the related technical report: Effective Communication of Energy Efficiency. While that report focused on the delivery method, format, and strategy of the information, this study examines the content being put forward.

  18. Needs of Non Energy-Focused Contractors

    SciTech Connect

    Liaukus, C.

    2012-12-01

    To better understand the informational needs of non energy-focused contractors, including what information they need to motivate them to become energy-focused, the BARA team studied the type of information provided by the national programs, trade associations, and manufacturers that were researched for the related technical report: Effective Communication of Energy Efficiency. While that report focused on the delivery method, format, and strategy of the information, this study examines the content being put forward.

  19. Study of Contractor Internal Reward Structures.

    DTIC Science & Technology

    1981-12-15

    Incentive Systems Negotiations 20) 149TRACT (Continue an reverse side It necessary and identify by block number) ~ a: -mhe overall objective of this study...Inc. to begin work on August 14, 1981 to collect data on contractor internal motivation systems in specified defense corporations. Study Focus The...awards. While we have already gathered somes data on your firm’s incentive program as reported In SEC filings, informtion on the award criteria was not

  20. Excessive Profits of German Defense Contractors

    DTIC Science & Technology

    2014-09-01

    largest German supplier for the European Ariane 5 rocket that is frequently used to carry cargo to an orbit around the earth. For the German armed...0704-0188) Washington, DC 20503. 1. AGENCY USE ONLY (Leave blank) 2. REPORT DATE September 2014 3. REPORT TYPE AND DATES COVERED Master’s...countries emphasize competition among defense contractors, but the perspectives on and uses of profit and fees differ for cost-based contracts. In the

  1. Final Report: Contractor Readiness Assessment (CRA) for TREAT Fuel Movement and Control Rod Drives Isolation

    SciTech Connect

    Rowsell, David Leon

    2015-06-01

    This report documents the Contractor Readiness Assessment (CRA) for TREAT Fuel Movement and Control Rod Drives Isolation. The review followed the approved Plan of Action (POA) and Implementation Plan (IP) using the identified core requirements. The activity was limited scope focusing on the control rod drives functional isolation and fuel element movement. The purpose of this review is to ensure the facility's readiness to move fuel elements thus supporting inspection and functionally isolate the control rod drives to maintain the required shutdown margin.

  2. Building America Expert Meeting Report: Transitioning Traditional HVAC Contractors to Whole House Performance Contractors

    SciTech Connect

    Burdick, A.

    2011-10-01

    This report outlines findings resulting from a U.S. Department of Energy Building America expert meeting to determine how HVAC companies can transition from a traditional contractor status to a service provider for whole house energy upgrade contracting. IBACOS has embarked upon a research effort under the Building America Program to understand business impacts and change management strategies for HVAC companies. HVAC companies can implement these strategies in order to quickly transition from a 'traditional' heating and cooling contractor to a service provider for whole house energy upgrade contracting. Due to HVAC service contracts, which allow repeat interaction with homeowners, HVAC companies are ideally positioned in the marketplace to resolve homeowner comfort issues through whole house energy upgrades. There are essentially two primary ways to define the routes of transition for an HVAC contractor taking on whole house performance contracting: (1) Sub-contracting out the shell repair/upgrade work; and (2) Integrating the shell repair/upgrade work into their existing business. IBACOS held an Expert Meeting on the topic of Transitioning Traditional HVAC Contractors to Whole House Performance Contractors on March 29, 2011 in San Francisco, CA. The major objectives of the meeting were to: Review and validate the general business models for traditional HVAC companies and whole house energy upgrade companies Review preliminary findings on the differences between the structure of traditional HVAC Companies and whole house energy upgrade companies Seek industry input on how to structure information so it is relevant and useful for traditional HVAC contractors who are transitioning to becoming whole house energy upgrade contractors Seven industry experts identified by IBACOS participated in the session along with one representative from the National Renewable Energy Laboratory (NREL). The objective of the meeting was to validate the general operational profile of an

  3. 75 FR 69687 - Office of Biotechnology Activities Recombinant DNA Research: Proposed Actions Under the NIH...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-15

    ... of Biotechnology Activities Recombinant DNA Research: Proposed Actions Under the NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines) ACTION: Notice of consideration of proposed...- vector system may be certified only after review by the NIH Recombinant DNA Advisory Committee (RAC)...

  4. Rac2 is involved in bleomycin-induced lung inflammation leading to pulmonary fibrosis

    PubMed Central

    2014-01-01

    Background Pulmonary fibrotic diseases induce significant morbidity and mortality, for which there are limited therapeutic options available. Rac2, a ras-related guanosine triphosphatase expressed mainly in hematopoietic cells, is a crucial molecule regulating a diversity of mast cell, macrophage, and neutrophil functions. All these cell types have been implicated in the development of pulmonary fibrosis in a variety of animal models. For the studies described here we hypothesized that Rac2 deficiency protects mice from bleomycin-induced pulmonary fibrosis. Methods To determine the role of Rac2 in pulmonary fibrosis we used a bleomycin-induced mouse model. Anesthetized C57BL/6 wild type and rac2 -/- mice were instilled intratracheally with bleomycin sulphate (1.25 U/Kg) or saline as control. Bronchoalveolar lavage (BAL) samples were collected at days 3 and 7 of treatment and analyzed for matrix metalloproteinases (MMPs). On day 21 after bleomycin treatment, we measured airway resistance and elastance in tracheotomized animals. Lung sections were stained for histological analysis, while homogenates were analyzed for hydroxyproline and total collagen content. Results BLM-treated rac2 -/- mice had reduced MMP-9 levels in the BAL on day 3 and reduced neutrophilia and TNF and CCL3/MIP-1α levels in the BAL on day 7 compared to BLM-treated WT mice. We also showed that rac2 -/- mice had significantly lower mortality (30%) than WT mice (70%) at day 21 of bleomycin treatment. Lung function was diminished in bleomycin-treated WT mice, while it was unaffected in bleomycin-treated rac2 -/- mice. Histological analysis of inflammation and fibrosis as well as collagen and hydroxyproline content in the lungs did not show significant differences between BLM-treated rac2 -/- and WT and mice that survived to day 21. Conclusion Rac2 plays an important role in bleomycin-induced lung injury. It is an important signaling molecule leading to BLM-induced mortality and it also mediates the

  5. Regulation of microtubule destabilizing activity of Op18/stathmin downstream of Rac1.

    PubMed

    Wittmann, Torsten; Bokoch, Gary M; Waterman-Storer, Clare M

    2004-02-13

    In the leading edge of migrating cells, a subset of microtubules exhibits net growth in a Rac1- and p21-activated kinase-dependent manner. Here, we explore the possibility of whether phosphorylation and inactivation of the microtubule-destabilizing protein Op18/stathmin could be a mechanism regulating microtubule dynamics downstream of Rac1 and p21-activated kinases. We find that, in vitro, Pak1 phosphorylates Op18/stathmin specifically at serine 16 and inactivates its catastrophe promoting activity in biochemical and time lapse microscopy microtubule assembly assays. Furthermore, phosphorylation of either serine 16 or 63 is sufficient to inhibit Op18/stathmin in vitro. In cells, the microtubule-destabilizing effect of an excess of Op18/stathmin can be partially overcome by expression of constitutively active Rac1(Q61L), which is dependent on Pak activity, suggesting that the microtubule cytoskeleton can be regulated through inactivation of Op18/stathmin downstream of Rac1 and Pak in vivo. However, in vivo, Pak1 activity alone is not sufficient to phosphorylate Op18, indicating that additional pathways downstream of Rac1 are required for Op18 regulation.

  6. Tiam1/Rac1 complex controls Il17a transcription and autoimmunity

    PubMed Central

    Kurdi, Ahmed T.; Bassil, Ribal; Olah, Marta; Wu, Chuan; Xiao, Sheng; Taga, Mariko; Frangieh, Michael; Buttrick, Thomas; Orent, William; Bradshaw, Elizabeth M.; Khoury, Samia J.; Elyaman, Wassim

    2016-01-01

    RORγt is a master transcription factor of Th17 cells and considered as a promising drug target for the treatment of autoimmune diseases. Here, we show the guanine nucleotide exchange factor, Tiam1, and its cognate Rho-family G protein, Rac1, regulate interleukin (IL)17A transcription and autoimmunity. Whereas Tiam1 genetic deficiency weakens IL-17A expression partially and inhibits the development of experimental autoimmune encephalomyelitis (EAE), deletion of Rac1 in T cells exhibits more robust effects on Th17 cells and EAE. We demonstrate Tiam1 and Rac1 form a complex with RORγt in the nuclear compartment of Th17 cells, and together bind and activate the Il17 promoter. The clinical relevance of these findings is emphasized by pharmacological targeting of Rac1 that suppresses both murine and human Th17 cells as well as EAE. Thus, our findings highlight a regulatory pathway of Tiam1/Rac1 in Th17 cells and suggest that it may be a therapeutic target in multiple sclerosis. PMID:27725632

  7. CD81 regulates cell migration through its association with Rac GTPase

    PubMed Central

    Tejera, Emilio; Rocha-Perugini, Vera; López-Martín, Soraya; Pérez-Hernández, Daniel; Bachir, Alexia I.; Horwitz, Alan Rick; Vázquez, Jesús; Sánchez-Madrid, Francisco; Yáñez-Mo, María

    2013-01-01

    CD81 is a member of the tetraspanin family that has been described to have a key role in cell migration of tumor and immune cells. To unravel the mechanisms of CD81-regulated cell migration, we performed proteomic analyses that revealed an interaction of the tetraspanin C-terminal domain with the small GTPase Rac. Direct interaction was confirmed biochemically. Moreover, microscopy cross-correlation analysis demonstrated the in situ integration of both molecules into the same molecular complex. Pull-down experiments revealed that CD81-Rac interaction was direct and independent of Rac activation status. Knockdown of CD81 resulted in enhanced protrusion rate, altered focal adhesion formation, and decreased cell migration, correlating with increased active Rac. Reexpression of wild-type CD81, but not its truncated form lacking the C-terminal cytoplasmic domain, rescued these effects. The phenotype of CD81 knockdown cells was mimicked by treatment with a soluble peptide with the C-terminal sequence of the tetraspanin. Our data show that the interaction of Rac with the C-terminal cytoplasmic domain of CD81 is a novel regulatory mechanism of the GTPase activity turnover. Furthermore, they provide a novel mechanism for tetraspanin-dependent regulation of cell motility and open new avenues for tetraspanin-targeted reagents by the use of cell-permeable peptides. PMID:23264468

  8. Defective Rac-mediated proliferation and survival after targeted mutation of the β1 integrin cytodomain

    PubMed Central

    Hirsch, Emilio; Barberis, Laura; Brancaccio, Mara; Azzolino, Ornella; Xu, Dazhong; Kyriakis, John M.; Silengo, Lorenzo; Giancotti, Filippo G.; Tarone, Guido; Fässler, Reinhard; Altruda, Fiorella

    2002-01-01

    Cell matrix adhesion is required for cell proliferation and survival. Here we report that mutation by gene targeting of the cytoplasmic tail of β1 integrin leads to defective proliferation and survival both in vivo and in vitro. Primary murine embryonic fibroblasts (MEFs) derived from mutant homozygotes display defective cell cycle coupled to impaired activation of the FAK-PI3K-Akt and Rac-JNK signaling pathways. Expression in homozygous MEFs of a constitutively active form of Rac is able to rescue proliferation, survival, and JNK activation. Moreover, although showing normal Erk phosphorylation, mutant cells fail to display Erk nuclear translocation upon fibronectin adhesion. However, expression of the constitutively activated form of Rac restores Erk nuclear localization, suggesting that adhesion-dependent Rac activation is necessary to integrate signals directed to promote MAPK activity. Altogether, our data provide the evidence for an epistatic interaction between the β1 integrin cytoplasmic domain and Rac, and indicate that this anchorage-dependent signaling pathway is crucial for cell growth control. PMID:11980921

  9. TIPE1 induces apoptosis by negatively regulating Rac1 activation in hepatocellular carcinoma cells.

    PubMed

    Zhang, Z; Liang, X; Gao, L; Ma, H; Liu, X; Pan, Y; Yan, W; Shan, H; Wang, Z; Chen, Y H; Ma, C

    2015-05-14

    TIPE1 (tumor necrosis factor-α-induced protein 8-like 1 or TNFAIP8L1) is a newly identified member of the TIPE (TNFAIP8) family, which play roles in regulating cell death. However, the biologic functions of TIPE1 in physiologic and pathologic conditions are largely unknown. Here, we report the roles of TIPE1 in hepatocellular carcinoma (HCC). Evaluated by immunohistochemical staining, HCC tissues showed significantly downregulated TIPE1 expression compared with adjacent non-tumor tissues, which positively correlated with tumor pathologic grades and patient survival. Using a homograft tumor model in Balb/c mice, we discovered that TIPE1 significantly diminished the growth and tumor weight of murine liver cancer homografts. Consistently, TIPE1 inhibited both cell growth and colony formation ability of cultured HCC cell lines, which was further identified to be due to TIPE1-inducing apoptosis in a caspase-independent, necrostatin-1 (Nec-1)-insensitive manner. Furthermore, mechanistic investigations revealed that TIPE1 interacted with Rac1, and inhibited the activation of Rac1 and its downstream p65 and c-Jun N-terminal kinase pathway. Moreover, overexpression of constitutively active Rac1 partially rescued the apoptosis induced by TIPE1, and Rac1 knockdown significantly restored the deregulated cell growth induced by TIPE1 small interfering RNA. Our findings revealed that TIPE1 induced apoptosis in HCC cells by negatively regulating Rac1 pathway, and loss of TIPE1 might be a new prognostic indicator for HCC patients.

