Science.gov

Sample records for 10-11 mol l-1

  1. Determination of inorganic ionic mercury down to 5x10(-14) mol l(-1) by differential-pulse anodic stripping voltammetry.

    PubMed

    Meyer, S; Scholz, F; Trittler, R

    1996-09-01

    A new method is described for the reliable and ultrasensitive determination of inorganic ionic mercury, using differential-pulse anodic stripping voltammetry on a glassy carbon electrode. It has been possible to determine mercury down to a concentration of 5x10(-14) mol l(-1) (the lowest detection limit ever reported for a voltammetric method). This success was achieved by using a thiocyanate electrolyte and relatively long deposition times. The mercury ions are stabilized in the solution by the formation of strong thiocyanate complexes. This leads to a highly reproducible cathodic plating and anodic dissolution of mercury. A speciation analysis allowing to distinguish between dissolved atomic and ionic mercury in water is possible. PMID:15048362

  2. 44 CFR 10.11 - Environmental information.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 44 Emergency Management and Assistance 1 2011-10-01 2011-10-01 false Environmental information. 10.11 Section 10.11 Emergency Management and Assistance FEDERAL EMERGENCY MANAGEMENT AGENCY, DEPARTMENT OF HOMELAND SECURITY GENERAL ENVIRONMENTAL CONSIDERATIONS Agency Implementing Procedures § 10.11 Environmental information. Interested persons...

  3. 44 CFR 10.11 - Environmental information.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 44 Emergency Management and Assistance 1 2010-10-01 2010-10-01 false Environmental information. 10.11 Section 10.11 Emergency Management and Assistance FEDERAL EMERGENCY MANAGEMENT AGENCY, DEPARTMENT OF HOMELAND SECURITY GENERAL ENVIRONMENTAL CONSIDERATIONS Agency Implementing Procedures §...

  4. 44 CFR 10.11 - Environmental information.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 44 Emergency Management and Assistance 1 2014-10-01 2014-10-01 false Environmental information. 10... OF HOMELAND SECURITY GENERAL ENVIRONMENTAL CONSIDERATIONS Agency Implementing Procedures § 10.11 Environmental information. Interested persons may contact the Environmental Officer or the...

  5. 44 CFR 10.11 - Environmental information.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 44 Emergency Management and Assistance 1 2012-10-01 2011-10-01 true Environmental information. 10... OF HOMELAND SECURITY GENERAL ENVIRONMENTAL CONSIDERATIONS Agency Implementing Procedures § 10.11 Environmental information. Interested persons may contact the Environmental Officer or the...

  6. 44 CFR 10.11 - Environmental information.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 44 Emergency Management and Assistance 1 2013-10-01 2013-10-01 false Environmental information. 10... OF HOMELAND SECURITY GENERAL ENVIRONMENTAL CONSIDERATIONS Agency Implementing Procedures § 10.11 Environmental information. Interested persons may contact the Environmental Officer or the...

  7. 46 CFR 90.10-11 - Coastwise.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) CARGO AND MISCELLANEOUS VESSELS GENERAL PROVISIONS Definition of Terms Used in This Subchapter § 90.10-11 Coastwise. Under this designation shall be included all vessels normally navigating the waters of any ocean or the Gulf of Mexico 20 nautical miles...

  8. 46 CFR 90.10-11 - Coastwise.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) CARGO AND MISCELLANEOUS VESSELS GENERAL PROVISIONS Definition of Terms Used in This Subchapter § 90.10-11 Coastwise. Under this designation shall be included all vessels normally navigating the waters of any ocean or the Gulf of Mexico 20 nautical miles...

  9. 46 CFR 90.10-11 - Coastwise.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) CARGO AND MISCELLANEOUS VESSELS GENERAL PROVISIONS Definition of Terms Used in This Subchapter § 90.10-11 Coastwise. Under this designation shall be included all vessels normally navigating the waters of any ocean or the Gulf of Mexico 20 nautical miles...

  10. 46 CFR 188.10-11 - Chemistry laboratory.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 7 2010-10-01 2010-10-01 false Chemistry laboratory. 188.10-11 Section 188.10-11 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OCEANOGRAPHIC RESEARCH VESSELS GENERAL PROVISIONS Definition of Terms Used in This Subchapter § 188.10-11 Chemistry laboratory. This term...

  11. 46 CFR 188.10-11 - Chemistry laboratory.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 7 2013-10-01 2013-10-01 false Chemistry laboratory. 188.10-11 Section 188.10-11 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OCEANOGRAPHIC RESEARCH VESSELS GENERAL PROVISIONS Definition of Terms Used in This Subchapter § 188.10-11 Chemistry laboratory. This term...

  12. 46 CFR 188.10-11 - Chemistry laboratory.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 7 2011-10-01 2011-10-01 false Chemistry laboratory. 188.10-11 Section 188.10-11 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OCEANOGRAPHIC RESEARCH VESSELS GENERAL PROVISIONS Definition of Terms Used in This Subchapter § 188.10-11 Chemistry laboratory. This term...

  13. 46 CFR 188.10-11 - Chemistry laboratory.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 7 2014-10-01 2014-10-01 false Chemistry laboratory. 188.10-11 Section 188.10-11 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OCEANOGRAPHIC RESEARCH VESSELS GENERAL PROVISIONS Definition of Terms Used in This Subchapter § 188.10-11 Chemistry laboratory. This term...

  14. 46 CFR 188.10-11 - Chemistry laboratory.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 7 2012-10-01 2012-10-01 false Chemistry laboratory. 188.10-11 Section 188.10-11 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OCEANOGRAPHIC RESEARCH VESSELS GENERAL PROVISIONS Definition of Terms Used in This Subchapter § 188.10-11 Chemistry laboratory. This term...

  15. 46 CFR 30.10-11 - Coastwise-TB/C.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 1 2011-10-01 2011-10-01 false Coastwise-TB/C. 30.10-11 Section 30.10-11 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY TANK VESSELS GENERAL PROVISIONS Definitions § 30.10-11 Coastwise—TB/C. Under this designation shall be included all tank vessels normally navigating the waters of...

  16. 1 CFR 10.11 - Scope and sources.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 1 General Provisions 1 2011-01-01 2011-01-01 false Scope and sources. 10.11 Section 10.11 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER SPECIAL EDITIONS OF THE FEDERAL REGISTER PRESIDENTIAL PAPERS Annual Publication § 10.11 Scope and sources. The basic text of the Public Papers...

  17. 1 CFR 10.11 - Scope and sources.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 1 General Provisions 1 2010-01-01 2010-01-01 false Scope and sources. 10.11 Section 10.11 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER SPECIAL EDITIONS OF THE FEDERAL REGISTER PRESIDENTIAL PAPERS Annual Publication § 10.11 Scope and sources. The basic text of the Public Papers...

  18. 1 CFR 10.11 - Scope and sources.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 1 General Provisions 1 2012-01-01 2012-01-01 false Scope and sources. 10.11 Section 10.11 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER SPECIAL EDITIONS OF THE FEDERAL REGISTER PRESIDENTIAL PAPERS Annual Publication § 10.11 Scope and sources. The basic text of the Public Papers...

  19. 1 CFR 10.11 - Scope and sources.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 1 General Provisions 1 2013-01-01 2012-01-01 true Scope and sources. 10.11 Section 10.11 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER SPECIAL EDITIONS OF THE FEDERAL REGISTER PRESIDENTIAL PAPERS Annual Publication § 10.11 Scope and sources. The basic text of the Public Papers...

  20. 1 CFR 10.11 - Scope and sources.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 1 General Provisions 1 2014-01-01 2012-01-01 true Scope and sources. 10.11 Section 10.11 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER SPECIAL EDITIONS OF THE FEDERAL REGISTER PRESIDENTIAL PAPERS Annual Publication § 10.11 Scope and sources. The basic text of the Public Papers...

  1. L1 retrotransposition

    PubMed Central

    Viollet, Sébastien; Monot, Clément; Cristofari, Gaël

    2014-01-01

    LINE-1 (L1) elements are the only active and autonomous transposable elements in humans. The core retrotransposition machinery is a ribonucleoprotein particle (RNP) containing the L1 mRNA, with endonuclease and reverse transcriptase activities. It initiates reverse transcription directly at genomic target sites upon endonuclease cleavage. Recently, using a direct L1 extension assay (DLEA), we systematically tested the ability of native L1 RNPs to extend DNA substrates of various sequences and structures. We deduced from these experiments the general rules guiding the initiation of L1 reverse transcription, referred to as the snap-velcro model. In this model, L1 target choice is not only mediated by the sequence specificity of the endonuclease, but also through base-pairing between the L1 mRNA and the target site, which permits the subsequent L1 reverse transcription step. In addition, L1 reverse transcriptase efficiently primes L1 DNA synthesis only when the 3′ end of the DNA substrate is single-stranded, suggesting so-far unrecognized DNA processing steps at the integration site. PMID:24818067

  2. 47 CFR 10.11 - CMAS implementation timeline.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 1 2010-10-01 2010-10-01 false CMAS implementation timeline. 10.11 Section 10.11 Telecommunication FEDERAL COMMUNICATIONS COMMISSION GENERAL COMMERCIAL MOBILE ALERT SYSTEM General... Federal Alert Aggregator and Alert Gateway makes the Government Interface Design specifications available....

  3. 47 CFR 10.11 - WEA implementation timeline.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 1 2014-10-01 2014-10-01 false WEA implementation timeline. 10.11 Section 10.11 Telecommunication FEDERAL COMMUNICATIONS COMMISSION GENERAL WIRELESS EMERGENCY ALERTS General... Alert Aggregator and Alert Gateway makes the Government Interface Design specifications available....

  4. 47 CFR 10.11 - WEA implementation timeline.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 1 2013-10-01 2013-10-01 false WEA implementation timeline. 10.11 Section 10.11 Telecommunication FEDERAL COMMUNICATIONS COMMISSION GENERAL WIRELESS EMERGENCY ALERTS General... Alert Aggregator and Alert Gateway makes the Government Interface Design specifications available....

  5. 47 CFR 10.11 - CMAS implementation timeline.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 1 2012-10-01 2012-10-01 false CMAS implementation timeline. 10.11 Section 10.11 Telecommunication FEDERAL COMMUNICATIONS COMMISSION GENERAL COMMERCIAL MOBILE ALERT SYSTEM General... Federal Alert Aggregator and Alert Gateway makes the Government Interface Design specifications available....

  6. 47 CFR 10.11 - CMAS implementation timeline.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 1 2011-10-01 2011-10-01 false CMAS implementation timeline. 10.11 Section 10.11 Telecommunication FEDERAL COMMUNICATIONS COMMISSION GENERAL COMMERCIAL MOBILE ALERT SYSTEM General... Federal Alert Aggregator and Alert Gateway makes the Government Interface Design specifications available....

  7. 27 CFR 10.11 - Meaning of terms.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2014-04-01 2014-04-01 false Meaning of terms. 10.11... OF THE TREASURY ALCOHOL COMMERCIAL BRIBERY Definitions § 10.11 Meaning of terms. As used in this part, unless the context otherwise requires, terms have the meanings given in this section. Any other...

  8. 27 CFR 10.11 - Meaning of terms.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2011-04-01 2011-04-01 false Meaning of terms. 10.11... OF THE TREASURY LIQUORS COMMERCIAL BRIBERY Definitions § 10.11 Meaning of terms. As used in this part, unless the context otherwise requires, terms have the meanings given in this section. Any other...