  10. RhoB controls endothelial barrier recovery by inhibiting Rac1 trafficking to the cell border

    PubMed Central

    Marcos-Ramiro, Beatriz; García-Weber, Diego; Barroso, Susana; Feito, Jorge; Ortega, María C.; Cernuda-Morollón, Eva; Reglero-Real, Natalia; Fernández-Martín, Laura; Durán, Maria C.; Alonso, Miguel A.; Correas, Isabel; Cox, Susan; Ridley, Anne J.

    2016-01-01

    Endothelial barrier dysfunction underlies chronic inflammatory diseases. In searching for new proteins essential to the human endothelial inflammatory response, we have found that the endosomal GTPase RhoB is up-regulated in response to inflammatory cytokines and expressed in the endothelium of some chronically inflamed tissues. We show that although RhoB and the related RhoA and RhoC play additive and redundant roles in various aspects of endothelial barrier function, RhoB specifically inhibits barrier restoration after acute cell contraction by preventing plasma membrane extension. During barrier restoration, RhoB trafficking is induced between vesicles containing RhoB nanoclusters and plasma membrane protrusions. The Rho GTPase Rac1 controls membrane spreading and stabilizes endothelial barriers. We show that RhoB colocalizes with Rac1 in endosomes and inhibits Rac1 activity and trafficking to the cell border during barrier recovery. Inhibition of endosomal trafficking impairs barrier reformation, whereas induction of Rac1 translocation to the plasma membrane accelerates it. Therefore, RhoB-specific regulation of Rac1 trafficking controls endothelial barrier integrity during inflammation. PMID:27138256

  11. Tum/RacGAP functions as a switch activating the Pav/kinesin-6 motor

    PubMed Central

    Tao, Li; Fasulo, Barbara; Warecki, Brandt; Sullivan, William

    2016-01-01

    Centralspindlin is essential for central spindle and cleavage furrow formation. Drosophila centralspindlin consists of a kinesin-6 motor (Pav/kinesin-6) and a GTPase-activating protein (Tum/RacGAP). Centralspindlin localization to the central spindle is mediated by Pav/kinesin-6. While Tum/RacGAP has well-documented scaffolding functions, whether it influences Pav/kinesin-6 function is less well-explored. Here we demonstrate that both Pav/kinesin-6 and the centralspindlin complex (co-expressed Pav/Tum) have strong microtubule bundling activity. Centralspindlin also has robust plus-end-directed motility. In contrast, Pav/kinesin-6 alone cannot move microtubules. However, the addition of Tum/RacGAP or a 65 amino acid Tum/RacGAP fragment to Pav/kinesin-6 restores microtubule motility. Further, ATPase assays reveal that microtubule-stimulated ATPase activity of centralspindlin is seven times higher than that of Pav/kinesin-6. These findings are supported by in vivo studies demonstrating that in Tum/RacGAP-depleted S2 Drosophila cells, Pav/kinesin-6 exhibits severely reduced localization to the central spindle and an abnormal concentration at the centrosomes. PMID:27091402

  12. Mena associates with Rac1 and modulates connexin 43 remodeling in cardiomyocytes.

    PubMed

    Ram, Rashmi; Wescott, Andrew P; Varandas, Katherine; Dirksen, Robert T; Blaxall, Burns C

    2014-01-01

    Mena, a member of the Ena/VASP family of actin regulatory proteins, modulates microfilaments and interacts with cytoskeletal proteins associated with heart failure. Mena is localized at the intercalated disc (ICD) of adult cardiac myocytes, colocalizing with numerous cytoskeletal proteins. Mena's role in the maintainence of mechanical myocardial stability at the cardiomyocyte ICD remains unknown. We hypothesized that Mena may modulate signals from the sarcolemma to the actin cytoskeleton at the ICD to regulate the expression and localization of connexin 43 (Cx43). The small GTPase Rac1 plays a pivotal role in the regulation of actin cytoskeletal reorganization and mediating morphological and transcriptional changes in cardiomyocytes. We found that Mena is associated with active Rac1 in cardiomyocytes and that RNAi knockdown of Mena increased Rac1 activity significantly. Furthermore, Mena knockdown increased Cx43 expression and altered Cx43 localization and trafficking at the ICD, concomitant with faster intercellular communication, as assessed by dye transfer between cardiomyocyte pairs. In mice overexpressing constitutively active Rac1, left ventricular Mena expression was increased significantly, concomitant with lateral redistribution of Cx43. These results suggest that Mena is a critical regulator of the ICD and is required for normal localization of Cx43 in part via regulation of Rac1.

  13. Management assessment of tank waste remediation system contractor readiness to proceed with phase 1B privatization

    SciTech Connect

    Honeyman, J.O.

    1998-01-09

    This Management Assessment of Tank Waste Remediation System (TWRS) Contractor Readiness to Proceed With Phase 1B Privatization documents the processes used to determine readiness to proceed with tank waste treatment technologies from private industry, now known as TWRS privatization. An overall systems approach was applied to develop action plans to support the retrieval and disposal mission of the TWRS Project. The systems and infrastructure required to support the mission are known. Required systems are either in place or plans have been developed to ensure they exist when needed. Since October 1996 a robust system engineering approach to establishing integrated Technical Baselines, work breakdown structures, tank farms organizational structure and configurations, work scope, and costs has become part of the culture within the TWRS Project. An analysis of the programmatic, management, and technical activities necessary to declare readiness to proceed with execution of the mission demonstrates that the system, personnel, and hardware will be on-line and ready to support the private contractors. The systems approach included defining the retrieval and disposal mission requirements and evaluating the readiness of the Project Hanford Management Contract (PHMC) team to support initiation of waste processing by the private contractors in June 2002 and to receive immobilized waste shortly thereafter. The Phase 1 feed delivery requirements from the private contractor Requests for Proposal were reviewed. Transfer piping routes were mapped, existing systems were evaluated, and upgrade requirements were defined.

  14. RAC1 GTPase plays an important role in γ-irradiation induced G2/M checkpoint activation

    PubMed Central

    2012-01-01

    Introduction In response to gamma-irradiation (IR)-induced double-strand DNA breaks, cells undergo cell-cycle arrest, allowing time for DNA repair before reentering the cell cycle. G2/M checkpoint activation involves activation of ataxia telangiectasia mutated (ATM)/ATM- and rad3-related (ATR) kinases and inhibition of Cdc25 phosphatases, resulting in inhibition of Cdc2 kinase and subsequent G2/M cell-cycle arrest. Previous studies from our laboratory showed that the G2/M checkpoint activation after IR exposure of MCF-7 breast cancer cells is dependent on the activation of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) signaling. In the present studies, we investigated the role of Ras-related C3 botulinum toxin substrate 1 (Rac1) guanosine triphosphatase (GTPase) in IR-induced G2/M checkpoint response and ERK1/2 activation, as well as in cell survival after IR. Methods With Rac1-specific inhibitor, dominant negative mutant Rac1 (N17Rac1) and specific small interfering RNA, the effect of Rac1 on IR-induced G2/M checkpoint response and ERK1/2 activation was examined in human breast cancer cells. In addition, the effect of Rac1 on cell survival after irradiation was assessed by using Rac1-specific inhibitor. Results IR exposure of MCF-7 breast cancer cells was associated with a marked activation of Rac1 GTPase. Furthermore, inhibition of Rac1 by using specific inhibitor, dominant-negative Rac1 mutant, or specific siRNA resulted in attenuation of IR-induced G2/M arrest and concomitant diminution of IR-induced activation of ATM, ATR, Chk1, and Chk2 kinases, as well as phosphorylation of Cdc2-Tyr15. Moreover, Rac1 inhibition or decreased Rac1 expression also abrogated IR-induced phosphorylation of mitogen-activated protein kinase kinase 1 and 2 (MEK1/2) and ERK1/2. Ultimately, inhibition of Rac1 markedly increased cellular sensitivity to IR exposure, which involves induction of apoptosis. Conclusion Studies in this report suggest that Rac1 GTPase plays an

  15. The insert region of the Rac GTPases is dispensable for activation of superoxide-producing NADPH oxidases.

    PubMed

    Miyano, Kei; Koga, Hirofumi; Minakami, Reiko; Sumimoto, Hideki

    2009-08-13

    Rac1 and Rac2, which belong to the Rho subfamily of Ras-related GTPases, play an essential role in activation of gp91phox/Nox2 (cytochrome b-245, beta polypeptide; also known as Cybb), the catalytic core of the superoxide-producing NADPH oxidase in phagocytes. Rac1 also contributes to activation of the non-phagocytic oxidases Nox1 (NADPH oxidase 1) and Nox3 (NADPH oxidase 3), each related closely to gp91phox/Nox2. It has remained controversial whether the insert region of Rac (amino acids 123-135), unique to the Rho subfamily proteins, is involved in gp91phox/Nox2 activation. In the present study we show that removal of the insert region from Rac1 neither affects activation of gp91phox/Nox2, which is reconstituted under cell-free and whole-cell conditions, nor blocks its localization to phagosomes during ingestion of IgG-coated beads by macrophage-like RAW264.7 cells. The insert region of Rac2 is also dispensable for gp91phox/Nox2 activation at the cellular level. Although Rac2, as well as Rac1, is capable of enhancing superoxide production by Nox1 and Nox3, the enhancements by the two GTPases are both independent of the insert region. We also demonstrate that Rac3, a third member of the Rac family in mammals, has an ability to activate the three oxidases and that the activation does not require the insert region. Thus the insert region of the Rac GTPases does not participate in regulation of the Nox family NADPH oxidases.

  16. Induction of Non-Apoptotic Cell Death by Activated Ras Requires Inverse Regulation of Rac1 and Arf6

    PubMed Central

    Bhanot, Haymanti; Young, Ashley M.; Overmeyer, Jean H.; Maltese, William A.

    2010-01-01

    Methuosis is a unique form of non-apoptotic cell death triggered by alterations in the trafficking of clathrin-independent endosomes, ultimately leading to extreme vacuolization and rupture of the cell. Methuosis can be induced in glioblastoma cells by expression of constitutively active Ras. This study identifies the small GTPases, Rac1 and Arf6, and the Arf6 GTPase-activating-protein, GIT1, as key downstream components of the signaling pathway underlying Ras-induced methuosis. The extent to which graded expression of active H-Ras(G12V) triggers cytoplasmic vacuolization correlates with the amount of endogenous Rac1 in the active GTP state. Blocking Rac1 activation with the specific Rac inhibitor, EHT 1864, or co-expression of dominant-negative Rac1(T17N), prevents the accumulation of vacuoles induced by H-Ras(G12V). Coincident with Rac1 activation, H-Ras(G12V) causes a decrease in the amount of active Arf6, a GTPase that functions in recycling of clathrin-independent endosomes. The effect of H-Ras(G12V) on Arf6 is blocked by EHT 1864, indicating that the decrease in Arf6-GTP is directly linked to activation of Rac1. Constitutively active Rac1(G12V) interacts with GIT1 in immunoprecipitation assays. Ablation of GIT1 by shRNA prevents the decrease in active Arf6, inhibits vacuolization, and prevents loss of cell viability in cells expressing Rac1(G12V). Together the results suggest that perturbations of endosome morphology associated with Ras-induced methuosis are due to downstream activation of Rac1, combined with reciprocal inactivation of Arf6. The latter appears to be mediated through Rac1 stimulation of GIT1. Further insights into this pathway could suggest opportunities for induction of methuosis in cancers that are resistant to apoptotic cell death. PMID:20713492

  17. miR-101 inhibits cell proliferation by targeting Rac1 in papillary thyroid carcinoma

    PubMed Central

    LIN, XIAOJIE; GUAN, HONGYU; LI, HAI; LIU, LIEHUA; LIU, JUAN; WEI, GUOHONG; HUANG, ZHIMIN; LIAO, ZHIHONG; LI, YANBING

    2014-01-01

    Accumulating evidence suggests that some microRNAs (miRNAs) are involved in papillary thyroid carcinoma (PTC) progression. However, it remains necessary to elucidate the underlying molecular mechanisms involved. In the present study, we investigated the role of microRNA-101 (miR-101) in PTC via targeting of Ras-related C3 botulinum toxin substrate 1 (Rac1). The results showed that miR-101 was significantly downregulated in PTC tissues compared with adjacent normal tissues. Restoration of miR-101 expression significantly inhibited cell proliferation in the K1 PTC cell line. Moreover, algorithm-based and experimental strategies verified Rac1 as a direct target of miR-101 in the K1 cell line. Taken together, these findings suggest that miR-101 inhibited PTC growth via the downregulation of Rac1 expression, providing a better understanding of miRNA-modulated signaling networks for future cancer therapeutics. PMID:24649082

  18. p95-APP1 links membrane transport to Rac-mediated reorganization of actin.

    PubMed

    Di Cesare, A; Paris, S; Albertinazzi, C; Dariozzi, S; Andersen, J; Mann, M; Longhi, R; de Curtis, I

    2000-08-01

    Motility requires protrusive activity at the cellular edge, where Rho family members regulate actin dynamics. Here we show that p95-APP1 (ArfGAP-putative, Pix-interacting, paxillin-interacting protein 1), a member of the GIT1/PKL family, is part of a complex that interacts with Rac. Wild-type and truncated p95-APP1 induce actin-rich protrusions mediated by Rac and ADP-ribosylation factor 6 (Arf6). Distinct p95-APP1-derived polypeptides have different distributions, indicating that p95-APP1 cycles between the cell surface and endosomes. Our results show that p95-APP1 functionally interacts with Rac and localizes to endosomal compartments, thus identifying p95-APP1 as a molecular link between actin organization, adhesion, and membrane transport during cell motility.

  19. Coronin7 regulates WASP and SCAR through CRIB mediated interaction with Rac proteins

    PubMed Central

    Swaminathan, Karthic; Stumpf, Maria; Müller, Rolf; Horn, Anna-Carolin; Schmidbauer, Julia; Eichinger, Ludwig; Müller-Taubenberger, Annette; Faix, Jan; Noegel, Angelika A.

    2015-01-01

    Coronin7 (CRN7) stabilizes F-actin and is a regulator of processes associated with the actin cytoskeleton. Its loss leads to defects in phagocytosis, motility and development. It harbors a CRIB (Cdc42- and Rac-interactive binding) domain in each of its WD repeat domains which bind to Rac GTPases preferably in their GDP-loaded forms. Expression of wild type CRN7 in CRN7 deficient cells rescued these defects, whereas proteins with mutations in the CRIB motifs which were associated with altered Rac binding were effective to varying degrees. The presence of one functional CRIB was sufficient to reestablish phagocytosis, cell motility and development. Furthermore, by molecular modeling and mutational analysis we identified the contact regions between CRN7 and the GTPases. We also identified WASP, SCAR and PAKa as downstream effectors in phagocytosis, development and cell surface adhesion, respectively, since ectopic expression rescued these functions. PMID:26411260

  20. GEFs and Rac GTPases control directional specificity of neurite extension along the anterior–posterior axis

    PubMed Central

    Zheng, Chaogu; Diaz-Cuadros, Margarete; Chalfie, Martin

    2016-01-01

    Although previous studies have identified many extracellular guidance molecules and intracellular signaling proteins that regulate axonal outgrowth and extension, most were conducted in the context of unidirectional neurite growth, in which the guidance cues either attract or repel growth cones. Very few studies addressed how intracellular signaling molecules differentially specify bidirectional outgrowth. Here, using the bipolar PLM neurons in Caenorhabditis elegans, we show that the guanine nucleotide exchange factors (GEFs) UNC-73/Trio and TIAM-1 promote anterior and posterior neurite extension, respectively. The Rac subfamily GTPases act downstream of the GEFs; CED-10/Rac1 is activated by TIAM-1, whereas CED-10 and MIG-2/RhoG act redundantly downstream of UNC-73. Moreover, these two pathways antagonize each other and thus regulate the directional bias of neuritogenesis. Our study suggests that directional specificity of neurite extension is conferred through the intracellular activation of distinct GEFs and Rac GTPases. PMID:27274054

  1. The semaphorin receptor plexin-B1 specifically interacts with active Rac in a ligand-dependent manner

    PubMed Central

    Vikis, Haris G.; Li, Weiquan; He, Zhigang; Guan, Kun-Liang

    2000-01-01

    Semaphorin molecules serve as axon guidance signals that regulate the navigation of neuronal growth cones. Semaphorins have also been implicated in other biological processes, including the immune response. Plexins, acting either alone or in complex with neuropilins, have recently been identified as functional semaphorin receptors. However, the mechanisms of signal transduction by plexins remain largely unknown. We have demonstrated a direct interaction between plexin-B1 and activated Rac. Rac specifically interacts with the cytosolic domain of plexin-B1, but not with that of plexin-A3 or -C1. Neither RhoA nor Cdc42 interacts with plexin-B1, indicating that the Rac/plexin-B1 interaction is highly specific. The binding of GTP and the integrity of the Rac effector domain are required for the interaction with plexin-B1. Furthermore, we have identified that a Cdc42/Rac interactive binding (CRIB) motif in the cytosolic domain of plexin-B1 is essential for its interaction with active Rac. We have also observed that the semaphorin CD100, a ligand for plexin-B1, stimulates the interaction between plexin-B1 and active Rac. Our results support a model by which activated Rac plays a role in mediating semaphorin signals, resulting in reorganization of actin cytoskeletal structure. PMID:11035813

  2. Vav1 and Rac Control Chemokine-promoted T Lymphocyte Adhesion Mediated by the Integrin α4β1D⃞

    PubMed Central

    García-Bernal, David; Wright, Natalia; Sotillo-Mallo, Elena; Nombela-Arrieta, César; Stein, Jens V.; Bustelo, Xosé R.; Teixidó, Joaquin

    2005-01-01

    The chemokine CXCL12 promotes T lymphocyte adhesion mediated by the integrin α4β1. CXCL12 activates the GTPase Rac, as well as Vav1, a guanine-nucleotide exchange factor for Rac, concomitant with up-regulation of α4β1-dependent adhesion. Inhibition of CXCL12-promoted Rac and Vav1 activation by transfection of dominant negative Rac or Vav1 forms, or by transfection of their siRNA, remarkably impaired the increase in T lymphocyte attachment to α4β1 ligands in response to this chemokine. Importantly, inhibition of Vav1 expression by RNA interference resulted in a blockade of Rac activation in response to CXCL12. Adhesions in flow chambers and soluble binding assays using these transfectants indicated that initial ligand binding and adhesion strengthening mediated by α4β1 were dependent on Vav1 and Rac activation by CXCL12. Finally, CXCL12-promoted T-cell transendothelial migration involving α4β1-mediated adhesion was notably inhibited by expression of dominant negative Vav1 and Rac. These results indicate that activation of Vav1-Rac signaling pathway by CXCL12 represents an important inside-out event controlling efficient up-regulation of α4β1-dependent T lymphocyte adhesion. PMID:15872091

  3. P-Rex1 links mammalian target of rapamycin signaling to Rac activation and cell migration.

    PubMed

    Hernández-Negrete, Ivette; Carretero-Ortega, Jorge; Rosenfeldt, Hans; Hernández-García, Ricardo; Calderón-Salinas, J Victor; Reyes-Cruz, Guadalupe; Gutkind, J Silvio; Vázquez-Prado, José

    2007-08-10

    Polarized cell migration results from the transduction of extra-cellular cues promoting the activation of Rho GTPases with the intervention of multidomain proteins, including guanine exchange factors. P-Rex1 and P-Rex2 are Rac GEFs connecting Gbetagamma and phosphatidylinositol 3-kinase signaling to Rac activation. Their complex architecture suggests their regulation by protein-protein interactions. Novel mechanisms of activation of Rho GTPases are associated with mammalian target of rapamycin (mTOR), a serine/threonine kinase known as a central regulator of cell growth and proliferation. Recently, two independent multiprotein complexes containing mTOR have been described. mTORC1 links to the classical rapamycin-sensitive pathways relevant for protein synthesis; mTORC2 links to the activation of Rho GTPases and cytoskeletal events via undefined mechanisms. Here we demonstrate that P-Rex1 and P-Rex2 establish, through their tandem DEP domains, interactions with mTOR, suggesting their potential as effectors in the signaling of mTOR to Rac activation and cell migration. This possibility was consistent with the effect of dominant-negative constructs and short hairpin RNA-mediated knockdown of P-Rex1, which decreased mTOR-dependent leucine-induced activation of Rac and cell migration. Rapamycin, a widely used inhibitor of mTOR signaling, did not inhibit Rac activity and cell migration induced by leucine, indicating that P-Rex1, which we found associated to both mTOR complexes, is only active when in the mTORC2 complex. mTORC2 has been described as the catalytic complex that phosphorylates AKT/PKB at Ser-473 and elicits activation of Rho GTPases and cytoskeletal reorganization. Thus, P-Rex1 links mTOR signaling to Rac activation and cell migration.

  4. Testing of a Receiver-Absorber-Converter (RAC) for the Integrated Solar Upper Stage (ISUS) program

    NASA Astrophysics Data System (ADS)

    Westerman, Kurt O.; Miles, Barry J.