  9. 27 CFR 10.11 - Meaning of terms.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2012-04-01 2012-04-01 false Meaning of terms. 10.11... OF THE TREASURY LIQUORS COMMERCIAL BRIBERY Definitions § 10.11 Meaning of terms. As used in this part, unless the context otherwise requires, terms have the meanings given in this section. Any other...

  10. 27 CFR 10.11 - Meaning of terms.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2013-04-01 2013-04-01 false Meaning of terms. 10.11... OF THE TREASURY ALCOHOL COMMERCIAL BRIBERY Definitions § 10.11 Meaning of terms. As used in this part, unless the context otherwise requires, terms have the meanings given in this section. Any other...

  11. 40 CFR 10.11 - Relationship to other agency regulations.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 1 2012-07-01 2012-07-01 false Relationship to other agency regulations. 10.11 Section 10.11 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GENERAL... regulations in this part apply to the consideration by the Environmental Protection Agency of...

  12. 40 CFR 10.11 - Relationship to other agency regulations.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 1 2011-07-01 2011-07-01 false Relationship to other agency regulations. 10.11 Section 10.11 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GENERAL... regulations in this part apply to the consideration by the Environmental Protection Agency of...

  13. 40 CFR 10.11 - Relationship to other agency regulations.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 1 2014-07-01 2014-07-01 false Relationship to other agency regulations. 10.11 Section 10.11 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GENERAL... regulations in this part apply to the consideration by the Environmental Protection Agency of...

  14. 40 CFR 10.11 - Relationship to other agency regulations.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Relationship to other agency regulations. 10.11 Section 10.11 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GENERAL... regulations in this part apply to the consideration by the Environmental Protection Agency of...

  15. 40 CFR 10.11 - Relationship to other agency regulations.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 1 2013-07-01 2013-07-01 false Relationship to other agency regulations. 10.11 Section 10.11 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GENERAL... regulations in this part apply to the consideration by the Environmental Protection Agency of...

  16. MICAL-L1

    PubMed Central

    Sharma, Mahak; Giridharan, Sai Srinivas Panapakkam; Rahajeng, Juliati

    2010-01-01

    A key regulator of the slow recycling of receptors and lipids that occurs from the endocytic recycling compartment (ERC) back to the cell surface is EHD1. We have recently identified the Rab8a-interacting protein, MICAL-L1, as a novel binding partner for EHD1 that both recruits and interacts with EHD1 on tubular recycling endosomes. MICAL-L1 belongs to the MICALfamily of proteins that are highly expressed in neurons and involved in plexin-mediated repulsive axon guidance. Interestingly, MICAL-L1 contains a coiled coil region in its C-terminus that is both necessary and sufficient for its localization to the EHD1-containing long tubular membranes of the ERC. Furthermore, MICAL-L1-depletion also impaired recycling of both transferrin and integrin receptors from the ERC back to the plasma membrane. In conclusion, our studies implicate MICAL-L1 as a novel regulator of endocytic recycling, and raises the possibility that additional neuronal-expressed proteins may mediate endocytic events in non-neuronal cells. PMID:20585517

  17. 6. Historic view, Pier 9, 10, 11. Aerial Views to ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    6. Historic view, Pier 9, 10, 11. Aerial Views to east, 1943. Photographic copy of photo. Boston National Historical Park Archives, Charlestown Navy Yard. - Charlestown Navy Yard, Pier 9, Between Piers 8 & 10, along Mystic River on Charlestown Waterfront at eastern edge of Navy Yard, Boston, Suffolk County, MA

  18. 37 CFR 10.11 - Removing names from the register.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 37 Patents, Trademarks, and Copyrights 1 2012-07-01 2012-07-01 false Removing names from the..., DEPARTMENT OF COMMERCE REPRESENTATION OF OTHERS BEFORE THE PATENT AND TRADEMARK OFFICE § 10.11 Removing names... desires to remain on the register. The name of any individual failing to reply and give any...

  19. 46 CFR 30.10-11 - Coastwise-TB/C.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... GUARD, DEPARTMENT OF HOMELAND SECURITY TANK VESSELS GENERAL PROVISIONS Definitions § 30.10-11 Coastwise—TB/C. Under this designation shall be included all tank vessels normally navigating the waters of any ocean or the Gulf of Mexico 20 nautical miles or less offshore....

  20. 46 CFR 30.10-11 - Coastwise-TB/C.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... GUARD, DEPARTMENT OF HOMELAND SECURITY TANK VESSELS GENERAL PROVISIONS Definitions § 30.10-11 Coastwise—TB/C. Under this designation shall be included all tank vessels normally navigating the waters of any ocean or the Gulf of Mexico 20 nautical miles or less offshore....

  1. An orthorhombic polymorph of 10,11-dihydrocarbamazepine.

    PubMed

    Harrison, William T A; Yathirajan, H S; Anilkumar, H G

    2006-05-01

    The title compound (systematic name: 10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide), C15H14N2O, is shown to crystallize as an orthorhombic polymorph to complement the known monoclinic form. The molecular conformations of both forms are very similar, involving a bent conformation for the seven-membered azepine ring and an overall ;butterfly' shape. The molecules assemble into chains by way of N-H...O bonds and N-H...pi interactions in both crystal modifications. The two polymorphs appear to form due to different van der Waals interactions between the layer-like sheets of molecules. PMID:16679591

  2. MolView users guide

    SciTech Connect

    Walenz, B.P.

    1996-06-01

    A system for viewing molecular data in a CAVE virtual reality environment is presented. The system, called MolView, consists of a frontend driver program that prepares the data and a backend CAVE program that displays the data. Both are written so that modifications and extensions are relatively easy to accomplish.

  3. COSMIC OPTICAL BACKGROUND: THE VIEW FROM PIONEER 10/11

    SciTech Connect

    Matsuoka, Y.; Oyabu, S.; Ienaka, N.; Kawara, K.

    2011-08-01

    We present the new constraints on the cosmic optical background (COB) obtained from an analysis of the Pioneer 10/11 Imaging Photopolarimeter (IPP) data. After careful examination of data quality, the usable measurements free from the zodiacal light are integrated into sky maps at the blue ({approx}0.44 {mu}m) and red ({approx}0.64 {mu}m) band. Accurate starlight subtraction is achieved by referring to all-sky star catalogs and a Galactic stellar population synthesis model down to 32.0 mag. We find that the residual light is separated into two components: one component shows a clear correlation with thermal 100 {mu}m brightness, while another betrays a constant level in the lowest 100 {mu}m brightness region. The presence of the second component is significant after all the uncertainties and possible residual light in the Galaxy are taken into account, and thus it most likely has the extragalactic origin (i.e., the COB). The derived COB brightness is (1.8 {+-} 0.9) x 10{sup -9} and (1.2 {+-} 0.9) x 10{sup -9} erg s{sup -1} cm{sup -2} sr{sup -1} A{sup -1} at the blue and red bands, respectively, or 7.9 {+-} 4.0 and 7.7 {+-} 5.8 nW m{sup -2} sr{sup -1}. From comparison with the integrated brightness of galaxies, we conclude that bulk of the COB is comprised of normal galaxies which have already been resolved in the current deepest observations. There seems to be little room for contributions of other populations including 'first stars' at these wavelengths. On the other hand, the first component of the IPP residual light represents the diffuse Galactic light (DGL)-scattered starlight by the interstellar dust. We derive mean DGL-to-100 {mu}m brightness ratios of 2.1 x 10{sup -3} and 4.6 x 10{sup -3} at the two bands, which are roughly consistent with the previous observations toward the denser dust regions. Extended red emission in the diffuse interstellar medium is also confirmed.

  4. 46 CFR 39.10-11 - Personnel training-TB/ALL.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 1 2011-10-01 2011-10-01 false Personnel training-TB/ALL. 39.10-11 Section 39.10-11 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY TANK VESSELS VAPOR CONTROL SYSTEMS General § 39.10-11 Personnel training—TB/ALL. (a) A person in charge of a transfer operation utilizing a vapor...

  5. 46 CFR 39.10-11 - Personnel training-TB/ALL.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 1 2010-10-01 2010-10-01 false Personnel training-TB/ALL. 39.10-11 Section 39.10-11 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY TANK VESSELS VAPOR CONTROL SYSTEMS General § 39.10-11 Personnel training—TB/ALL. (a) A person in charge of a transfer operation utilizing a vapor collection system must have completed a...

  6. In vivo exposure of marine mussels to carbamazepine and 10-hydroxy-10,11-dihydro-carbamazepine: Bioconcentration and metabolization.

    PubMed

    Boillot, C; Martinez Bueno, M J; Munaron, D; Le Dreau, M; Mathieu, O; David, A; Fenet, H; Casellas, C; Gomez, E

    2015-11-01

    Aquatic organisms are exposed to pharmaceuticals present in natural waters, but few data are available on the accumulation of these substances in such organisms. The present study evaluated the in vivo bioconcentration of two anticonvulsants--carbamazepine (CBZ) and 10-hydroxy-10,11-dihydro-carbamazepine (10 OH)--in marine mussels (Mytilus galloprovincialis) exposed to nominal 10 μg L(-1) concentrations for one week. The bioconcentration factors (BCFs) were 3.9 and 4.5 L kg(-1) dry weight (dw) for CBZ and 10 OH, respectively. CBZ accumulation reached an average tissue concentration of 29.3 ± 4.8 ng g(-1) dw, and 10 OH accumulated up to 40.9 ± 4.6 ng g(-1) dw in tissues within one week, showing first-order kinetics. BCF obtained with linear QSAR models correctly estimated the CBZ bioconcentration and overestimated the 10 OH bioconcentration to some extent. The detection of two metabolites (carbamazepine-10,11-epoxide and acridine) among the five sought suggested an active metabolism for CBZ. In contrast, none of the 10 OH metabolites were detected in mussels exposed to 10 OH. CBZ showed higher accumulation in the digestive gland, where some relevant metabolites were detected, than in other studied tissues. The implication of those findings on field biomonitoring is discussed. PMID:26102056

  7. 20 CFR 10.11 - Who maintains custody and control of FECA records?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ..., guidelines and provisions of this part, as well as those contained in 29 CFR parts 70 and 71, and with the... 20 Employees' Benefits 1 2013-04-01 2012-04-01 true Who maintains custody and control of FECA records? 10.11 Section 10.11 Employees' Benefits OFFICE OF WORKERS' COMPENSATION PROGRAMS, DEPARTMENT...

  8. 20 CFR 10.11 - Who maintains custody and control of FECA records?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ..., guidelines and provisions of this part, as well as those contained in 29 CFR parts 70 and 71, and with the... 20 Employees' Benefits 1 2011-04-01 2011-04-01 false Who maintains custody and control of FECA records? 10.11 Section 10.11 Employees' Benefits OFFICE OF WORKERS' COMPENSATION PROGRAMS, DEPARTMENT...

  9. 43 CFR 10.11 - Disposition of culturally unidentifiable human remains.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 43 Public Lands: Interior 1 2012-10-01 2011-10-01 true Disposition of culturally unidentifiable human remains. 10.11 Section 10.11 Public Lands: Interior Office of the Secretary of the Interior NATIVE AMERICAN GRAVES PROTECTION AND REPATRIATION REGULATIONS Human Remains, Funerary Objects, Sacred Objects, or Objects of Cultural Patrimony...

  10. 43 CFR 10.11 - Disposition of culturally unidentifiable human remains.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... human remains. 10.11 Section 10.11 Public Lands: Interior Office of the Secretary of the Interior NATIVE AMERICAN GRAVES PROTECTION AND REPATRIATION REGULATIONS Human Remains, Funerary Objects, Sacred Objects, or... unidentifiable human remains. (a) General. This section implements section 8(c)(5) of the Act and applies...