    1998-01-01

    The Integrated Solar Upper Stage (ISUS) is a solar bi-modal system based on a concept developed by Babcock & Wilcox in 1992. ISUS will provide advanced power and propulsion capabilities that will enable spacecraft designers to either increase the mass to orbit or decrease the cost to orbit for their satellites. In contrast to the current practice of using chemical propulsion for orbit transfer and photovoltaic conversion/battery storage for electrical power, ISUS uses a single collection, storage, and conversion system for both the power and propulsion functions. The ISUS system is currently being developed by the Air Force's Phillips Laboratory. The ISUS program consists of a systems analysis, design, and integration (SADI) effort, and three major sub-system development efforts: the Concentrator Array and Tracking (CATS) sub-system which tracks the sun and collects/focuses the energy; the Receiver-Absorber-Converter (RAC) sub-system which receives and stores the solar energy, transfers the stored energy to the propellant during propulsion operations, and converts the stored energy to electricity during power operations; and the Cryogenic Storage and Propellant Feed Sub-system (CSPFS) which stores the liquid hydrogen propellant and provides it to the RAC during propulsion operations. This paper discuses the evolution of the RAC sub-system as a result of the component level testing, and provides the initial results of systems level ground testing. A total of 5 RACs were manufactured as part of the Phillips Laboratory ISUS Technology Development program. The first series of component tests were carried out at the Solar Rocket Propulsion Laboratory at Edwards AFB, California. These tests provided key information on the propulsion mode of operations. The second series of RAC tests were performed at the Thermionic Evaluation Facility (TEF) in Albuquerque, New Mexico and provided information on the electrical performance of the RAC. The systems level testing was

  5. Cleavage of Hyaluronan and CD44 Adhesion Molecule Regulate Astrocyte Morphology via Rac1 Signalling

    PubMed Central

    Konopka, Anna; Zeug, Andre; Skupien, Anna; Kaza, Beata; Mueller, Franziska; Chwedorowicz, Agnieszka; Ponimaskin, Evgeni; Wilczynski, Grzegorz M.; Dzwonek, Joanna

    2016-01-01

    Communication of cells with their extracellular environment is crucial to fulfill their function in physiological and pathophysiological conditions. The literature data provide evidence that such a communication is also important in case of astrocytes. Mechanisms that contribute to the interaction between astrocytes and extracellular matrix (ECM) proteins are still poorly understood. Hyaluronan is the main component of ECM in the brain, where its major receptor protein CD44 is expressed by a subset of astrocytes. Considering the fact that functions of astrocytes are tightly coupled with changes in their morphology (e.g.: glutamate clearance in the synaptic cleft, migration, astrogliosis), we investigated the influence of hyaluronan cleavage by hyaluronidase, knockdown of CD44 by specific shRNA and CD44 overexpression on astrocyte morphology. Our results show that hyaluronidase treatment, as well as knockdown of CD44, in astrocytes result in a “stellate”-like morphology, whereas overexpression of CD44 causes an increase in cell body size and changes the shape of astrocytes into flattened cells. Moreover, as a dynamic reorganization of the actin cytoskeleton is supposed to be responsible for morphological changes of cells, and this reorganization is controlled by small GTPases of the Rho family, we hypothesized that GTPase Rac1 acts as a downstream effector for hyaluronan and CD44 in astrocytes. We used FRET-based biosensor and a dominant negative mutant of Rac1 to investigate the involvement of Rac1 activity in hyaluronidase- and CD44-dependent morphological changes of astrocytes. Both, hyaluronidase treatment and knockdown of CD44, enhances Rac1 activity while overexpression of CD44 reduces the activity state in astrocytes. Furthermore, morphological changes were blocked by specific inhibition of Rac1 activity. These findings indicate for the first time that regulation of Rac1 activity is responsible for hyaluronidase and CD44-driven morphological changes of

  6. Cyclooxygenase-2 knockdown using retinoic acid chalcone (RAC), a promising therapeutic strategy for colon cancer

    PubMed Central

    Jiang, Chao; Wang, Qiong; Xu, Zhe; Li, Wei-Su; Chen, Che; Yao, Xue-Quan; Liu, Fu-Kun

    2015-01-01

    Retinoic acid is an effective agent in the treatment of epithelial and hematological malignancies. The present study demonstrates that retinoic acid chalcone (RAC), an analogue of retinoic acid inhibits cell proliferation and induces apoptosis in HCT-15 and CT26.WT colon cancer cell lines. In HCT-15 cells the percentage of apoptotic cells increased from 32.4 ± 3, 45.0 ± 3 to 72.6 ± 5% respectively at 10, 15 and 20 μg/mL compared to 3.7% in control. Similarly in CT26.WT cells the percentage increased from 28.6 ± 3, 41.2 ± 3 to 65.4 ± 5% on treatment with 10, 15 and 20 μg/mL concentrations of RAC after 72 h compared to 2.9 ± 1% in control. Western blotting, fluorescence-activated cell sorting analysis and reverse transcription-PCR assays were used to investigate these effects. RAC inhibited the overexpression of COX-2, PGE2 and PGE2 receptor (EP1 and EP4) in the colon cancer cell lines. RAC mediated inhibition of cell growth and induction of apoptosis through COX-2 inhibition was also confirmed by treating the HCT-15 and CT26.WT colon cancer cells with COX-2 inhibitor, indomethacin and transfection of cells with COX-2 small interfering RNA. In nude mice with tumor xenografts, treatment with RAC-supplemented diet caused inhibition of COX-2, PGE2, and PGE2 receptors (EP1, EP3, and EP4) in tumors. Thus RAC can be a potential candidate for the treatment of colon cancer through the inhibition of COX-2 expression and subsequent inhibition of PGE2 and PGE2 receptors. PMID:26269760

  7. Rac-1 as a new therapeutic target in cerebro- and cardio-vascular diseases.

    PubMed

    Carrizzo, Albino; Forte, Maurizio; Lembo, Maria; Formisano, Luigi; Puca, Annibale A; Vecchione, Carmine

    2014-01-01

    Growing evidence indicates that overproduction of reactive oxygen species (ROS) plays a prominent role in the development of cardio- and cerebro-vascular diseases. Among the mechanisms identified to produce oxidative stress in the vascular wall, those mediated by membrane-bound NAD(P)H oxidases represent a major one. NAD(P)H oxidases are a family of enzymes that generate ROS both in phagocytic and non-phagocytic cell types. Vascular NAD(P)H oxidase contains the membrane-bound subunits Nox1, Nox2 (gp91phox), Nox4 and p22phox, the catalytic site of the oxidase, and the cytosolic components p47phox and p67phox. Rac1 (Ras-related C3 botulinum toxin substrate1) is a small GTPase essential for the assembly and activation of NADPH oxidase. Several molecular and cellular studies have reported the involvement of Rac1 in different cardiovascular pathologies, such as vascular smooth muscle proliferation, cardiomyocyte hypertrophy, endothelial cell shape change, atherosclerosis and endothelial dysfunction in hypertension. In addition, increased activation of NADPH oxidase by Rac1 has been reported in animals and humans after myocardial infarction and heart failure. The Rac1/NADPH pathway has also been found involved in different pathologies of the cerebral district, such as ischemic stroke, cognitive impairment, subaracnoid hemorrhage and neuronal oxidative damage typical of several neurodegenerative disorders. In addition, thrombotic events are an important step in the onset of cardio- and cerebrovascular diseases. Rac1 has been found involved also in platelet activation, inducing actin polymerization and lamellipodia formation, which are necessary steps for platelet aggregation. Taken together, the evidence candidates Rac1 as a new pharmacological target of cardiovascular and cerebrovascular diseases. Although the involvement of Rac1 in the beneficial pleiotropic effects of drugs such as statins is well known, and the onset of numerous side effects has raised concern for the

  8. Maintenance and operations contractor plan for transition to the project Hanford management contract (PHMC)

    SciTech Connect

    Waite, J.L.

    1996-04-12

    This plan has been developed by Westinghouse Hanford Company (WHC), and its subcontractors ICF Kaiser Hanford (ICF KH) and BCS Richland, Inc. (BCSR), at the direction of the US Department of Energy (DOE), Richland Operations Office (RL). WHC and its subcontractors are hereafter referred to as the Maintenance and Operations (M and O) Contractor. The plan identifies actions involving the M and O Contractor that are critical to (1) prepare for a smooth transition to the Project Hanford Management Contractor (PHMC), and (2) support and assist the PHMC and RL in achieving transition as planned, with no or minimal impact to ongoing baseline activities. The plan is structured around two primary phases. The first is the pre-award phase, which started in mid-February 1996 and is currently scheduled to be completed on June 1, 1996, at which time the contract is currently planned to be awarded. The second is the follow-on four-month post-award phase from June 1, 1996, until October 1, 1996. Considering the magnitude and complexity of the scope of work being transitioned, completion in four months will require significant effort by all parties. To better ensure success, the M and O Contractor has developed a pre-award phase that is intended to maximize readiness for transition. Priority is given to preparation for facility assessments and processing of personnel, as these areas are determined to be on the critical path for transition. In addition, the M and O Contractor will put emphasis during the pre-award phase to close out open items prior to contract award, to include grievances, employee concerns, audit findings, compliance issues, etc.

  9. Contingency Contractor Optimization Phase 3 Sustainment Database Design Document - Contingency Contractor Optimization Tool - Prototype

    SciTech Connect

    Frazier, Christopher Rawls; Durfee, Justin David; Bandlow, Alisa; Gearhart, Jared Lee; Jones, Katherine A

    2016-05-01

    The Contingency Contractor Optimization Tool – Prototype (CCOT-P) database is used to store input and output data for the linear program model described in [1]. The database allows queries to retrieve this data and updating and inserting new input data.

  10. Inhibition of the Rho GTPase, Rac1, decreases estrogen receptor levels and is a novel therapeutic strategy in breast cancer.

    PubMed

    Rosenblatt, Adena E; Garcia, Maria Ines; Lyons, Leah; Xie, Yingqiu; Maiorino, Carol; Désiré, Laurent; Slingerland, Joyce; Burnstein, Kerry L

    2011-04-01

    Rac1, a Rho GTPase, modulates diverse cellular processes and is hyperactive in some cancers. Estrogen receptor-alpha (ERα) in concert with intracellular signaling pathways regulates genes associated with cell proliferation, tumor development, and breast cancer cell survival. Therefore, we examined the possibility of Rac1 and ERα crosstalk in breast cancer cells. We found that Rac1 enhanced ERα transcriptional activity in breast cancer cells. Vav3, a Rho guanine nucleotide exchange factor that activates Rac1, was an upstream mediator, and P21/Cdc42/Rac1 activating kinase-1 (Pak-1) was a downstream effector of Rac1 enhancement of ERα activity. These results suggest that Rac1 may prove to be a therapeutic target. To test this hypothesis, we used a small molecule Rac inhibitor, EHT 1864, and found that EHT 1864 inhibited ERα transcriptional activity. Furthermore, EHT 1864 inhibited estrogen-induced cell proliferation in breast cancer cells and decreased tamoxifen-resistant breast cancer cell growth. EHT 1864 decreased activity of the promoter of the ERα gene resulting in down-regulation of ERα mRNA and protein levels. Therefore, ERα down-regulation by EHT 1864 is the likely mechanism of EHT 1864-mediated inhibition of ERα activity and estrogen-stimulated breast cancer cell proliferation. Since ERα plays a critical role in the pathogenesis of breast cancer and the Rac inhibitor EHT 1864 down-regulates ERα expression and breast cancer cell proliferation, further investigation of the therapeutic potential of Rac1 targeting in the treatment of breast cancer is warranted.

  11. The Crystal Structure of the Plant Small GTPase OsRac1 Reveals Its Mode of Binding to NADPH Oxidase*

    PubMed Central

    Kosami, Ken-ichi; Ohki, Izuru; Nagano, Minoru; Furuita, Kyoko; Sugiki, Toshihiko; Kawano, Yoji; Kawasaki, Tsutomu; Fujiwara, Toshimichi; Nakagawa, Atsushi; Shimamoto, Ko; Kojima, Chojiro

    2014-01-01

    Rac/Rop proteins are Rho-type small GTPases that act as molecular switches in plants. Recent studies have identified these proteins as key components in many major plant signaling pathways, such as innate immunity, pollen tube growth, and root hair formation. In rice, the Rac/Rop protein OsRac1 plays an important role in regulating the production of reactive oxygen species (ROS) by the NADPH oxidase OsRbohB during innate immunity. However, the molecular mechanism by which OsRac1 regulates OsRbohB remains unknown. Here, we report the crystal structure of OsRac1 complexed with the non-hydrolyzable GTP analog guanosine 5′-(β,γ-imido)triphosphate at 1.9 Å resolution; this represents the first active-form structure of a plant small GTPase. To elucidate the ROS production in rice cells, structural information was used to design OsRac1 mutants that displayed reduced binding to OsRbohB. Only mutations in the OsRac1 Switch I region showed attenuated interactions with OsRbohB in vitro. In particular, Tyr39 and Asp45 substitutions suppressed ROS production in rice cells, indicating that these residues are critical for interaction with and activation of OsRbohB. Structural comparison of active-form OsRac1 with AtRop9 in its GDP-bound inactive form showed a large conformational difference in the vicinity of these residues. Our results provide new insights into the molecular mechanism of the immune response through OsRac1 and the various cellular responses associated with plant Rac/Rop proteins. PMID:25128531

  12. A Rac1 GTPase is a critical factor in the immune response of shrimp (Litopenaeus vannamei) to Vibrio alginolyticus infection.