  11. 43 CFR 10.11 - Disposition of culturally unidentifiable human remains.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... prove that it has right of possession, as defined at § 10.10(a)(2), to culturally unidentifiable human... human remains. 10.11 Section 10.11 Public Lands: Interior Office of the Secretary of the Interior NATIVE AMERICAN GRAVES PROTECTION AND REPATRIATION REGULATIONS Human Remains, Funerary Objects, Sacred Objects,...

  12. 43 CFR 10.11 - Disposition of culturally unidentifiable human remains.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 43 Public Lands: Interior 1 2010-10-01 2010-10-01 false Disposition of culturally unidentifiable human remains. 10.11 Section 10.11 Public Lands: Interior Office of the Secretary of the Interior NATIVE AMERICAN GRAVES PROTECTION AND REPATRIATION REGULATIONS Human Remains, Funerary Objects, Sacred Objects, or Objects of Cultural Patrimony...

  13. Genetics Home Reference: L1 syndrome

    MedlinePlus

    ... A, Gal A. Intronic mutations in the L1CAM gene may cause X-linked hydrocephalus by aberrant splicing. Hum Mutat. 2004 May;23(5):526. Citation on PubMed Kanemura Y, Okamoto N, Sakamoto H, Shofuda T, ... (L1 disease): Mutations in the L1CAM gene. Hum Mutat. 2001;18(1):1-12. Review. ...

  14. DSCOVR_EPIC_L1A

    Atmospheric Science Data Center

    2015-09-29

    DSCOVR_EPIC_L1A Full sun-light Earth images calibrated with ... 680NM 688NM 551NM LAGRANGE L1B IMAGERY EPIC DSCOVR 325NM Order Data:  ASDC Order Tool: Order Data Readme Files:  EPIC Data Format Control Book Read Software Files :  ...

  15. Easy Growth Experiment on Peas Stimulates Interest in Biology for 10-11 Year Old Pupils

    ERIC Educational Resources Information Center

    McEwen, Birgitta

    2007-01-01

    How do we support the enthusiasm children show for biology in school? Unfortunately, lack of exciting practical work and boring biology lessons seem to make science less popular. As a senior lecturer in plant physiology at Karlstad University I have simplified experiments intended for students at university and then tested them on 10-11 year old…

  16. Checking the Goldbach conjecture up to 4\\cdot 10^11

    NASA Astrophysics Data System (ADS)

    Sinisalo, Matti K.

    1993-10-01

    One of the most studied problems in additive number theory, Goldbach's conjecture, states that every even integer greater than or equal to 4 can be expressed as a sum of two primes. In this paper checking of this conjecture up to 4 \\cdot {10^{11}} by the IBM 3083 mainframe with vector processor is reported.

  17. 15 CFR 10.11 - Revision or amendment of a standard.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... DEVELOPMENT OF VOLUNTARY PRODUCT STANDARDS § 10.11 Revision or amendment of a standard. (a) A published... Committee serves in the development of a new standard. The processing of a revision of a standard shall be... or the design characteristics of the product being standardized, or which cannot reasonably...

  18. DNA damage and L1 retrotransposition.

    PubMed

    Farkash, Evan A; Luning Prak, Eline T

    2006-01-01

    Barbara McClintock was the first to suggest that transposons are a source of genome instability and that genotoxic stress assisted in their mobilization. The generation of double-stranded DNA breaks (DSBs) is a severe form of genotoxic stress that threatens the integrity of the genome, activates cell cycle checkpoints, and, in some cases, causes cell death. Applying McClintock's stress hypothesis to humans, are L1 retrotransposons, the most active autonomous mobile elements in the modern day human genome, mobilized by DSBs? Here, evidence that transposable elements, particularly retrotransposons, are mobilized by genotoxic stress is reviewed. In the setting of DSB formation, L1 mobility may be affected by changes in the substrate for L1 integration, the DNA repair machinery, or the L1 element itself. The review concludes with a discussion of the potential consequences of L1 mobilization in the setting of genotoxic stress. PMID:16877815

  19. PD-1/PD-L1 inhibitors.

    PubMed

    Sunshine, Joel; Taube, Janis M

    2015-08-01

    Tumors may adopt normal physiologic checkpoints for immunomodulation leading to an imbalance between tumor growth and host surveillance. Antibodies targeting the PD-1/PD-L1 checkpoint have shown dynamic and durable tumor regressions, suggesting a rebalancing of the host-tumor interaction. Nivolumab and pembrolizumab are the anti-PD-1 antibodies that are currently the furthest in clinical development, and anti-PD-L1 agents under investigation include MPDL3280A, MEDI4736, and BMS-936559. These agents have been used to treat advanced melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer and Hodgkin lymphoma, amongst other tumor types. In this article, we review the updated response results for early clinical trials, note recent FDA actions regarding this class of agents, and summarize results across trials looking at PD-L1 status as a predictor of response to anti-PD-1/PD-L1. PMID:26047524

  20. L1 libration point manned space habitat

    NASA Technical Reports Server (NTRS)

    Luttges, Marvin; Johnson, Steve; Banks, Gary; Johnson, Richard; Meyer, Christian; Pepin, Scott; Macelroy, Robert

    1989-01-01

    Second generation stations or Manned Space Habitats (MSHs) are discussed for an Earth-Moon libration point and in lunar orbit. The conceptual design of such a station is outlined. Systems and subsystems described reflect anticipation of moderate technology growth. The evolution of the L1 environments is discussed, several selected subsystems are outlined, and how the L1 MSH will complete some of its activities is described.

  1. Markedly Elevated Carbamazepine-10,11-epoxide/Carbamazepine Ratio in a Fatal Carbamazepine Ingestion

    PubMed Central

    Russell, Jason L.; Spiller, Henry A.; Baker, Daniel D.

    2015-01-01

    Carbamazepine is a widely used anticonvulsant. Its metabolite, carbamazepine-10,11-epoxide, has been found to display similar anticonvulsant and neurotoxic properties. While the ratio of parent to metabolite concentration varies significantly, at therapeutic doses the epoxide concentration is generally about 20% of the parent. We report a case of fatal carbamazepine overdose in which the epoxide metabolite concentration was found to be 450% higher than the parent compound, suggesting a potential role for metabolite quantification in severe toxicity. PMID:26550016

  2. Cytoplasmic domain mutations of the L1 cell adhesion molecule reduce L1-ankyrin interactions.

    PubMed

    Needham, L K; Thelen, K; Maness, P F

    2001-03-01

    The neural adhesion molecule L1 mediates the axon outgrowth, adhesion, and fasciculation that are necessary for proper development of synaptic connections. L1 gene mutations are present in humans with the X-linked mental retardation syndrome CRASH (corpus callosum hypoplasia, retardation, aphasia, spastic paraplegia, hydrocephalus). Three missense mutations associated with CRASH syndrome reside in the cytoplasmic domain of L1, which contains a highly conserved binding region for the cytoskeletal protein ankyrin. In a cellular ankyrin recruitment assay that uses transfected human embryonic kidney (HEK) 293 cells, two of the pathologic mutations located within the conserved SFIGQY sequence (S1224L and Y1229H) strikingly reduced the ability of L1 to recruit 270 kDa ankyrinG protein that was tagged with green fluorescent protein (ankyrin-GFP) to the plasma membrane. In contrast, the L1 missense mutation S1194L and an L1 isoform lacking the neuron-specific sequence RSLE in the cytoplasmic domain were as effective as RSLE-containing neuronal L1 in the recruitment of ankyrin-GFP. Ankyrin binding by L1 was independent of cell-cell interactions. Receptor-mediated endocytosis of L1 regulates intracellular signal transduction, which is necessary for neurite outgrowth. In rat B35 neuroblastoma cell lines stably expressing L1 missense mutants, antibody-induced endocytosis was unaffected by S1224L or S1194L mutations but appeared to be enhanced by the Y1229H mutation. These results suggested a critical role for tyrosine residue 1229 in the regulation of L1 endocytosis. In conclusion, specific mutations within key residues of the cytoplasmic domain of L1 (Ser(1224), Tyr(1229)) destabilize normal L1-ankyrin interactions and may influence L1 endocytosis to contribute to the mechanism of neuronal dysfunction in human X-linked mental retardation. PMID:11222639

  3. Face recognition with L1-norm subspaces

    NASA Astrophysics Data System (ADS)

    Maritato, Federica; Liu, Ying; Colonnese, Stefania; Pados, Dimitris A.

    2016-05-01

    We consider the problem of representing individual faces by maximum L1-norm projection subspaces calculated from available face-image ensembles. In contrast to conventional L2-norm subspaces, L1-norm subspaces are seen to offer significant robustness to image variations, disturbances, and rank selection. Face recognition becomes then the problem of associating a new unknown face image to the "closest," in some sense, L1 subspace in the database. In this work, we also introduce the concept of adaptively allocating the available number of principal components to different face image classes, subject to a given total number/budget of principal components. Experimental studies included in this paper illustrate and support the theoretical developments.

  4. Mapping L1 Ligase ribozyme conformational switch

    PubMed Central

    Giambaşu, George M.; Lee, Tai-Sung; Scott, William G.; York, Darrin M.

    2012-01-01

    L1 Ligase (L1L)molecular switch is an in vitro optimized synthetic allosteric ribozyme that catalyzes the regioselective formation of a 5’-to-3’ phosphodiester bond, a reaction for which there is no known naturally occurring RNA catalyst. L1L serves as a proof of principle that RNA can catalyze a critical reaction for prebiotic RNA self-replication according to the RNA World hypothesis. L1L crystal structure captures two distinct conformations that differ by a re-orientation of one of the stems by around 80 Å and are presumed to correspond to the active and inactive state, respectively. It is of great interest to understand the nature of these two states in solution, and the pathway for their interconversion. In this study, we use explicit solvent molecular simulation together with a novel enhanced sampling method that utilizes concepts from network theory to map out the conformational transition between active and inactive states of L1L. We find that the overall switching mechanism can be described as a 3-state/2-step process. The first step involves a large-amplitude swing that re-orients stem C. The second step involves the allosteric activation of the catalytic site through distant contacts with stem C. Using a conformational space network representation of the L1L switch transition, it is shown that the connection between the three states follows different topographical patterns: the stem C swing step passes through a narrow region of the conformational space network, whereas the allosteric activation step covers a much wider region and a more diverse set of pathways through the network. PMID:22771572

  5. Brain alpha-dystroglycan displays unique glycoepitopes and preferential binding to laminin-10/11.

    PubMed

    McDearmon, Erin L; Combs, Ariana C; Sekiguchi, Kiyotoshi; Fujiwara, Hironobu; Ervasti, James M

    2006-06-12

    alpha-Dystroglycan was quantitatively enriched from mammalian brain based on its uniform reactivity with Vicia villosa agglutinin and resolved into sub-populations possessing or lacking the sulfated glucuronic acid epitope recognized by monoclonal antibody HNK-1. We generated a new monoclonal antibody specific for a glycoepitope on brain alpha-dystroglycan but absent from alpha-dystroglycan expressed in all other tissues examined. Finally, we found that laminin-10/11 preferentially bound to brain alpha-dystroglycan compared to skeletal muscle alpha-dystroglycan. Our results suggest that tissue-specific glycosylation modifies the laminin binding specificity of alpha-dystroglycan. PMID:16709410

  6. Neutron dosimetry and damage calculation for the JP-10, 11, 13, and 16 experiments in HFIR

    SciTech Connect

    Greenwood, L.R.; Ratner, R.T.