    PubMed

    Cha, Gui-Hong; Wang, Wei-Na; Peng, Ting; Huang, Ming-Zhu; Liu, Yuan

    2015-08-01

    The small GTPase Rac1 acts as a molecular switch for signal transduction that regulates various cellular functions. However, its functions in crustaceans remain unclear. In this study, a cDNA encoding a RAS GTPase (LvRac1) in the Pacific white shrimp (L. vannamei) was identified and characterized. A recombinant variant of this GTPase, rLvRac1, was expressed in the model organism P. pastoris and its expression was confirmed by mass spectrometry. Biochemical assays indicated that the recombinant protein retained GTPase activity and was expressed in all of the organism's tested tissues. Injection of the bacterium V. alginolyticus into L. vannamei induced hepatopancreatic upregulation of LvRac1 expression. Moreover, knocking down LvRac1 in vivo significantly reduced the expression of the L. vannamei p53 and Cu/Zn superoxide dismutase genes (Lvp53 and LvCu/Zn SOD, respectively) while increasing that of the galectin gene (Lvgal). Hemolymph samples from control and LvRac1-silenced L. vannamei individuals were analyzed by flow cytometry, revealing that the latter exhibited significantly reduced respiratory burst activity and total hemocyte counts. Cumulative mortality in shrimp lacking LvRac1 was significantly greater than in control groups following V. alginolyticus challenge. The silencing of LvRac1 by double-stranded RNA injection thus increased the V. alginolyticus challenge sensitivity of L. vannamei and weakened its bacterial clearance ability in vivo. Suppressing LvRac1 also promoted the upregulation of Lvp53, LvCu/ZnSOD, and Lvgal following V. alginolyticus injection. Taken together, these results suggest that LvRac1 is important in the innate immune response of shrimp to V. alginolyticus infection.

  13. 48 CFR 970.0309 - Whistleblower Protection of Contractor Employees.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... OF ENERGY AGENCY SUPPLEMENTARY REGULATIONS DOE MANAGEMENT AND OPERATING CONTRACTS Improper Business Practices and Personal Conflicts of Interest 970.0309 Whistleblower Protection of Contractor Employees....

  14. 48 CFR 970.0309 - Whistleblower Protection of Contractor Employees.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... OF ENERGY AGENCY SUPPLEMENTARY REGULATIONS DOE MANAGEMENT AND OPERATING CONTRACTS Improper Business Practices and Personal Conflicts of Interest 970.0309 Whistleblower Protection of Contractor Employees....

  15. 48 CFR 970.0309 - Whistleblower Protection of Contractor Employees.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... OF ENERGY AGENCY SUPPLEMENTARY REGULATIONS DOE MANAGEMENT AND OPERATING CONTRACTS Improper Business Practices and Personal Conflicts of Interest 970.0309 Whistleblower Protection of Contractor Employees....

  16. 48 CFR 970.0309 - Whistleblower Protection of Contractor Employees.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... OF ENERGY AGENCY SUPPLEMENTARY REGULATIONS DOE MANAGEMENT AND OPERATING CONTRACTS Improper Business Practices and Personal Conflicts of Interest 970.0309 Whistleblower Protection of Contractor Employees....

  17. 10 CFR 824.16 - Direction to NNSA contractors.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... INFORMATION SECURITY VIOLATIONS § 824.16 Direction to NNSA contractors. (a) Notwithstanding any other... compel attendance; (3) Disclosures of information or documents obtained during an investigation...

  18. 10 CFR 824.16 - Direction to NNSA contractors.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... INFORMATION SECURITY VIOLATIONS § 824.16 Direction to NNSA contractors. (a) Notwithstanding any other... compel attendance; (3) Disclosures of information or documents obtained during an investigation...

  19. 10 CFR 824.16 - Direction to NNSA contractors.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... INFORMATION SECURITY VIOLATIONS § 824.16 Direction to NNSA contractors. (a) Notwithstanding any other... compel attendance; (3) Disclosures of information or documents obtained during an investigation...

  20. 10 CFR 824.16 - Direction to NNSA contractors.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... INFORMATION SECURITY VIOLATIONS § 824.16 Direction to NNSA contractors. (a) Notwithstanding any other... compel attendance; (3) Disclosures of information or documents obtained during an investigation...

  1. 76 FR 50714 - Federal Acquisition Regulation; Documenting Contractor Performance; Correction

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-16

    ... Federal Acquisition Regulation; Documenting Contractor Performance; Correction AGENCY: Department of... Performance. DATES: The comment period for the proposed rule published June, 28, 2011, at 76 FR 37704,...

  2. The contractor`s role in low-level waste disposal facility application review and licensing

    SciTech Connect

    Serie, P.J.; Dressen, A.L.

    1991-12-31

    The California Department of Health Services will soon reach a licensing decision on the proposed Ward Valley low-level radioactive waste disposal facility. As the first regulatory agency in the country to address the 10 CFR Part 61 requirements for a new disposal facility, California`s program has broken new ground in its approach. Throughout the review process, the Department has relied on contractor support to augment its technical and administrative staff. A team consisting of Roy F. Weston, Inc., supported by ERM-Program Management Corp., Environmental Issues Management, Inc., and Rogers and Associates Engineering Corporation, has worked closely with the Department in a staff extension role. The authors have been involved with the project in contractor project management roles since 1987, and continue to support the Department`s program as it proceeds to finalize its licensing process. This paper describes the selection process used to identify a contractor team with the needed skills and experience, and the makeup of team capabilities. It outlines the management, communication, and technical approaches used to assure a smooth agency-contractor function and relationship. It describes the techniques used to ensure that decisions and documents represented the Department credibly in its role as the regulatory and licensing agency under the Nuclear Regulatory Commission (NRC) Agreement State program. The paper outlines the license application review process and activities, through preparation of licensing documentation and responses to public comments. Lessons learned in coordination of an agency-contractor team effort to review and license a low-level waste disposal facility are reviewed and suggestions made for approaching a similar license application review and licensing situation.

  3. Fast changes in the functional status of release sites during short-term plasticity: involvement of a frequency-dependent bypass of Rac at Aplysia synapses

    PubMed Central

    Humeau, Yann; Doussau, Frédéric; Popoff, Michel R; Benfenati, Fabio; Poulain, Bernard

    2007-01-01

    silenced by Rac inactivation. This effect did not appear to result from reversion of LT inhibitory action but from bypassing the step regulated by Rac. Altogether the data suggest that Rac and the intracellular pathway which allows the bypassing of Rac are key players in new forms of short-term plasticity that rely on fast, activity-dependent changes in the functional status of the release sites. PMID:17656428

  4. 48 CFR 52.247-16 - Contractor Responsibility for Returning Undelivered Freight.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... no fault of the Contractor, a shipment cannot be delivered, the Contractor shall contact the shipper... shall maintain a record of the goods that, through no fault of the Contractor, could not be delivered... fault of the Contractor, a shipment cannot be delivered, the Contractor shall return the shipment to...

  5. 48 CFR 52.247-16 - Contractor Responsibility for Returning Undelivered Freight.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... no fault of the Contractor, a shipment cannot be delivered, the Contractor shall contact the shipper... shall maintain a record of the goods that, through no fault of the Contractor, could not be delivered... fault of the Contractor, a shipment cannot be delivered, the Contractor shall return the shipment to...

  6. 48 CFR 52.247-16 - Contractor Responsibility for Returning Undelivered Freight.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... no fault of the Contractor, a shipment cannot be delivered, the Contractor shall contact the shipper... shall maintain a record of the goods that, through no fault of the Contractor, could not be delivered... fault of the Contractor, a shipment cannot be delivered, the Contractor shall return the shipment to...

  7. 48 CFR 52.247-16 - Contractor Responsibility for Returning Undelivered Freight.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... no fault of the Contractor, a shipment cannot be delivered, the Contractor shall contact the shipper... shall maintain a record of the goods that, through no fault of the Contractor, could not be delivered... fault of the Contractor, a shipment cannot be delivered, the Contractor shall return the shipment to...

  8. 48 CFR 2427.305-2 - Follow-up by contractor.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 6 2010-10-01 2010-10-01 true Follow-up by contractor....305-2 Follow-up by contractor. (b) Contractor reports. Contractors shall complete and submit to the... Contracting Officer shall send the form to those contractors whose contract work may have required...

  9. 77 FR 69715 - Federal Acquisition Regulation; Updates to Contract Reporting and Central Contractor Registration

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-11-20

    ... Contractor Registration AGENCY: Department of Defense (DoD), General Services Administration (GSA), and... changes the clauses requiring contractor registration in the Central Contractor Registration (CCR... unique identifier for contractors. It is used (1) to uniquely identify a contractor entity, and (2)...

  10. Remedial Action Contacts Directory - 1997

    SciTech Connect

    1997-05-01

    This document, which was prepared for the US Department of Energy (DOE) Office of Environmental Restoration (ER), is a directory of 2628 individuals interested or involved in environmental restoration and/or remedial actions at radioactively contaminated sites. This directory contains a list of mailing addresses and phone numbers of DOE operations, area, site, project, and contractor offices; an index of DOE operations, area, site, project, and contractor office sorted by state; a list of individuals, presented by last name, facsimile number, and e-mail address; an index of affiliations presented alphabetically, with individual contacts appearing below each affiliation name; and an index of foreign contacta sorted by country and affiliation. This document was generated from the Remedial Action Contacts Database, which is maintained by the Remedial Action Program Information Center (RAPIC).

  11. 44 CFR 352.23 - Functions of a Regional Assistance Committee (RAC).

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 44 Emergency Management and Assistance 1 2013-10-01 2013-10-01 false Functions of a Regional Assistance Committee (RAC). 352.23 Section 352.23 Emergency Management and Assistance FEDERAL EMERGENCY MANAGEMENT AGENCY, DEPARTMENT OF HOMELAND SECURITY PREPAREDNESS COMMERCIAL NUCLEAR POWER PLANTS:...

  12. 44 CFR 352.23 - Functions of a Regional Assistance Committee (RAC).

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 44 Emergency Management and Assistance 1 2010-10-01 2010-10-01 false Functions of a Regional Assistance Committee (RAC). 352.23 Section 352.23 Emergency Management and Assistance FEDERAL EMERGENCY MANAGEMENT AGENCY, DEPARTMENT OF HOMELAND SECURITY PREPAREDNESS COMMERCIAL NUCLEAR POWER PLANTS:...

  13. Role of Rac GTPases in Chemokine-Stimulated Breast Carcinoma Metastasis

    DTIC Science & Technology

    2008-07-01

    clinically relevant, including hypoxia, ionizing radiation and chemotherapeutic drugs. We also examined whether rhMMP9 or MDA-MB-231 conditioned medium...Interestingly, Rac1b is poorly expressed in MCF10A , a normal human breast epithelial cell line, and is undetectable in all the highly invasive breast

  14. Junctional actin assembly is mediated by Formin-like 2 downstream of Rac1

    PubMed Central

    Grikscheit, Katharina; Frank, Tanja; Wang, Ying

    2015-01-01

    Epithelial integrity is vitally important, and its deregulation causes early stage cancer. De novo formation of an adherens junction (AJ) between single epithelial cells requires coordinated, spatial actin dynamics, but the mechanisms steering nascent actin polymerization for cell–cell adhesion initiation are not well understood. Here we investigated real-time actin assembly during daughter cell–cell adhesion formation in human breast epithelial cells in 3D environments. We identify formin-like 2 (FMNL2) as being specifically required for actin assembly and turnover at newly formed cell–cell contacts as well as for human epithelial lumen formation. FMNL2 associates with components of the AJ complex involving Rac1 activity and the FMNL2 C terminus. Optogenetic control of Rac1 in living cells rapidly drove FMNL2 to epithelial cell–cell contact zones. Furthermore, Rac1-induced actin assembly and subsequent AJ formation critically depends on FMNL2. These data uncover FMNL2 as a driver for human epithelial AJ formation downstream of Rac1. PMID:25963818

  15. Antiviral activity of a Rac GEF inhibitor characterized with a sensitive HIV/SIV fusion assay

    SciTech Connect

    Pontow, Suzanne; Harmon, Brooke; Campbell, Nancy; Ratner, Lee

    2007-11-10

    A virus-dependent fusion assay was utilized to examine the activity of a panel of HIV-1, -2, and SIV isolates of distinct coreceptor phenotypes. This assay allowed identification of entry inhibitors, and characterization of an antagonist of a Rac guanine nucleotide exchange factor, as an inhibitor of HIV-mediated fusion.

  16. Benefit of Mineralocorticoid Receptor Antagonism in AKI: Role of Vascular Smooth Muscle Rac1.

    PubMed

    Barrera-Chimal, Jonatan; André-Grégoire, Gwennan; Nguyen Dinh Cat, Aurelie; Lechner, Sebastian M; Cau, Jérôme; Prince, Sonia; Kolkhof, Peter; Loirand, Gervaise; Sauzeau, Vincent; Hauet, Thierry; Jaisser, Frédéric

    2017-01-13

    AKI is a frequent complication in hospitalized patients. Unfortunately, there is no effective pharmacologic approach for treating or preventing AKI. In rodents, mineralocorticoid receptor (MR) antagonism prevents AKI induced by ischemia-reperfusion (IR). We investigated the specific role of vascular MR in mediating AKI induced by IR. We also assessed the protective effect of MR antagonism in IR-induced AKI in the Large White pig, a model of human AKI. In mice, MR deficiency in smooth muscle cells (SMCs) protected against kidney IR injury. MR blockade by the novel nonsteroidal MR antagonist, finerenone, or genetic deletion of MR in SMCs associated with weaker oxidative stress production. Moreover, ischemic kidneys had higher levels of Rac1-GTP, required for NADPH oxidase activation, than sham control kidneys, and genetic deletion of Rac1 in SMCs protected against AKI. Furthermore, genetic deletion of MR in SMCs blunted the production of Rac1-GTP after IR. Pharmacologic inhibition of MR also prevented AKI induced by IR in the Large White pig. Altogether, we show that MR antagonism, or deletion of the MR gene in SMCs, limited the renal injury induced by IR through effects on Rac1-mediated MR signaling. The benefits of MR antagonism in the pig provide a rational basis for future clinical trials assessing the benefits of this approach in patients with IR-mediated AKI.

  17. MAP1B Regulates Axonal Development by Modulating Rho-GTPase Rac1 Activity

    PubMed Central

    Montenegro-Venegas, Carolina; Tortosa, Elena; Rosso, Silvana; Peretti, Diego; Bollati, Flavia; Bisbal, Mariano; Jausoro, Ignacio; Avila, Jesus; Cáceres, Alfredo

    2010-01-01

    Cultured neurons obtained from MAP1B-deficient mice have a delay in axon outgrowth and a reduced rate of axonal elongation compared with neurons from wild-type mice. Here we show that MAP1B deficiency results in a significant decrease in Rac1 and cdc42 activity and a significant increase in Rho activity. We found that MAP1B interacted with Tiam1, a guanosine nucleotide exchange factor for Rac1. The decrease in Rac1/cdc42 activity was paralleled by decreases in the phosphorylation of the downstream effectors of these proteins, such as LIMK-1 and cofilin. The expression of a constitutively active form of Rac1, cdc42, or Tiam1 rescued the axon growth defect of MAP1B-deficient neurons. Taken together, these observations define a new and crucial function of MAP1B that we show to be required for efficient cross-talk between microtubules and the actin cytoskeleton during neuronal polarization. PMID:20719958

  18. 48 CFR 45.105 - Contractors' property management system compliance.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Contractors' property management system compliance. 45.105 Section 45.105 Federal Acquisition Regulations System FEDERAL... the contractor's property management policies, procedures, practices, and systems. This analysis...

  19. 48 CFR 253.209-1 - Responsible prospective contractors.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... required service. (B) Production capability. An evaluation of the prospective contractor's ability to plan, control, and integrate manpower, facilities, and other resources necessary for successful contract... prospective contractor's system provides for timely placement of orders and for vendor follow-up and...

  20. 48 CFR 52.204-7 - Central Contractor Registration.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... Contractor Registration (APR 2008) (a) Definitions. As used in this clause— Central Contractor Registration... obtain one. (1) An offeror may obtain a DUNS number— (i) Via the Internet at http://fedgov.dnb.comwebform or if the offeror does not have internet access, it may call Dun and Bradstreet at 1-866-705-5711...

  1. 24 CFR 5.1004 - Central contractor registration.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 24 Housing and Urban Development 1 2011-04-01 2011-04-01 false Central contractor registration. 5... Urban Development GENERAL HUD PROGRAM REQUIREMENTS; WAIVERS Application, Registration, and Submission Requirements § 5.1004 Central contractor registration. Applicants for HUD financial assistance that are...

  2. 48 CFR 752.7013 - Contractor-mission relationships.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ....7013 Contractor-mission relationships. For use in all USAID contracts involving performance overseas... contract, and for advising USAID regarding the performance of the work under the contract and its effect on... restrictive of academic freedom. Notwithstanding these academic freedoms, the Contractor's employees, while...

  3. 48 CFR 1646.301 - Contractor inspection requirements.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 6 2010-10-01 2010-10-01 true Contractor inspection requirements. 1646.301 Section 1646.301 Federal Acquisition Regulations System OFFICE OF PERSONNEL MANAGEMENT... Clauses 1646.301 Contractor inspection requirements. The clause set forth at 1652.246-70 shall be...

  4. 10 CFR 436.32 - Qualified contractors lists.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 3 2010-01-01 2010-01-01 false Qualified contractors lists. 436.32 Section 436.32 Energy... Procedures for Energy Savings Performance Contracting § 436.32 Qualified contractors lists. (a) DOE shall... energy savings performance contracts. (c) DOE may remove a firm from DOE's list of qualified...

  5. 48 CFR 45.501 - Prime contractor alternate locations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Prime contractor alternate... CONTRACT MANAGEMENT GOVERNMENT PROPERTY Support Government Property Administration 45.501 Prime contractor... administration from another contract administration office, for purposes of evaluating prime...

  6. 48 CFR 36.201 - Evaluation of contractor performance.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Evaluation of contractor performance. 36.201 Section 36.201 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION... Contracting for Construction 36.201 Evaluation of contractor performance. See 42.1502(e) for the...

  7. 14 CFR 1274.402 - Contractor acquired property.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false Contractor acquired property. 1274.402 Section 1274.402 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION COOPERATIVE AGREEMENTS WITH COMMERCIAL FIRMS Property § 1274.402 Contractor acquired property. As provided in §...

  8. 21 CFR 20.90 - Disclosure to contractors.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 1 2011-04-01 2011-04-01 false Disclosure to contractors. 20.90 Section 20.90 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PUBLIC... exempt from public disclosure may be disclosed to contractors with the Food and Drug Administration...

  9. 48 CFR 1403.570 - Restrictions on contractor advertising.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 5 2014-10-01 2014-10-01 false Restrictions on contractor advertising. 1403.570 Section 1403.570 Federal Acquisition Regulations System DEPARTMENT OF THE INTERIOR... 1403.570 Restrictions on contractor advertising....

  10. 48 CFR 1403.570 - Restrictions on contractor advertising.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 5 2012-10-01 2012-10-01 false Restrictions on contractor advertising. 1403.570 Section 1403.570 Federal Acquisition Regulations System DEPARTMENT OF THE INTERIOR... 1403.570 Restrictions on contractor advertising....

  11. 48 CFR 1403.570 - Restrictions on contractor advertising.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 5 2011-10-01 2011-10-01 false Restrictions on contractor advertising. 1403.570 Section 1403.570 Federal Acquisition Regulations System DEPARTMENT OF THE INTERIOR... 1403.570 Restrictions on contractor advertising....

  12. 48 CFR 307.108-70 - Telecommuting of contractor employees.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... telecommuting) for any part of an SOW/PWS, after determining that the work or any portion thereof must be... 48 Federal Acquisition Regulations System 4 2014-10-01 2014-10-01 false Telecommuting of... Telecommuting of contractor employees. (a) SOWs/PWSs shall permit offerors or contractors to specify their...

  13. 48 CFR 307.108-70 - Telecommuting of contractor employees.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... telecommuting) for any part of an SOW/PWS, after determining that the work or any portion thereof must be... 48 Federal Acquisition Regulations System 4 2010-10-01 2010-10-01 false Telecommuting of... Telecommuting of contractor employees. (a) SOWs/PWSs shall permit offerors or contractors to specify their...

  14. 48 CFR 307.108-70 - Telecommuting of contractor employees.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... telecommuting) for any part of an SOW/PWS, after determining that the work or any portion thereof must be... 48 Federal Acquisition Regulations System 4 2013-10-01 2013-10-01 false Telecommuting of... Telecommuting of contractor employees. (a) SOWs/PWSs shall permit offerors or contractors to specify their...

  15. 48 CFR 307.108-70 - Telecommuting of contractor employees.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... telecommuting) for any part of an SOW/PWS, after determining that the work or any portion thereof must be... 48 Federal Acquisition Regulations System 4 2012-10-01 2012-10-01 false Telecommuting of... Telecommuting of contractor employees. (a) SOWs/PWSs shall permit offerors or contractors to specify their...

  16. 48 CFR 307.108-70 - Telecommuting of contractor employees.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... telecommuting) for any part of an SOW/PWS, after determining that the work or any portion thereof must be... 48 Federal Acquisition Regulations System 4 2011-10-01 2011-10-01 false Telecommuting of... Telecommuting of contractor employees. (a) SOWs/PWSs shall permit offerors or contractors to specify their...

  17. 48 CFR 227.7203-11 - Contractor procedures and records.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... Rights in Computer Software and Computer Software Documentation 227.7203-11 Contractor procedures and records. (a) The clause at 252.227-7014, Rights in Noncommercial Computer Software and Noncommercial Computer Software Documentation, requires a contractor, and its subcontractors or suppliers that...

  18. 48 CFR 642.1503-70 - Contractor Performance System (CPS).

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... System (CPS). 642.1503-70 Section 642.1503-70 Federal Acquisition Regulations System DEPARTMENT OF STATE...-70 Contractor Performance System (CPS). (a) The Department of State subscribes to the Contractor Performance System (CPS) maintained by the National Institutes of Health. CPS is an Internet-based...

  19. 48 CFR 642.1503-70 - Contractor Performance System (CPS).

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... System (CPS). 642.1503-70 Section 642.1503-70 Federal Acquisition Regulations System DEPARTMENT OF STATE...-70 Contractor Performance System (CPS). (a) The Department of State subscribes to the Contractor Performance System (CPS) maintained by the National Institutes of Health. CPS is an Internet-based...

  20. 48 CFR 642.1503-70 - Contractor Performance System (CPS).

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... System (CPS). 642.1503-70 Section 642.1503-70 Federal Acquisition Regulations System DEPARTMENT OF STATE...-70 Contractor Performance System (CPS). (a) The Department of State subscribes to the Contractor Performance System (CPS) maintained by the National Institutes of Health. CPS is an Internet-based...

  1. 48 CFR 642.1503-70 - Contractor Performance System (CPS).

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... System (CPS). 642.1503-70 Section 642.1503-70 Federal Acquisition Regulations System DEPARTMENT OF STATE...-70 Contractor Performance System (CPS). (a) The Department of State subscribes to the Contractor Performance System (CPS) maintained by the National Institutes of Health. CPS is an Internet-based...

  2. 48 CFR 642.1503-70 - Contractor Performance System (CPS).

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... System (CPS). 642.1503-70 Section 642.1503-70 Federal Acquisition Regulations System DEPARTMENT OF STATE...-70 Contractor Performance System (CPS). (a) The Department of State subscribes to the Contractor Performance System (CPS) maintained by the National Institutes of Health. CPS is an Internet-based...