    1996-04-01

    Neutron fluence measurements and radiation damage calculations are reported for the joint U.S./Japanese experiments JP-10, 11, 13, and 16 in the target of the High Flux Isotope Reactor (HFIR) at Oak Ridge National Lab (ORNL). These experiments were irradiated at 85 MW for 238.5 EFPD. The maximum fast neutron fluence >0.1 MeV was about 2.1E + 22 n/cm{sup 2} for all of the experiments resulting in about 17.3 dpa in 316 stainless steel.

  7. Virtual coupling potential for elastic scattering of 10,11Be on proton and carbon targets

    NASA Astrophysics Data System (ADS)

    Lapoux, V.; Alamanos, N.; Auger, F.; Blumenfeld, Y.; Casandjian, J.-M.; Chartier, M.; Cortina-Gil, M. D.; Fékou-Youmbi, V.; Gillibert, A.; Cormick, M. Mac; Maréchal, F.; Marie, F.; Mittig, W.; de Oliveira Santos, F.; Orr, N. A.; Ostrowski, A. N.; Ottini-Hustache, S.; Roussel-Chomaz, P.; Scarpaci, J.-A.; Sida, J.-L.; Suomijärvi, T.; Winfield, J. S.

    2008-01-01

    The 10,11Be(p, p) and (12C, 12C) reactions were analyzed to determine the influence of the weak binding energies of exotic nuclei on their interaction potential. The elastic cross sections were measured at GANIL in inverse kinematics using radioactive 10,11Be beams produced at energies of 39.1A and 38.4 A MeV. The elastic proton scattering data were analyzed within the framework of the microscopic Jeukenne-Lejeune-Mahaux (JLM) nucleon-nucleus potential. The angular distributions are found to be best reproduced by reducing the real part of the microscopic optical potential, as a consequence of the coupling to the continuum. These effects modify deeply the elastic potential. Including the Virtual Coupling Potential (VCP), we show the ability of the general optical potentials to reproduce the data for scattering of unstable nuclei, using realistic densities. Finally, the concepts needed to develop a more general and microscopic approach of the VCP are discussed.

  8. Small Molecule Agonists of Cell Adhesion Molecule L1 Mimic L1 Functions In Vivo.

    PubMed

    Kataria, Hardeep; Lutz, David; Chaudhary, Harshita; Schachner, Melitta; Loers, Gabriele

    2016-09-01

    Lack of permissive mechanisms and abundance of inhibitory molecules in the lesioned central nervous system of adult mammals contribute to the failure of functional recovery after injury, leading to severe disabilities in motor functions and pain. Peripheral nerve injury impairs motor, sensory, and autonomic functions, particularly in cases where nerve gaps are large and chronic nerve injury ensues. Previous studies have indicated that the neural cell adhesion molecule L1 constitutes a viable target to promote regeneration after acute injury. We screened libraries of known drugs for small molecule agonists of L1 and evaluated the effect of hit compounds in cell-based assays in vitro and in mice after femoral nerve and spinal cord injuries in vivo. We identified eight small molecule L1 agonists and showed in cell-based assays that they stimulate neuronal survival, neuronal migration, and neurite outgrowth and enhance Schwann cell proliferation and migration and myelination of neurons in an L1-dependent manner. In a femoral nerve injury mouse model, enhanced functional regeneration and remyelination after application of the L1 agonists were observed. In a spinal cord injury mouse model, L1 agonists improved recovery of motor functions, being paralleled by enhanced remyelination, neuronal survival, and monoaminergic innervation, reduced astrogliosis, and activation of microglia. Together, these findings suggest that application of small organic compounds that bind to L1 and stimulate the beneficial homophilic L1 functions may prove to be a valuable addition to treatments of nervous system injuries. PMID:26253722

  9. International key comparison CCQM-K94: 10 μmol/mol dimethyl sulfide in nitrogen

    NASA Astrophysics Data System (ADS)

    Lee, S.; Heo, G. S.; Kim, Y.; Oh, S.; Han, Q.; Wu, H.; Konopelko, L. A.; Kustikov, Y. A.; Kolobova, A. V.; Efremova, O. V.; Pankratov, V. V.; Pavlov, M. V.; Culleton, L. P.; Brown, A. S.; Brookes, C.; Li, J.; Ziel, P. R.; van der Veen, A. M. H.

    2016-01-01

    Dimethyl sulfide (DMS) is an important compound in monitoring climate change and is monitored by the World Meteorological Organization Global Atmospheric Watch Volatile Organic Compounds (WMO-GAW VOC) program at several monitoring sites. It is essential that measurement results are accurate and consistent among the assigned values for primary gas mixtures to meet the WMO requirement. The purpose of this comparison is to compare the measurement capability of DMS at approximately 10 μ­mol/mol and expectation to contribute the establishment of traceability to single measurement scale for DMS between NMIs. Main text To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

  10. Pioneer 10/11 data analysis of the magnetic field experiment

    NASA Technical Reports Server (NTRS)

    Jones, D. E.

    1982-01-01

    Work conducted in support of the Pioneer missions to Jupiter (10,11), and Saturn (11) as well as the reduction, analysis and interpretation of magnetic field data obtained by the vector helium magnetometer on the Pioneer 10 and 11 spacecraft is summarized. Initial efforts concentrated primarily on the interplanetary data, and those aspcts of the data of relevance to obtaining a better understanding of the interaction of the magnetized solar wind with the terrestrial magnetic field. After encounters of Jupiter and Saturn, the emphasis of research was directed primarily to an analysis of the planetary data. In particular, it soon became clear that there was a need for modelling of the various candidate magnetospheric currents suggested by the data. Results not published as yet, are also summarized.

  11. Geomagnetic activity during 10 - 11 solar cycles that has been observed by old Russian observatories.

    NASA Astrophysics Data System (ADS)

    Seredyn, Tomasz; Wysokinski, Arkadiusz; Kobylinski, Zbigniew; Bialy, Jerzy

    2016-07-01

    A good knowledge of solar-terrestrial relations during past solar activity cycles could give the appropriate tools for a correct space weather forecast. The paper focuses on the analysis of the historical collections of the ground based magnetic observations and their operational indices from the period of two sunspot solar cycles 10 - 11, period 1856 - 1878 (Bartels rotations 324 - 635). We use hourly observations of H and D geomagnetic field components registered at Russian stations: St. Petersburg - Pavlovsk, Barnaul, Ekaterinburg, Nertshinsk, Sitka, and compare them to the data obtained from the Helsinki observatory. We compare directly these records and also calculated from the data of the every above mentioned station IHV indices introduced by Svalgaard (2003), which have been used for further comparisons in epochs of assumed different polarity of the heliospheric magnetic field. We used also local index C9 derived by Zosimovich (1981) from St. Petersburg - Pavlovsk data. Solar activity is represented by sunspot numbers. The correlative and continuous wavelet analyses are applied for estimation of the correctness of records from different magnetic stations. We have specially regard to magnetic storms in the investigated period and the special Carrington event of 1-2 Sep 1859. Generally studied magnetic time series correctly show variability of the geomagnetic activity. Geomagnetic activity presents some delay in relation to solar one as it is seen especially during descending and minimum phase of the even 11-year cycle. This pattern looks similarly in the case of 16 - 17 solar cycles.

  12. Rare Mechanisms of Stopped Pion Absorption by 10,11B Nuclei

    NASA Astrophysics Data System (ADS)

    Chernyshev, B. A.; Gurov, Yu. B.; Korotkova, L. Yu.; Lapushkin, S. V.; Pritula, R. V.

    2015-06-01

    Correlation measurements of the stopped π--meson absorption reactions 10B(π-, dt)X and 11B(π-, tt)X were carried out at low energy pion channel of LAMPF with the two-arm multilayer semiconductor spectrometer of charged particles. The analysis of twodimensional distributions (Dalitz' diagram) and the momentum distribution of the residual nucleus allowed to identify the process of pion absorption on the intranuclear lithium clusters 5,6Li and to get the evidence on the existence of the configurations 5Li + 5Heg.s and 6Li + 5Heg.s in the boron nuclei 10,11B. The levels of 8Li* isotope with the resonance parameters (Ex, C): (8.7 ± 0.2, 1.9 ± 0.4) MeV and (10.1 ± 0.3, 4.0 ± 1.3) MeV were observed for the first time. These states break up with the triton emission: 8Li* → t + 5He..

  13. Social inequalities and health among children aged 10-11 in The Netherlands: causes and consequences.

    PubMed

    van der Lucht, F; Groothoff, J

    1995-05-01

    Socioeconomic health differences (SEHD) are relatively small in childhood. In adolescence they almost seem to disappear and among young adults they re-emerge. This article deals with mechanisms that contribute to the emergence of health differences by studying a group of 10-11 year old children in The Netherlands (n = 908). The role of determinants of health in the relation between socioeconomic status and health (causation) is studied, as well as the influence of health on school performance (selection). Both causation and selection mechanisms prove to exist. Life style and life circumstances are unequally distributed among the socioeconomic groups and can (partly) explain the relation between socioeconomic status and health. The health of the children is related with school performance, which can be seen as health selection. This relation however was only found in the lowest socioeconomic groups. In the lowest socioeconomic groups less healthy children perform worse at school than healthy children. The unequal distribution of determinants of health and health selection in the educational career among children probably contribute to SEHD in adult life. PMID:7610436

  14. PD-L1 Expression in Triple Negative Breast Cancer

    PubMed Central

    Mittendorf, Elizabeth A.; Philips, Anne V.; Meric-Bernstam, Funda; Qiao, Na; Wu, Yun; Harrington, Susan; Su, Xiaoping; Wang, Ying; Gonzalez-Angulo, Ana M.; Akcakanat, Argun; Chawla, Akhil; Curran, Michael; Hwu, Patrick; Sharma, Padmanee; Litton, Jennifer K.; Molldrem, Jeffrey J.; Alatrash, Gheath

    2014-01-01

    Early phase trials targeting the T-cell inhibitory molecule PD-L1 have shown clinical efficacy in cancer. This study was undertaken to determine whether PD-L1 is overexpressed in triple-negative breast cancer (TNBC) and to investigate the loss of the phosphatase and tensin homolog (PTEN) as a mechanism of PD-L1 regulation. The Cancer Genome Atlas (TCGA) RNA sequencing data showed significantly greater expression of the PD-L1 gene in TNBC (n=120) compared to non-TNBC (n=716) (P<0.001). Breast tumor tissue microarrays were evaluated for PD-L1 expression which was present in 19% (20 of 105) TNBC specimens. PD-L1+ tumors had greater CD8+ T-cell infiltrate than PD-L1− tumors (688 cells/mm versus 263 cells/mm; P<0.0001). To determine the effect of PTEN loss on PD-L1 expression, stable cell lines were generated using PTEN shRNA. PTEN knockdown led to significantly higher cell-surface PD-L1 expression and PD-L1 transcripts, suggesting transcriptional regulation. Moreover, PI3K pathway inhibition using the AKT inhibitor MK-2206 or rapamycin resulted in decreased PD-L1 expression, further linking PTEN and PI3K signaling to PD-L1 regulation. Co-culture experiments were performed to determine the functional effect of altered PD-L1 expression. Increased PD-L1 cell surface expression by tumor cells induced by PTEN loss led to decreased T cell proliferation and increased apoptosis. PD-L1 is expressed in 20% of TNBC, suggesting PD-L1 as a therapeutic target in TNBC. Since PTEN loss is one mechanism regulating PD-L1 expression, agents targeting the PI3K pathway may increase the antitumor adaptive immune responses. PMID:24764583

  15. L1 to Teach L2: Complexities and Contradictions

    ERIC Educational Resources Information Center

    Copland, Fiona; Neokleous, Georgios

    2011-01-01

    This article uncovers the complexities and contradictions inherent in making decisions about L1 use in the English language classroom. Through an analysis of data from classrooms in a Cypriot context and from interviews with Cypriot teachers, a number of functions for L1 use are identified, as are the teachers' rationales for using L1 for…

  16. 26 CFR 1.7701(l)-1 - Conduit financing arrangements.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 13 2013-04-01 2013-04-01 false Conduit financing arrangements. 1.7701(l)-1 Section 1.7701(l)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) General Actuarial Valuations § 1.7701(l)-1...