  3. 10 CFR 820.13 - Direction to NNSA contractors.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 4 2012-01-01 2012-01-01 false Direction to NNSA contractors. 820.13 Section 820.13 Energy DEPARTMENT OF ENERGY PROCEDURAL RULES FOR DOE NUCLEAR ACTIVITIES General § 820.13 Direction to NNSA contractors. (a) Notwithstanding any other provision of this part, and pursuant to section 3213...

  4. 48 CFR 2132.170 - Recurring premium payments to Contractors.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    .... (b) Withdrawals from the LOC account for benefit costs of $5,000 or more will be made on a claims-paid basis. Withdrawals from the LOC account for benefit costs of less than $5,000 and other FEGLI... Contractor's bank for payment. (c) Nothing in this chapter will affect the ability of the Contractor to...

  5. 48 CFR 2132.170 - Recurring premium payments to Contractors.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    .... (b) Withdrawals from the LOC account for benefit costs of $5,000 or more will be made on a claims-paid basis. Withdrawals from the LOC account for benefit costs of less than $5,000 and other FEGLI... Contractor's bank for payment. (c) Nothing in this chapter will affect the ability of the Contractor to...

  6. 48 CFR 2132.170 - Recurring premium payments to Contractors.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    .... (b) Withdrawals from the LOC account for benefit costs of $5,000 or more will be made on a claims-paid basis. Withdrawals from the LOC account for benefit costs of less than $5,000 and other FEGLI... Contractor's bank for payment. (c) Nothing in this chapter will affect the ability of the Contractor to...

  7. 48 CFR 2132.170 - Recurring premium payments to Contractors.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    .... (b) Withdrawals from the LOC account for benefit costs of $5,000 or more will be made on a claims-paid basis. Withdrawals from the LOC account for benefit costs of less than $5,000 and other FEGLI... Contractor's bank for payment. (c) Nothing in this chapter will affect the ability of the Contractor to...

  8. 32 CFR 516.21 - Litigation against government contractors.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 3 2014-07-01 2014-07-01 false Litigation against government contractors. 516... Litigation against government contractors. (a) General. A contract might require that the government... the underlying contract with the government requires reimbursement for adverse judgments or costs...

  9. 10 CFR 904.12 - Payments to contractors.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 Energy 4 2014-01-01 2014-01-01 false Payments to contractors. 904.12 Section 904.12 Energy DEPARTMENT OF ENERGY GENERAL REGULATIONS FOR THE CHARGES FOR THE SALE OF POWER FROM THE BOULDER CANYON PROJECT Power Marketing § 904.12 Payments to contractors. (a) Funds advanced to the Secretary of...

  10. 10 CFR 904.12 - Payments to contractors.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 4 2011-01-01 2011-01-01 false Payments to contractors. 904.12 Section 904.12 Energy DEPARTMENT OF ENERGY GENERAL REGULATIONS FOR THE CHARGES FOR THE SALE OF POWER FROM THE BOULDER CANYON PROJECT Power Marketing § 904.12 Payments to contractors. (a) Funds advanced to the Secretary of...

  11. 10 CFR 904.12 - Payments to contractors.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 4 2012-01-01 2012-01-01 false Payments to contractors. 904.12 Section 904.12 Energy DEPARTMENT OF ENERGY GENERAL REGULATIONS FOR THE CHARGES FOR THE SALE OF POWER FROM THE BOULDER CANYON PROJECT Power Marketing § 904.12 Payments to contractors. (a) Funds advanced to the Secretary of...

  12. 10 CFR 904.12 - Payments to contractors.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 4 2013-01-01 2013-01-01 false Payments to contractors. 904.12 Section 904.12 Energy DEPARTMENT OF ENERGY GENERAL REGULATIONS FOR THE CHARGES FOR THE SALE OF POWER FROM THE BOULDER CANYON PROJECT Power Marketing § 904.12 Payments to contractors. (a) Funds advanced to the Secretary of...

  13. 3 CFR - Addressing Tax Delinquency by Government Contractors

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 3 The President 1 2011-01-01 2011-01-01 false Addressing Tax Delinquency by Government Contractors Presidential Documents Other Presidential Documents Memorandum of January 20, 2010 Addressing Tax Delinquency by Government Contractors Memorandum for the Heads of Executive Departments and Agencies The Federal Government pays more than half...

  14. 48 CFR 227.7203-11 - Contractor procedures and records.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... Rights in Computer Software and Computer Software Documentation 227.7203-11 Contractor procedures and records. (a) The clause at 252.227-7014, Rights in Noncommercial Computer Software and Noncommercial Computer Software Documentation, requires a contractor, and its subcontractors or suppliers that...

  15. 48 CFR 227.7203-11 - Contractor procedures and records.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Rights in Computer Software and Computer Software Documentation 227.7203-11 Contractor procedures and records. (a) The clause at 252.227-7014, Rights in Noncommercial Computer Software and Noncommercial Computer Software Documentation, requires a contractor, and its subcontractors or suppliers that...

  16. 48 CFR 45.606 - Contractor scrap procedures.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... CONTRACT MANAGEMENT GOVERNMENT PROPERTY Reporting, Reutilization, and Disposal 45.606 Contractor scrap... proper disposition and are properly documented in the contractor's property management procedures. (b... precious or strategic metals; or (6) That is dangerous to public health or safety. (c) Absent...

  17. 48 CFR 45.606 - Contractor scrap procedures.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... CONTRACT MANAGEMENT GOVERNMENT PROPERTY Reporting, Reutilization, and Disposal 45.606 Contractor scrap... proper disposition and are properly documented in the contractor's property management procedures. (b... precious or strategic metals; or (6) That is dangerous to public health or safety. (c) Absent...

  18. 21 CFR 21.30 - Records of contractors.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 1 2013-04-01 2013-04-01 false Records of contractors. 21.30 Section 21.30 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROTECTION OF... contractors to accomplish Food and Drug Administration functions, from which information is retrieved...

  19. 21 CFR 21.30 - Records of contractors.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 1 2012-04-01 2012-04-01 false Records of contractors. 21.30 Section 21.30 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROTECTION OF... contractors to accomplish Food and Drug Administration functions, from which information is retrieved...

  20. 48 CFR 42.402 - Visits to contractors' facilities.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... visit will result in reviewing, auditing, or obtaining any information from the contractor relating to... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Visits to contractors' facilities. 42.402 Section 42.402 Federal Acquisition Regulations System FEDERAL ACQUISITION...

  1. 48 CFR 1403.570 - Restrictions on contractor advertising.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Restrictions on contractor advertising. 1403.570 Section 1403.570 Federal Acquisition Regulations System DEPARTMENT OF THE INTERIOR... 1403.570 Restrictions on contractor advertising....

  2. 48 CFR 970.5244-1 - Contractor purchasing system.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... SUPPLEMENTARY REGULATIONS DOE MANAGEMENT AND OPERATING CONTRACTS Solicitation Provisions and Contract Clauses for Management and Operating Contracts 970.5244-1 Contractor purchasing system. As prescribed in 970... transaction and the price paid. The Contractor's purchasing performance will be evaluated against...

  3. 42 CFR 405.1807 - Effect of contractor determination.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 2 2014-10-01 2014-10-01 false Effect of contractor determination. 405.1807 Section 405.1807 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN... Determinations and Appeals § 405.1807 Effect of contractor determination. The determination shall be final...

  4. 48 CFR 923.102 - Applicability to contractors.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... contractors. 923.102 Section 923.102 Federal Acquisition Regulations System DEPARTMENT OF ENERGY SOCIOECONOMIC PROGRAMS ENVIRONMENT, ENERGY AND WATER EFFICIENCY, RENEWABLE ENERGY TECHNOLOGIES, OCCUPATIONAL SAFETY, AND DRUG-FREE WORKPLACE Sustainable Acquisition 923.102 Applicability to contractors. Many of...

  5. 48 CFR 923.102 - Applicability to contractors.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... contractors. 923.102 Section 923.102 Federal Acquisition Regulations System DEPARTMENT OF ENERGY SOCIOECONOMIC PROGRAMS ENVIRONMENT, ENERGY AND WATER EFFICIENCY, RENEWABLE ENERGY TECHNOLOGIES, OCCUPATIONAL SAFETY, AND DRUG-FREE WORKPLACE Sustainable Acquisition 923.102 Applicability to contractors. Many of...

  6. 48 CFR 923.102 - Applicability to contractors.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... contractors. 923.102 Section 923.102 Federal Acquisition Regulations System DEPARTMENT OF ENERGY SOCIOECONOMIC PROGRAMS ENVIRONMENT, ENERGY AND WATER EFFICIENCY, RENEWABLE ENERGY TECHNOLOGIES, OCCUPATIONAL SAFETY, AND DRUG-FREE WORKPLACE Sustainable Acquisition 923.102 Applicability to contractors. Many of...

  7. 48 CFR 52.204-7 - Central Contractor Registration.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... (CCR) database means the primary Government repository for Contractor information required for the...) for the same concern. Registered in the CCR database means that— (1) The Contractor has entered all... Federal Funding Accountability and Transparency Act of 2006 (see subpart 4.14), into the CCR database;...

  8. 48 CFR 970.5203-3 - Contractor's organization.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    .... 970.5203-3 Section 970.5203-3 Federal Acquisition Regulations System DEPARTMENT OF ENERGY AGENCY... they occur. (b) Supervisory representative of Contractor. Unless otherwise directed by the Contracting... may require, with the approval of the Secretary of Energy, the Contractor to remove the employee...

  9. 48 CFR 1845.610 - Sale of surplus contractor inventory.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 6 2010-10-01 2010-10-01 true Sale of surplus contractor inventory. 1845.610 Section 1845.610 Federal Acquisition Regulations System NATIONAL AERONAUTICS AND SPACE... Inventory 1845.610 Sale of surplus contractor inventory....

  10. 48 CFR 2452.237-75 - Clearance of contractor personnel.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... URBAN DEVELOPMENT CLAUSES AND FORMS SOLICITATION PROVISIONS AND CONTRACT CLAUSES Texts of Provisions and... clause in solicitations and contracts. Clearance of Contractor Personnel (OCT 1999) (a) General. This contract requires contractor employees to work in, and have access to, a HUD facility. All such...

  11. 48 CFR 253.209-1 - Responsible prospective contractors.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... prospective contractor's quality assurance system, personnel, facilities, and equipment. (D) Financial..., and understanding of the requirements necessary to produce the required product or provide the... prospective contractor's system provides for timely placement of orders and for vendor follow-up and...

  12. 48 CFR 227.7203-11 - Contractor procedures and records.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... Rights in Computer Software and Computer Software Documentation 227.7203-11 Contractor procedures and records. (a) The clause at 252.227-7014, Rights in Noncommercial Computer Software and Noncommercial Computer Software Documentation, requires a contractor, and its subcontractors or suppliers that...

  13. 48 CFR 227.7203-11 - Contractor procedures and records.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... Rights in Computer Software and Computer Software Documentation 227.7203-11 Contractor procedures and records. (a) The clause at 252.227-7014, Rights in Noncommercial Computer Software and Noncommercial Computer Software Documentation, requires a contractor, and its subcontractors or suppliers that...