  17. 26 CFR 1.7701(l)-1 - Conduit financing arrangements.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 13 2014-04-01 2014-04-01 false Conduit financing arrangements. 1.7701(l)-1 Section 1.7701(l)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) General Actuarial Valuations § 1.7701(l)-1...

  18. 26 CFR 1.7701(l)-1 - Conduit financing arrangements.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 13 2010-04-01 2010-04-01 false Conduit financing arrangements. 1.7701(l)-1 Section 1.7701(l)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES General Actuarial Valuations § 1.7701(l)-1 Conduit...

  19. 26 CFR 1.7701(l)-1 - Conduit financing arrangements.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 13 2012-04-01 2012-04-01 false Conduit financing arrangements. 1.7701(l)-1 Section 1.7701(l)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) General Actuarial Valuations § 1.7701(l)-1...

  20. 26 CFR 1.7701(l)-1 - Conduit financing arrangements.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 13 2011-04-01 2011-04-01 false Conduit financing arrangements. 1.7701(l)-1 Section 1.7701(l)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) General Actuarial Valuations § 1.7701(l)-1...

  1. Rendezvous missions with minimoons from L1

    NASA Astrophysics Data System (ADS)

    Chyba, M.; Haberkorn, T.; Patterson, G.

    2014-07-01

    We propose to present asteroid capture missions with the so-called minimoons. Minimoons are small asteroids that are temporarily captured objects on orbits in the Earth-Moon system. It has been suggested that, despite their small capture probability, at any time there are one or two meter diameter minimoons, and progressively greater numbers at smaller diameters. The minimoons orbits differ significantly from elliptical orbits which renders a rendezvous mission more challenging, however they offer many advantages for such missions that overcome this fact. First, they are already on geocentric orbits which results in short duration missions with low Delta-v, this translates in cost efficiency and low-risk targets. Second, beside their close proximity to Earth, an advantage is their small size since it provides us with the luxury to retrieve the entire asteroid and not only a sample of material. Accessing the interior structure of a near-Earth satellite in its morphological context is crucial to an in-depth analysis of the structure of the asteroid. Historically, 2006 RH120 is the only minimoon that has been detected but work is ongoing to determine which modifications to current observation facilities is necessary to provide detection algorithm capabilities. In the event that detection is successful, an efficient algorithm to produce a space mission to rendezvous with the detected minimoon is highly desirable to take advantage of this opportunity. This is the main focus of our work. For the design of the mission we propose the following. The spacecraft is first placed in hibernation on a Lissajoux orbit around the liberation point L1 of the Earth-Moon system. We focus on eight-shaped Lissajoux orbits to take advantage of the stability properties of their invariant manifolds for our transfers since the cost to minimize is the spacecraft fuel consumption. Once a minimoon has been detected we must choose a point on its orbit to rendezvous (in position and velocities

  2. Phytoremediation of carbamazepine and its metabolite 10,11-epoxycarbamazepine by C3 and C4 plants.

    PubMed

    Ryšlavá, Helena; Pomeislová, Alice; Pšondrová, Šárka; Hýsková, Veronika; Smrček, Stanislav

    2015-12-01

    The anticonvulsant drug carbamazepine is considered as an indicator of sewage water pollution: however, its uptake by plants and effect on metabolism have not been sufficiently documented, let alone its metabolite (10,11-epoxycarbamazepine). In a model system of sterile, hydroponically cultivated Zea mays (as C4 plant) and Helianthus annuus (as C3 plant), the uptake and effect of carbamazepine and 10,11-epoxycarbamazepine were studied in comparison with those of acetaminophen and ibuprofen. Ibuprofen and acetaminophen were effectively extracted from drug-supplemented media by both plants, while the uptake of more hydrophobic carbamazepine was much lower. On the other hand, the carbamazepine metabolite, 10,11-epoxycarbamazepine, was, unlike sunflower, willingly taken up by maize plants (after 96 h 88 % of the initial concentration) and effectively stored in maize tissues. In addition, the effect of the studied pharmaceuticals on the plant metabolism (enzymes of Hatch-Slack cycle, peroxidases) was followed. The activity of bound peroxidases, which could cause xylem vessel lignification and reduction of xenobiotic uptake, was at the level of control plants in maize leaves contrary to sunflower. Therefore, our results indicate that maize has the potential to remove 10,11-epoxycarbamazepine from contaminated soils. PMID:26310701

  3. Study Of Reaction Mechanisms For {sup 9,10,11}Be+{sup 64}Zn Systems Around The Coulomb Barrier

    SciTech Connect

    Scuderi, V.; Amorini, F.; Fisichella, M.; Lattuada, M.; Rizzo, F.; Torresi, D.; Di Pietro, A.; Figuera, P.; Papa, M.; Pellegriti, M. G.; Santonocito, D.; Scalia, G.; Acosta, L.; Martel, I.; Borge, M. J. G.; Sanchez, E. M. R.; Tengblad, O.; Vidal, A. M.; Fraile, L. M.; Jeppesen, H.

    2010-04-26

    The reactions {sup 9,10,11}Be+{sup 64}Zn have been studied at energies around the Coulomb barrier in order to better understand the role played by the halo features on the reaction dynamics. Preliminary results on such studies will be reported in this paper.

  4. Evidence, from Pioneer 10/11, Galileo, and Ulysses Data, for an Anomalous, Weak, Long-Range Acceleration

    NASA Technical Reports Server (NTRS)

    Anderson, J. D.; Laing, P. A.; Lau, E. L.; Liu, A. S.; Nieto, M. M.; Turyshev, S. G.

    1998-01-01

    Radio metric data from the Pioneer 10/11, Galileo, and Ulysses Spacecraft indicate an apparent anomalous, constant, acceleration acting on the spacecraft with a magnitude 8.5 x 10(sup -8) cm/s(sup 2), directed towards the Sun.

  5. Evaluation of Low-Cost, Objective Instruments for Assessing Physical Activity in 10-11-Year-Old Children

    ERIC Educational Resources Information Center

    Hart, Teresa L.; Brusseau, Timothy; Kulinna, Pamela Hodges; McClain, James J.; Tudor-Locke, Catrine

    2011-01-01

    This study compared step counts detected by four, low-cost, objective, physical-activity-assessment instruments and evaluated their ability to detect moderate-to-vigorous physical activity (MVPA) compared to the ActiGraph accelerometer (AG). Thirty-six 10-11-year-old children wore the NL-1000, Yamax Digiwalker SW 200, Omron HJ-151, and Walk4Life…

  6. Systematic analysis of above-barrier fusion of {sup 9,10,11}Be+{sup 209}Bi

    SciTech Connect

    Hinde, D. J.; Dasgupta, M.

    2010-06-15

    Measurements of fusion for {sup 9,10,11}Be allow testing of the relative importance to fusion and breakup of the alpha-cluster structure found in all these Be isotopes, compared with the neutron-halo structure only present for {sup 11}Be. However, disagreements exist among different published experimental data sets for the reactions of {sup 9,10,11}Be with {sup 209}Bi. Accurate measurements of above-barrier cross sections for the products of complete fusion (fission and evaporation residues) in the reaction of {sup 9}Be with {sup 209}Bi and {sup 208}Pb provide the basis for a reanalysis of above-barrier fusion for {sup 10,11}Be+{sup 209}Bi. This includes procedures making full use of the higher precision stable beam data and resolves many of the disagreements. The improved self-consistency of the analysis allows investigation of the experimental average fusion barriers. Although showing some scatter, these suggest a higher barrier for the neutron halo nucleus {sup 11}Be. Comparison of published cross sections for fusion associated with capture of all the charge of the projectile suggest that all these Be isotopes show significant suppression of complete fusion, a surprising result given that the alpha-breakup threshold energies are 1.57 MeV for {sup 9}Be but over 7 MeV for {sup 10,11}Be. Further experimental studies to investigate in more detail the division between complete and incomplete fusion for reactions of {sup 10,11}Be are needed.

  7. Optimized MOL-PCR for Characterization of Microbial Pathogens.

    PubMed

    Wuyts, Véronique; Roosens, Nancy H C; Bertrand, Sophie; Marchal, Kathleen; De Keersmaecker, Sigrid C J

    2016-01-01

    Characterization of microbial pathogens is necessary for surveillance, outbreak detection, and tracing of outbreak sources. This unit describes a multiplex oligonucleotide ligation-PCR (MOL-PCR) optimized for characterization of microbial pathogens. With MOL-PCR, different types of markers, like unique sequences, single-nucleotide polymorphisms (SNPs) and indels, can be simultaneously analyzed in one assay. This assay consists of a multiplex ligation for detection of the markers, a singleplex PCR for signal amplification, and hybridization to MagPlex-TAG beads for readout on a Luminex platform after fluorescent staining. The current protocol describes the MOL-PCR, as well as methods for DNA isolation, probe design, and data interpretation and it is based on an optimized MOL-PCR assay for subtyping of Salmonella Typhimurium. PMID:26742655

  8. Complexation of iron with the orally active decorporation drug L1 (3-hydroxy-1,2-dimethyl-4-pyridinone).

    PubMed

    Kline, M A; Orvig, C

    1992-04-01

    The stability constants for the Fe(III) complexes of the orally active iron decorporation drug L1 (3-hydroxy-1,2-dimethyl-4-pyridinone) have been determined by potentiometric titration [glass electrode, 25.0 degrees C, mu = 0.15 mol/L (isotonic) NaCl]. A simple computer model of blood plasma (citrate 100 mumol/L, transferrin 37 mumol/L) has been used to compare the Fe(III) binding efficacies in blood of L1 and the clinically used intravenously administered chelating agent deferoxamine. PMID:1568323

  9. Relationships among L1 Print Exposure and Early L1 Literacy Skills, L2 Aptitude, and L2 Proficiency

    ERIC Educational Resources Information Center

    Sparks, Richard L.; Patton, Jon; Ganschow, Leonore; Humbach, Nancy

    2012-01-01

    Authors examined the relationship between individual differences in L1 print exposure and differences in early L1 skills and later L2 aptitude, L2 proficiency, and L2 classroom achievement. Participants were administered measures of L1 word decoding, spelling, phonemic awareness, reading comprehension, receptive vocabulary, and listening…

  10. MOL1 is required for cambium homeostasis in Arabidopsis.

    PubMed

    Gursanscky, Nial Rau; Jouannet, Virginie; Grünwald, Karin; Sanchez, Pablo; Laaber-Schwarz, Martina; Greb, Thomas

    2016-05-01

    Plants maintain pools of pluripotent stem cells which allow them to constantly produce new tissues and organs. Stem cell homeostasis in shoot and root tips depends on negative regulation by ligand-receptor pairs of the CLE peptide and leucine-rich repeat receptor-like kinase (LRR-RLK) families. However, regulation of the cambium, the stem cell niche required for lateral growth of shoots and roots, is poorly characterized. Here we show that the LRR-RLK MOL1 is necessary for cambium homeostasis in Arabidopsis thaliana. By employing promoter reporter lines, we reveal that MOL1 is active in a domain that is distinct from the domain of the positively acting CLE41/PXY signaling module. In particular, we show that MOL1 acts in an opposing manner to the CLE41/PXY module and that changing the domain or level of MOL1 expression both result in disturbed cambium organization. Underlining discrete roles of MOL1 and PXY, both LRR-RLKs are not able to replace each other when their expression domains are interchanged. Furthermore, MOL1 but not PXY is able to rescue CLV1 deficiency in the shoot apical meristem. By identifying genes mis-expressed in mol1 mutants, we demonstrate that MOL1 represses genes associated with stress-related ethylene and jasmonic acid hormone signaling pathways which have known roles in coordinating lateral growth of the Arabidopsis stem. Our findings provide evidence that common regulatory mechanisms in different plant stem cell niches are adapted to specific niche anatomies and emphasize the importance of a complex spatial organization of intercellular signaling cascades for a strictly bidirectional tissue production. PMID:26991973

  11. L1 expression and regulation in humans and rodents

    PubMed Central

    Rosser, James M.; An, Wenfeng

    2015-01-01

    Long interspersed elements type 1 (LINE-1s, or L1s) have impacted mammalian genomes at multiple levels. L1 transcription is mainly controlled by its 5’ untranslated region (5’UTR), which differs significantly among active human and rodent L1 families. In this review, L1 expression and its regulation are examined in the context of human and rodent development. First, endogenous L1 expression patterns in three different species—human, rat, and mouse—are compared and contrasted. A detailed account of relevant experimental evidence is presented according to the source material, such as cell lines, tumors, and normal somatic and germline tissues from different developmental stages. Second, factors involved in the regulation of L1 expression at both transcriptional and posttranscriptional levels are discussed. These include transcription factors, DNA methylation, PIWI-interacting RNAs (piRNAs), RNA interference (RNAi), and posttranscriptional host factors. Similarities and differences between human and rodent L1s are highlighted. Third, recent findings from transgenic mouse models of L1 are summarized and contrasted with those from endogenous L1 studies. Finally, the challenges and opportunities for L1 mouse models are discussed. PMID:22202032

  12. Comparison of primary standard gas mixtures: gravimetric production of carbon monoxide in nitrogen (3 μmol/mol)

    NASA Astrophysics Data System (ADS)

    Konopelko, L. A.; Kustikov, Y. A.; Kolobova, A. V.; Pankratov, V. V.; Pankov, A. A.; Efremova, O. V.; Augusto, Cristiane R.; Fioravante, Andreia L.; Ribeiro, Claudia C.; Teixeira, Denise C. G. S.; Elias, Elizandra C. S.; Oudwater, Rutger J.; Fagundes, Fátima A.; Silva, Marceli C.

    2016-01-01

    COOMET.QM-S3 is a supplementary comparison of primary standard gas mixtures—'Carbon monoxide in Nitrogen (3 μmol/mol)'. This is a bilateral comparison between VNIIM and INMETRO and it was conducted in 2013. Carbon monoxide is a toxic gas and in concentrations higher than 3-5 μmol/mol it is hazardous to human health. Therefore, it is important for NMIs to have the capability of an accurate carbon monoxide measurements. This comparison has shown that primary standard gas mixtures of carbon monoxide in nitrogen on the level of 3 μmol/mol, prepared in VNIIM and Inmetro, do not agree—the pair-wise degree of equivalence D (0.77%) is higher than the appropriate expanded uncertainty U(D) (0.29%). Main text To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

  13. Evaluation of eye irritation by S-(-)-10,11-dihydroxyfarnesic acid methyl ester secreted by Beauveria bassiana CS1029.

    PubMed

    Son, Hyeong-U; Lee, Sang-Han

    2013-10-01

    The aim of this study was to investigate whether S-(-)-10,11-dihydroxyfarnesic acid methyl ester produced by cell subtype Beauveria bassiana CS1029 causes acute toxicity when used for cosmetic purposes by performing an eye irritation test. New Zealand white (NZW) rabbits were treated with a 100 mg/dose of S-(-)-10,11-dihydroxyfarnesic acid methyl ester according to standard procedure guidelines. No significant changes in terms of ocular lesions of the cornea, turbidity of the cornea, swelling of the eyelid or ocular discharge were observed in the methyl ester-treated groups, while sodium dioctyl sulfosuccinate, a positive control, caused severe toxicity. The anatomical and pathological observations indicate that the methyl ester produced by Beauveria bassiana CS1029 did not induce eye irritation in the lenses of the rabbits. The data suggest that the methyl ester evaluated in this study has promising potential as a cosmetic ingredient that does not irritate the eye. PMID:24137288

  14. Evaluation of eye irritation by S-(-)-10,11-dihydroxyfarnesic acid methyl ester secreted by Beauveria bassiana CS1029

    PubMed Central

    SON, HYEONG-U; LEE, SANG-HAN

    2013-01-01

    The aim of this study was to investigate whether S-(-)-10,11-dihydroxyfarnesic acid methyl ester produced by cell subtype Beauveria bassiana CS1029 causes acute toxicity when used for cosmetic purposes by performing an eye irritation test. New Zealand white (NZW) rabbits were treated with a 100 mg/dose of S-(-)-10,11-dihydroxyfarnesic acid methyl ester according to standard procedure guidelines. No significant changes in terms of ocular lesions of the cornea, turbidity of the cornea, swelling of the eyelid or ocular discharge were observed in the methyl ester-treated groups, while sodium dioctyl sulfosuccinate, a positive control, caused severe toxicity. The anatomical and pathological observations indicate that the methyl ester produced by Beauveria bassiana CS1029 did not induce eye irritation in the lenses of the rabbits. The data suggest that the methyl ester evaluated in this study has promising potential as a cosmetic ingredient that does not irritate the eye. PMID:24137288

  15. Suppression of complete fusion due to breakup in the reactions {sup 10,11}B+{sup 209}Bi

    SciTech Connect

    Gasques, L. R.; Hinde, D. J.; Dasgupta, M.; Mukherjee, A.; Thomas, R. G.

    2009-03-15

    Above-barrier cross sections of fission and {alpha}-active heavy reaction products were measured for the reactions of {sup 10,11}B with {sup 209}Bi. Systematic analysis showed that the fission originates almost exclusively from complete fusion (CF). Existing measurements of above-barrier fusion products for the {sup 30}Si+{sup 186}W reaction, assumed to proceed exclusively through CF, were extrapolated to the current systems using statistical model calculations. This extrapolation showed that the heavy reaction products from the {sup 10,11}B+{sup 209}Bi reactions include substantial components from incomplete fusion as well as from CF. Compared with fusion calculations without breakup, the CF cross sections are suppressed by 15% for {sup 10}B and 7% for {sup 11}B. A consistent and systematic variation of the suppression of CF for reactions of the weakly bound nuclei {sup 6,7}Li, {sup 9}Be, and {sup 10,11}B on targets of {sup 208}Pb and {sup 209}Bi is found as a function of the breakup threshold energy.

  16. Learning With l1 -Regularizer Based on Markov Resampling.

    PubMed

    Gong, Tieliang; Zou, Bin; Xu, Zongben

    2016-05-01

    Learning with l1 -regularizer has brought about a great deal of research in learning theory community. Previous known results for the learning with l1 -regularizer are based on the assumption that samples are independent and identically distributed (i.i.d.), and the best obtained learning rate for the l1 -regularization type algorithms is O(1/√m) , where m is the samples size. This paper goes beyond the classic i.i.d. framework and investigates the generalization performance of least square regression with l1 -regularizer ( l1 -LSR) based on uniformly ergodic Markov chain (u.e.M.c) samples. On the theoretical side, we prove that the learning rate of l1 -LSR for u.e.M.c samples l1 -LSR(M) is with the order of O(1/m) , which is faster than O(1/√m) for the i.i.d. counterpart. On the practical side, we propose an algorithm based on resampling scheme to generate u.e.M.c samples. We show that the proposed l1 -LSR(M) improves on the l1 -LSR(i.i.d.) in generalization error at the low cost of u.e.M.c resampling. PMID:26011874

  17. Micropropagation of Prosopis chilensis (Mol.) Stuntz from young and mature plants.

    PubMed

    Caro, L A; Polci, P A; Lindström, L I; Echenique, C V; Hernández, L F

    2002-04-01

    Prosopis chilensis (Mol.) Stuntz (Algarrobo de Chile) is an important native tree species that can be grown in arid and semiarid regions for wood and forage production and environmental protection. Developing a simple and reliable in vitro protocol for cloning it would enable to improve it genetically. Explants of P. chilensis were taken from 4 months-old plants grown in the greenhouse or from adult trees grown in a natural environment. Nodal segments 1-2 cm long containing an axillary bud were selected from elongating shoots. These cuttings were aseptically cultured on two agar-solid basal media, MS or BTMm, and treated with 0.05 mg L-1 BA and 3 mg L-1 of either IAA, IBA or NAA. Sucrose (3% w/v) was used as carbon source. The percentage of sprouted cuttings and whole plant regeneration as well as its shoot and root length were recorded. Number, length and dry weight of shoots and roots were also measured. Rooting was successful with cuttings taken from young or adult plants, but explants from young plants showed a better response. Culturing in BTMm resulted in significantly greater shoot and root biomass than culturing in MS. Moreover, this response was higher in young explants when IBA was used as growth regulator. This paper reports a simple and effective method to micropropagate P. chilensis from young and adult plants. PMID:12058379

  18. Oleanolic acid reduces markers of differentiation in 3T3-L1 adipocytes.

    PubMed

    Sung, Hye-Young; Kang, Sang-Wook; Kim, Jung-Lye; Li, Jing; Lee, Eun-Sook; Gong, Ju-Hyun; Han, Seoung Jun; Kang, Young-Hee

    2010-12-01

    Oleanolic acid is a triterpenoid compound that is widely present in vegetables, medicinal herbs, and other plants and has potent antioxidant and antiinflammatory properties. However, the potential of oleanolic acid to offset obesity is not clear. This study tested the hypothesis that oleanolic acid suppresses the differentiation of 3T3-L1 adipocytes by downregulating cellular induction of peroxisome proliferators-activated receptor γ (PPARγ) and cytidine-cytidine-adenosine-adenosine-thymidine (CCAAT) enhancer binding protein α (C/EBPα). The 3T3-L1 adipocytes were cultured and differentiated in Dulbecco modified Eagle medium containing 10% fetal bovine serum for 6 to 8 days in the absence and presence of 1 to 25 μmol/L oleanolic acid according to differentiating protocols. Nontoxic oleanolic acid, at 25 μmol/L or less, dose-dependently attenuated lipid accumulation in differentiated adipocytes as evidenced by Oil Red O staining. Western blot analysis showed that the induction of PPARγ and C/EBPα was markedly attenuated in differentiated and oleanolic acid-treated adipocytes at their transcriptional messenger RNA levels. Furthermore, this study examined whether oleanolic acid dampened the induction of visfatin, a proinflammatory and visceral fat-specific adipokine expressed in adipocytes. Visfatin expression was inhibited in differentiated adipocytes exposed to a PPARγ inhibitor GW9662. In addition, the visfatin production was significantly repressed in 25 μmol/L oleanolic acid-treated adipocytes, possibly through blocking PPARγ activation. These results demonstrate that oleanolic acid may be a promising agent to disturb adipocyte differentiation and suppress obesity-associated inflammation. PMID:21147366

  19. Teachers' Language: L1 Attrition in Russian-English Bilinguals

    ERIC Educational Resources Information Center

    Isurin, Ludmila

    2007-01-01

    The present study reports on the evidence of first language (L1) attrition in a population that may appear to be the most resistant to L1 changes. Russian monolinguals (n=3) and Russian-English bilinguals (n=10) participated in the study. The bilinguals were graduate students teaching Russian as a foreign language at a U.S. university. The data…

  20. L2 Effects on L1 Event Conceptualization

    ERIC Educational Resources Information Center

    Bylund, Emanuel; Jarvis, Scott

    2011-01-01

    The finding that speakers of aspect languages encode event endpoints to a lesser extent than do speakers of non-aspect languages has led to the hypothesis that there is a relationship between grammatical aspect and event conceptualization (e.g., von Stutterheim and Nuse, 2003). The present study concerns L1 event conceptualization in 40 L1

  1. Proposed amendments to UN ST/SG/AC.10/11: transport of dangerous goods—lithium batteries

    NASA Astrophysics Data System (ADS)

    Farrington, Michael D.