  14. The Rac Inhibitor EHop-016 Inhibits Mammary Tumor Growth and Metastasis in a Nude Mouse Model

    PubMed Central

    Castillo-Pichardo, Linette; Humphries-Bickley, Tessa; De La Parra, Columba; Forestier-Roman, Ingrid; Martinez-Ferrer, Magaly; Hernandez, Eliud; Vlaar, Cornelis; Ferrer-Acosta, Yancy; Washington, Anthony V.; Cubano, Luis A.; Rodriguez-Orengo, Jose; Dharmawardhane, Suranganie

    2014-01-01

    Metastatic disease still lacks effective treatments, and remains the primary cause of cancer mortality. Therefore, there is a critical need to develop better strategies to inhibit metastatic cancer. The Rho family GTPase Rac is an ideal target for anti-metastatic cancer therapy, because Rac is a key molecular switch that is activated by a myriad of cell surface receptors to promote cancer cell migration/invasion and survival. Previously, we reported the design and development of EHop-016, a small molecule compound, which inhibits Rac activity of metastatic cancer cells with an IC50 of 1 μM. EHop-016 also inhibits the activity of the Rac downstream effector p21-activated kinase (PAK), lamellipodia extension, and cell migration in metastatic cancer cells. Herein, we tested the efficacy of EHop-016 in a nude mouse model of experimental metastasis, where EHop-016 administration at 25 mg/kg body weight (BW) significantly reduced mammary fat pad tumor growth, metastasis, and angiogenesis. As quantified by UPLC MS/MS, EHop-016 was detectable in the plasma of nude mice at 17 to 23 ng/ml levels at 12 h following intraperitoneal (i.p.) administration of 10 to 25 mg/kg BW EHop-016. The EHop-016 mediated inhibition of angiogenesis In Vivo was confirmed by immunohistochemistry of excised tumors and by In Vitro tube formation assays of endothelial cells. Moreover, EHop-016 affected cell viability by down-regulating Akt and Jun kinase activities and c-Myc and Cyclin D expression, as well as increasing caspase 3/7 activities in metastatic cancer cells. In conclusion, EHop-016 has potential as an anticancer compound to block cancer progression via multiple Rac-directed mechanisms. PMID:25389450

  15. Rac1b enhances cell survival through activation of the JNK2/c-JUN/Cyclin-D1 and AKT2/MCL1 pathways

    PubMed Central

    Wang, Hong; Wei, Si-Si; Chen, Jie; Chen, Yi-He; Xu, Wei-Ping; Jie, Qi-Qiang; Zhou, Qing; Li, Yi-Gang; Wei, Yi-Dong; Wang, Yue-Peng

    2016-01-01

    Rac1b is a constitutively activated, alternatively spliced form of the small GTPase Rac1. Previous studies showed that Rac1b promotes cell proliferation and inhibits apoptosis. In the present study, we used microarray analysis to detect genes differentially expressed in HEK293T cells and SW480 human colon cancer cells stably overexpressing Rac1b. We found that the pro-proliferation genes JNK2, c-JUN and cyclin-D1 as well as anti-apoptotic AKT2 and MCL1 were all upregulated in both lines. Rac1b promoted cell proliferation and inhibited apoptosis by activating the JNK2/c-JUN/cyclin-D1 and AKT2/MCL1 pathways, respectively. Very low Rac1b levels were detected in the colonic epithelium of wild-type Sprague-Dawley rats. Knockout of the rat Rac1 gene exon-3b or knockdown of endogenous Rac1b in HT29 human colon cancer cells downregulated only the AKT2/MCL1 pathway. Our study revealed that very low levels of endogenous Rac1b inhibit apoptosis, while Rac1b upregulation both promotes cell proliferation and inhibits apoptosis. It is likely the AKT2/MCL1 pathway is more sensitive to Rac1b regulation. PMID:26918455

  16. Rac1 regulates skin tumors by regulation of keratin 17 through recruitment and interaction with CD11b+Gr1+ cells

    PubMed Central

    Zhou, Ying; Zhu, Shaojun; Liu, Juanjuan; Wang, Dong; Deng, Anmei; Wang, Zhipeng

    2014-01-01

    Rac1 is a member of the Rho family of small GTPases that control cells proliferation, differentiation, migration, and inflammation. Rac1 is crucial in tumorigenesis and development. Keratin17 and CD11b+Gr1+ cells are considered to regulate skin inflmmation. Here we discuss the regulation of Rac1 on skin tumor formation and its relationship. In samples from human skin squamous cell carcinoma (SCC), Rac1 activity was higher in cancer tissues than in normal skin and activity correlated with keratin 17 overexpression. In a DMBA/TPA-induced mouse skin tumor model, inhibition of Rac1 activity and depletion of CD11b+Gr1+ cells resulted in significant tumor formation. TPA induced recruitment of CD11b+Gr1+ cells into dermis; however, Rac1 inhibitor abolished this recruitment. In vitro, Rac1 induced interferon (IFN) and interlukin (IL6) production in keratinocytes, repression of keratin 17 inhibited IFN and IL6 production induced by Rac1. Moreover, both inhibition of Rac1 activity and repression of keratin 17 restricted proliferation and induction of differentiation in keratinocytes. Coculture of CD11b+Gr1+ cells with keratinocytes activated Wnt pathway in keratinocytes, resulting in enhanced Rac1 activity, overexpression of keratin 17, and hyperproliferation of keratinocytes. Our results suggested that hyperactive Rac1 recruited and interacted with CD11b+Gr1+ cells, inducing keratin 17-regulated inflammation and promoting skin tumor formation. PMID:24962779

  17. The positive allosteric modulator of the GABA(B) receptor, rac-BHFF, suppresses alcohol self-administration.

    PubMed

    Maccioni, Paola; Thomas, Andrew W; Carai, Mauro A M; Gessa, Gian Luigi; Malherbe, Pari; Colombo, Giancarlo

    2010-06-01

    The present study was designed to extend to the newly synthesized rac-BHFF [(R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one] the investigation on the capacity of positive allosteric modulators of the GABA(B) receptor to reduce alcohol self-administration in rats. To this end, selectively bred Sardinian alcohol-preferring (sP) rats were initially trained to respond on a lever [on a fixed ratio 4 (FR4) schedule of reinforcement] to orally self-administer alcohol (15%, v/v) or sucrose (0.7%, w/v) in daily 30-min sessions. Once responding reached stable levels, the effect of rac-BHFF (0, 50, 100, and 200mg/kg; i.g.) on responding for alcohol and sucrose was determined. Pretreatment with rac-BHFF produced a dose-dependent suppression in responding for alcohol; reduction in the total number of responses for alcohol, in comparison to vehicle-treated rats, averaged approximately 30%, 65%, and 90% in 50, 100, and 200mg/kg rac-BHFF-treated rats, respectively. Pretreatment with 200mg/kg rac-BHFF markedly increased the latency to the first response on the alcohol lever. The effect of pretreatment with rac-BHFF on alcohol self-administration was highly specific, since (a) responding for sucrose was reduced (to approximately 50%, in comparison to vehicle-treated rats) only by pretreatment with 200mg/kg rac-BHFF, and (b) latency to the first response on the sucrose lever was completely unaltered by any rac-BHFF dose. Treatment with rac-BHFF did not alter spontaneous locomotor activity in an independent group of sP rats. The present data constitute a further piece of evidence on the capacity of positive allosteric modulators of the GABA(B) receptor to reduce alcohol's reinforcing properties in rats.

  18. Cryptococcus neoformans phospholipase B1 activates host cell Rac1 for traversal across the blood-brain barrier.

    PubMed

    Maruvada, Ravi; Zhu, Longkun; Pearce, Donna; Zheng, Yi; Perfect, John; Kwon-Chung, Kyung J; Kim, Kwang Sik

    2012-10-01

    Cryptococcus neoformans penetration into the central nervous system (CNS) requires traversal of the blood-brain barrier that is composed of a single layer of human brain microvascular endothelial cells (HBMEC), but the underlying mechanisms of C. neoformans traversal remain incompletely understood. C. neoformans transcytosis of HBMEC monolayer involves rearrangements of the host cell actin cytoskeleton and small GTP-binding Rho family proteins such as Rac1 are shown to regulate host cell actin cytoskeleton. We, therefore, examined whether C. neoformans traversal of the blood-brain barrier involves host Rac1. While the levels of activated Rac1 (GTP-Rac1) in HBMEC increased significantly upon incubation with C. neoformans strains, pharmacological inhibition and down-modulation of Rac1 significantly decreased C. neoformans transcytosis of HBMEC monolayer. Also, Rac1 inhibition was efficient in preventing C. neoformans penetration into the brain. In addition, C. neoformans phospholipase B1 (Plb1) was shown to contribute to activating host cell Rac1, andSTAT3 was observed to associate with GTP-Rac1 in HBMEC that were incubated with C. neoformans strain but not with its Δplb1 mutant. These findings demonstrate for the first time that C. neoformans Plb1 aids fungal traversal across the blood-brain barrier by activating host cell Rac1 and its association with STAT3, and suggest that pharmacological intervention of host-microbial interaction contributing to traversal of the blood-brain barrier may prevent C. neoformans penetration into the brain.

  19. Rac1 GTPase-deficient mouse lens exhibits defects in shape, suture formation, fiber cell migration and survival.

    PubMed

    Maddala, Rupalatha; Chauhan, Bharesh K; Walker, Christopher; Zheng, Yi; Robinson, Michael L; Lang, Richard A; Rao, Ponugoti V

    2011-12-01

    Morphogenesis and shape of the ocular lens depend on epithelial cell elongation and differentiation into fiber cells, followed by the symmetric and compact organization of fiber cells within an enclosed extracellular matrix-enriched elastic capsule. The cellular mechanisms orchestrating these different events however, remain obscure. We investigated the role of the Rac1 GTPase in these processes by targeted deletion of expression using the conditional gene knockout (cKO) approach. Rac1 cKO mice were derived from two different Cre (Le-Cre and MLR-10) transgenic mice in which lens-specific Cre expression starts at embryonic day 8.75 and 10.5, respectively, in both the lens epithelium and fiber cells. The Le-Cre/Rac1 cKO mice exhibited an early-onset (E12.5) and severe lens phenotype compared to the MLR-10/Rac1 cKO (E15.5) mice. While the Le-Cre/Rac1 cKO lenses displayed delayed primary fiber cell elongation, lenses from both Rac1 cKO strains were characterized by abnormal shape, impaired secondary fiber cell migration, sutural defects and thinning of the posterior capsule which often led to rupture. Lens fiber cell N-cadherin/β-catenin/Rap1/Nectin-based cell-cell junction formation and WAVE-2/Abi-2/Nap1-regulated actin polymerization were impaired in the Rac1 deficient mice. Additionally, the Rac1 cKO lenses were characterized by a shortened epithelial sheet, reduced levels of extracellular matrix (ECM) proteins and increased apoptosis. Taken together, these data uncover the essential role of Rac1 GTPase activity in establishment and maintenance of lens shape, suture formation and capsule integrity, and in fiber cell migration, adhesion and survival, via regulation of actin cytoskeletal dynamics, cell adhesive interactions and ECM turnover.

  20. VE-cadherin trans-interactions modulate Rac activation and enhancement of lung endothelial barrier by iloprost.

    PubMed

    Birukova, Anna A; Tian, Yufeng; Dubrovskyi, Oleksii; Zebda, Noureddine; Sarich, Nicolene; Tian, Xinyong; Wang, Yingxiao; Birukov, Konstantin G

    2012-10-01

    Small GTPase Rac is important regulator of endothelial cell (EC) barrier enhancement by prostacyclin characterized by increased peripheral actin cytoskeleton and increased interactions between VE-cadherin and other adherens junction (AJ) proteins. This study utilized complementary approaches including siRNA knockdown, culturing in Ca(2+) -free medium, and VE-cadherin blocking antibody to alter VE-cadherin extracellular interactions to investigate the role of VE-cadherin outside-in signaling in modulation of Rac activation and EC barrier regulation by prostacyclin analog iloprost. Spatial analysis of Rac activation in pulmonary EC by FRET revealed additional spike in iloprost-induced Rac activity at the sites of newly formed cell-cell junctions. In contrast, disruption of VE-cadherin extracellular trans-interactions suppressed iloprost-activated Rac signaling and attenuated EC barrier enhancement and cytoskeletal remodeling. These inhibitory effects were associated with decreased membrane accumulation and activation of Rac-specific guanine nucleotide exchange factors (GEFs) Tiam1 and Vav2. Conversely, plating of pulmonary EC on surfaces coated with extracellular VE-cadherin domain further promoted iloprost-induced Rac signaling. In the model of thrombin-induced EC barrier recovery, blocking of VE-cadherin trans-interactions attenuated activation of Rac pathway during recovery phase and delayed suppression of Rho signaling and restoration of EC barrier properties. These results suggest that VE-cadherin outside-in signaling controls locally Rac activity stimulated by barrier protective agonists. This control is essential for maximal EC barrier enhancement and accelerated barrier recovery.