    UN Document ST/SG/AC.10/11 [ST/SG/AC.10/11, The UN recommendations on the Transport of Dangerous Goods, Manual of Tests and Criteria, 2nd revision] outlines a test plan that is fundamental to the classification for transport of lithium batteries with metallic lithium or lithium alloy anodes. Cells and batteries that fall within its scope are considered dangerous goods. The test plan requires amendment to address many shortcomings. Some tests assess risks that do not exist, other risks are not addressed. This paper outlines the issues we have identified with the test plan, the proposed amendments, the rationale behind the proposed amendments, and issues we have not addressed in the current round of amendments. Transport of lithium batteries has an excellent record. Packaging requirements are essential to continued safe transport. Tests that address known risks relevant to conditions normal to transport are discussed. It is for consideration that non-metallic anode systems such as some polymer and lithium-ion systems should be treated as distinctly different technologies with their own set of transportation risks. The use of the marketing term lithium battery when applied to lithium polymer and lithium-ion products has erroneously lead to the suggestion that they be included in the scope of UN Document ST/SG/AC.10/11. A recommendation to classify such systems under a new UN number is presented. It is suggested that UN 3090 or UN 3091 should be reserved for lithium metal or lithium metal alloy products.

  2. Indication, from Pioneer 10/11, Galileo, and Ulysses Data, of an Apparent Anomalous, Weak, Long-Range Acceleration

    SciTech Connect

    Anderson, J.D.; Lau, E.L.; Turyshev, S.G.; Laing, P.A.; Liu, A.S.; Nieto, M.M.

    1998-10-01

    Radio metric data from the Pioneer 10/11, Galileo, and Ulysses spacecraft indicate an apparent anomalous, constant, acceleration acting on the spacecraft with a magnitude {approximately}8.5{times}10{sup {minus}8} cm/s{sup 2} , directed towards the Sun. Two independent codes and physical strategies have been used to analyze the data. A number of potential causes have been ruled out. We discuss future kinematic tests and possible origins of the signal. {copyright} {ital 1998} {ital The American Physical Society}

  3. VERIFICATION SURVEY ACTIVITIES IN FS SURVEY UNITS 7, 8, 9, 10, 11, 13 & 14 AT THE SEPARATIONS PROCESS RESEARCH UNIT

    SciTech Connect

    M.G. JADICK

    2010-05-26

    FINAL INTERIM REPORT VERIFICATION SURVEY ACTIVITIES IN FINAL STATUS SURVEY UNITS 7, 8, 9, 10, 11, 13 AND 14 AT THE SEPARATIONS PROCESS RESEARCH UNIT, Niskayuna, New York 0496-SR-03-0. The Separations Process Research Unit (SPRU) facilities were constructed in the late 1940s to research the chemical separation of plutonium and uranium. SPRU operated between February 1950 and October 1953. The research activities ceased following the successful development of the reduction/oxidation and plutonium/uranium extraction processes that were subsequently used by the Hanford and the Savannah River sites.

  4. Multivalent Human Papillomavirus L1 DNA Vaccination Utilizing Electroporation

    PubMed Central

    Kwak, Kihyuck; Jiang, Rosie; Jagu, Subhashini; Wang, Joshua W.; Wang, Chenguang; Christensen, Neil D.; Roden, Richard B. S.

    2013-01-01

    Objectives Naked DNA vaccines can be manufactured simply and are stable at ambient temperature, but require improved delivery technologies to boost immunogenicity. Here we explore in vivo electroporation for multivalent codon-optimized human papillomavirus (HPV) L1 and L2 DNA vaccination. Methods Balb/c mice were vaccinated three times at two week intervals with a fusion protein comprising L2 residues ∼11−88 of 8 different HPV types (11−88×8) or its DNA expression vector, DNA constructs expressing L1 only or L1+L2 of a single HPV type, or as a mixture of several high-risk HPV types and administered utilizing electroporation, i.m. injection or gene gun. Serum was collected two weeks and 3 months after the last vaccination. Sera from immunized mice were tested for in-vitro neutralization titer, and protective efficacy upon passive transfer to naive mice and vaginal HPV challenge. Heterotypic interactions between L1 proteins of HPV6, HPV16 and HPV18 in 293TT cells were tested by co-precipitation using type-specific monoclonal antibodies. Results Electroporation with L2 multimer DNA did not elicit detectable antibody titer, whereas DNA expressing L1 or L1+L2 induced L1-specific, type-restricted neutralizing antibodies, with titers approaching those induced by Gardasil. Co-expression of L2 neither augmented L1-specific responses nor induced L2-specific antibodies. Delivery of HPV L1 DNA via in vivo electroporation produces a stronger antibody response compared to i.m. injection or i.d. ballistic delivery via gene gun. Reduced neutralizing antibody titers were observed for certain types when vaccinating with a mixture of L1 (or L1+L2) vectors of multiple HPV types, likely resulting from heterotypic L1 interactions observed in co-immunoprecipitation studies. High titers were restored by vaccinating with individual constructs at different sites, or partially recovered by co-expression of L2, such that durable protective antibody titers were achieved for each type

  5. Ubiquitin C-terminal hydrolase L1 (UCH-L1): structure, distribution and roles in brain function and dysfunction.

    PubMed

    Bishop, Paul; Rocca, Dan; Henley, Jeremy M

    2016-08-15

    Ubiquitin C-terminal hydrolase L1 (UCH-L1) is an extremely abundant protein in the brain where, remarkably, it is estimated to make up 1-5% of total neuronal protein. Although it comprises only 223 amino acids it has one of the most complicated 3D knotted structures yet discovered. Beyond its expression in neurons UCH-L1 has only very limited expression in other healthy tissues but it is highly expressed in several forms of cancer. Although UCH-L1 is classed as a deubiquitinating enzyme (DUB) the direct functions of UCH-L1 remain enigmatic and a wide array of alternative functions has been proposed. UCH-L1 is not essential for neuronal development but it is absolutely required for the maintenance of axonal integrity and UCH-L1 dysfunction is implicated in neurodegenerative disease. Here we review the properties of UCH-L1, and how understanding its complex structure can provide new insights into its roles in neuronal function and pathology. PMID:27515257

  6. Ubiquitin C-terminal hydrolase L1 (UCH-L1): structure, distribution and roles in brain function and dysfunction

    PubMed Central

    Bishop, Paul; Rocca, Dan; Henley, Jeremy M.

    2016-01-01

    Ubiquitin C-terminal hydrolase L1 (UCH-L1) is an extremely abundant protein in the brain where, remarkably, it is estimated to make up 1–5% of total neuronal protein. Although it comprises only 223 amino acids it has one of the most complicated 3D knotted structures yet discovered. Beyond its expression in neurons UCH-L1 has only very limited expression in other healthy tissues but it is highly expressed in several forms of cancer. Although UCH-L1 is classed as a deubiquitinating enzyme (DUB) the direct functions of UCH-L1 remain enigmatic and a wide array of alternative functions has been proposed. UCH-L1 is not essential for neuronal development but it is absolutely required for the maintenance of axonal integrity and UCH-L1 dysfunction is implicated in neurodegenerative disease. Here we review the properties of UCH-L1, and how understanding its complex structure can provide new insights into its roles in neuronal function and pathology. PMID:27515257

  7. Do L1 Reading Achievement and L1 Print Exposure Contribute to the Prediction of L2 Proficiency?

    ERIC Educational Resources Information Center

    Sparks, Richard L.; Patton, Jon; Ganschow, Leonore; Humbach, Nancy

    2012-01-01

    The study examined whether individual differences in high school first language (L1) reading achievement and print exposure would account for unique variance in second language (L2) written (word decoding, spelling, writing, reading comprehension) and oral (listening/speaking) proficiency after adjusting for the effects of early L1 literacy and…

  8. Apollo 10 - 11

    NASA Technical Reports Server (NTRS)

    2001-01-01

    This video gives overviews of the Apollo 10 and Apollo 11 missions to the moon, including footage from the launches and landings of the Command Module Columbia, which is used for both flights. The Apollo 10 crewmembers, Commander Thomas Stafford, Command Module Pilot John Young, and Lunar Module Pilot Eugene Cernan, are seen as they suit-up in preparation for launch and then as they experiment with the microgravity environment on their way to the moon. The moon's surface is seen in detail as the Command Module orbits at an altitude of 69 miles. The Apollo 11 crewmembers, Commander Neil Armstrong, Command Module Pilot Michael Collins, and Lunar Module Pilot Buzz Aldrin, are seen during various training activities, including simulated lunar gravity training, practicing collecting lunar material, and using the moonquake detector. Footage shows the approach and landing of the Lunar Module Eagle on the moon. Armstrong and Aldrin descend to the moon's surface, collect a sample of lunar dust, and erect the American flag. Eagle's liftoff from the moon is seen.

  9. Crystal and mol-ecular structure of aflatrem.

    PubMed

    Lenta, Bruno N; Ngatchou, Jules; Kenfack, Patrice T; Neumann, Beate; Stammler, Hans-Georg; Sewald, Norbert

    2015-11-01

    The crystal structure of the title compound, C32H39NO4, confirms the absolute configuration of the seven chiral centres in the mol-ecule. The molecule has a 1,1-dimethylprop-2-enyl substituent on the indole nucleus and this nucleus shares one edge with the five-membered ring which is, in turn, connected to a sequence of three edge-shared fused rings. The skeleton is completed by the 7,7-trimethyl-6,8-dioxabi-cyclo-[3.2.1]oct-3-en-2-one group connected to the terminal cyclohexene ring. The two cyclohexane rings adopt chair and half-chair conformations, while in the dioxabi-cyclo-[3.2.1]oct-3-en-2-one unit, the six-membered ring has a half-chair conformation. The indole system of the mol-ecule exhibits a tilt of 2.02 (1)° between its two rings. In the crystal, O-H⋯O hydrogen bonds connect mol-ecules into chains along [010]. Weak N-H⋯π inter-actions connect these chains, forming sheets parallel to (10-1). PMID:26594569

  10. Crystal and mol­ecular structure of aflatrem

    PubMed Central

    Lenta, Bruno N.; Ngatchou, Jules; Kenfack, Patrice T.; Neumann, Beate; Stammler, Hans-Georg; Sewald, Norbert

    2015-01-01

    The crystal structure of the title compound, C32H39NO4, confirms the absolute configuration of the seven chiral centres in the mol­ecule. The molecule has a 1,1-dimethylprop-2-enyl substituent on the indole nucleus and this nucleus shares one edge with the five-membered ring which is, in turn, connected to a sequence of three edge-shared fused rings. The skeleton is completed by the 7,7-trimethyl-6,8-dioxabi­cyclo­[3.2.1]oct-3-en-2-one group connected to the terminal cyclohexene ring. The two cyclohexane rings adopt chair and half-chair conformations, while in the dioxabi­cyclo­[3.2.1]oct-3-en-2-one unit, the six-membered ring has a half-chair conformation. The indole system of the mol­ecule exhibits a tilt of 2.02 (1)° between its two rings. In the crystal, O—H⋯O hydrogen bonds connect mol­ecules into chains along [010]. Weak N—H⋯π inter­actions connect these chains, forming sheets parallel to (10-1). PMID:26594569

  11. Mechanised flow system for on-line microwave digestion of food samples with off-line catalytic spectrophotometric determination of cobalt at ng l-1 levels.

    PubMed

    Pereira-Filho, E R; Arruda, M A

    1999-12-01

    A mechanised system for on-line slurry food sample digestion was developed and an off-line cobalt determination was performed. The stabilised slurry sample was introduced into an air carrier stream until reaching the digestion coils located inside a household microwave oven. Software written in Visual Basic 3.0 was developed to permit the transport of the slurry samples and the programming of the microwave oven and also the control of the mineralization valve. The proposed system was optimized for determination of cobalt in certified samples such as mussels, bovine liver and fish and also uncertified fish samples. The digestion parameters were established as 3 mol l-1 HNO3 for mussels, 3 mol l-1 HNO3 plus 0.16% v/v H2O2 for bovine liver and 12 mol l-1 HNO3 for fish employing maximum power for 5 min of microwave actuation. In the subsequent spectrophotometric method for the catalytic determination of cobalt, the Tiron and hydrogen peroxide concentrations were 1.8 x 10(-3) and 3.0 x 10(-4) mol l-1, respectively, and the sample residence time was 300 s as determined by an optimisation process. The proposed method features a linear range from 10 to 200 ng l-1 Co (r > 0.996) with detection and quantification limits of 1.7 and 5.5 ng l-1 Co, respectively. The precision, expressed as RSD, was 2.4% (n = 12) for repeatability and 5.2% (n = 10) for reproducibility and the accuracy of the proposed method was assessed by using certified samples and an alternative technique (ETAAS). PMID:10746313

  12. Characterization of the cell adhesion molecules L1, N-CAM and J1 in the mouse intestine.

    PubMed Central

    Thor, G; Probstmeier, R; Schachner, M

    1987-01-01

    To gain insight into the cellular and molecular mechanisms underlying epithelial cell surface interactions in the adult mouse intestine, we have characterized the cell adhesion molecules L1, N-CAM and J1 by immunocytological, biochemical and cell biological methods. Whereas N-CAM and J1 expression was found to be confined to the mesenchymal and neuroectodermally-derived parts of the intestine, L1 was localized in the proliferating epithelial progenitor cells of crypts, but not in the more differentiated epithelial cells of villi. L1 was detected in crypt cells by Western blot analysis in the molecular forms characteristic of peripheral neural cells, with apparent mol. wts of 230, 180 and 150 kd. Aggregation of single, enriched crypt, but not villus cells, was strongly inhibited in the presence of Fab fragments of polyclonal L1 antibodies. These observations show that L1 is not confined to the nervous system and that it may play a functional role in the histogenesis of the intestine in the adult animal. Images Fig. 1. Fig. 2. Fig. 3. Fig. 4. Fig. 5. PMID:3315649

  13. Identical by descent L1CAM mutation in two apparently unrelated families with intellectual disability without L1 syndrome.

    PubMed

    Shaw, Marie; Yap, Tzu Ying; Henden, Lyndal; Bahlo, Melanie; Gardner, Alison; Kalscheuer, Vera M; Haan, Eric; Christie, Louise; Hackett, Anna; Gecz, Jozef

    2015-01-01

    Mutations in the L1 Cell Adhesion Molecule (L1CAM) gene (MIM#308840) cause a variety of X-linked recessive neurological disorders collectively called L1 syndrome. Using massively parallel sequencing (MPS) of the X-chromosome exome, we identified a novel missense variant in L1CAM in two Caucasian families with mild-moderate intellectual disability without obvious L1 syndrome features. These families were not known to be related. SNP data extracted from MPS identified a 5.6 cM tract of identity by descent (IBD), encompassing the L1CAM gene, between the DNA of the two probands. This cannot be explained by chance alone and strongly implies that the two families are related. It also suggests that the L1CAM (NM_000425.3, c.604G > A, p.D202N) variant is pathogenic. This report also demonstrates the usefulness of additional information, which can be extracted from exome sequencing data. PMID:25934484

  14. Aerobic vinyl chloride metabolism in Mycobacterium aurum L1

    SciTech Connect

    Hartmans, S.; Bont, J.A.M. de )

    1992-04-01

    Mycobacterium aurum L1, capable of growth on vinyl chloride as a sole carbon and energy source, was previously isolated from soil contaminated with vinyl chloride. The initial step in vinyl chloride metabolism in strain L1 is catalyzed by alkene monooxygenase, transforming vinyl chloride into the reactive epoxide chlorooxirane. The enzyme responsible for chlorooxirane degradation appeared to be very unstable and thus hampered the characterization of the second step in vinyl chloride metabolism. Dichloroethenes are also oxidized by vinyl chloride-grown cells of strain L1, but they are not utilized as growth substrates. Three additional bacterial strains which utilize vinyl chloride as a sole carbon and energy source were isolated from environments with no known vinyl chloride contamination. The three new isolates were similar to strain L1 and were also identified as Mycobacterium aurum.

  15. Gold nanoparticles functionalized with a fragment of the neural cell adhesion molecule L1 stimulate L1-mediated functions

    NASA Astrophysics Data System (ADS)

    Schulz, Florian; Lutz, David; Rusche, Norman; Bastús, Neus G.; Stieben, Martin; Höltig, Michael; Grüner, Florian; Weller, Horst; Schachner, Melitta; Vossmeyer, Tobias; Loers, Gabriele

    2013-10-01

    The neural cell adhesion molecule L1 is involved in nervous system development and promotes regeneration in animal models of acute and chronic injury of the adult nervous system. To translate these conducive functions into therapeutic approaches, a 22-mer peptide that encompasses a minimal and functional L1 sequence of the third fibronectin type III domain of murine L1 was identified and conjugated to gold nanoparticles (AuNPs) to obtain constructs that interact homophilically with the extracellular domain of L1 and trigger the cognate beneficial L1-mediated functions. Covalent conjugation was achieved by reacting mixtures of two cysteine-terminated forms of this L1 peptide and thiolated poly(ethylene) glycol (PEG) ligands (~2.1 kDa) with citrate stabilized AuNPs of two different sizes (~14 and 40 nm in diameter). By varying the ratio of the L1 peptide-PEG mixtures, an optimized layer composition was achieved that resulted in the expected homophilic interaction of the AuNPs. These AuNPs were stable as tested over a time period of 30 days in artificial cerebrospinal fluid and interacted with the extracellular domain of L1 on neurons and Schwann cells, as could be shown by using cells from wild-type and L1-deficient mice. In vitro, the L1-derivatized particles promoted neurite outgrowth and survival of neurons from the central and peripheral nervous system and stimulated Schwann cell process formation and proliferation. These observations raise the hope that, in combination with other therapeutic approaches, L1 peptide-functionalized AuNPs may become a useful tool to ameliorate the deficits resulting from acute and chronic injuries of the mammalian nervous system.The neural cell adhesion molecule L1 is involved in nervous system development and promotes regeneration in animal models of acute and chronic injury of the adult nervous system. To translate these conducive functions into therapeutic approaches, a 22-mer peptide that encompasses a minimal and functional L1

  16. Fitness cost of LINE-1 (L1) activity in humans

    PubMed Central

    Boissinot, Stephane; Davis, Jerel; Entezam, Ali; Petrov, Dimitri; Furano, Anthony V.

    2006-01-01

    The self-replicating LINE-1 (L1) retrotransposon family is the dominant retrotransposon family in mammals and has generated 30–40% of their genomes. Active L1 families are present in modern mammals but the important question of whether these currently active families affect the genetic fitness of their hosts has not been addressed. This issue is of particular relevance to humans as Homo sapiens contains the active L1 Ta1 subfamily of the human specific Ta (L1Pa1) L1 family. Although DNA insertions generated by the Ta1 subfamily can cause genetic defects in current humans, these are relatively rare, and it is not known whether Ta1-generated inserts or any other property of Ta1 elements have been sufficiently deleterious to reduce the fitness of humans. Here we show that full-length (FL) Ta1 elements, but not the truncated Ta1 elements or SINE (Alu) insertions generated by Ta1 activity, were subject to negative selection. Thus, one or more properties unique to FL L1 elements constitute a genetic burden for modern humans. We also found that the FL Ta1 elements became more deleterious as the expansion of Ta1 has proceeded. Because this expansion is ongoing, the Ta1 subfamily almost certainly continues to decrease the fitness of modern humans. PMID:16766655

  17. Generation of Femtosecond Laser Pulse at 1053 nm with Contrast of 10-11 by Optical-Parametric Amplification

    NASA Astrophysics Data System (ADS)

    Shen, Zhong-Wei; Wang, Zhao-Hua; Zhang, Wei; Fan, Hai-Tao; Teng, Hao; Wei, Zhi-Yi

    2014-01-01

    A high contrast 1053 nm femtosecond laser pulse with free background is demonstrated based on non-collinear optical-parametric amplification (NOPA). By permuting the signal and idler in two stages of NOPAs, 48.2 fs, 62 μJ laser pulse at 1053 nm with contrast ratio of 2.3 × 10-11 is obtained within the time scale of sub-5 ps. The beam quality factors M2 for tangential and sagittal directions are 1.59 and 1.30, respectively. This work not only proves a feasible way to generate a clean femtosecond laser pulse but can also be employed as an ideal frontend for ultrashort ultrahigh intensity Nd:glass-based laser systems.

  18. New results on the Pioneer Venus Orbiter February 10-11, 1982 events - A solar wind disturbance not a comet

    NASA Technical Reports Server (NTRS)

    Intriligator, D. S.

    1985-01-01

    The characteristics of a series of disturbances observed on February 10-11, 1982 by the plasma analyzer and the magnetometer on the Pioneer Venus Orbiter, obtained in the solar wind upstream of Venus are studied. It is concluded that the events were associated with the propagation of a solar wind disturbance of coronal origin and not with an encounter with a comet or other local outgassing object (Russel, et al., 1983). The plasma analyzer spectra clearly show the presence of increases in He(2) and they argue strongly against Russell, et al.'s interpretatation. The peak in magnetic field magnitude on February 11 is identified as the magnetic signature of a thin, trailing 'filament' at the end of a series of solar-initiated events. Corresponding increases in He(2) and magnetic field fluctuations were observed near earth by ISEE-3 about a day later, and this strongly supports the concept of a solar origin.

  19. Factors influencing plasma concentrations of carbamazepine and carbamazepine-10,11-epoxide in epileptic children and adults.

    PubMed

    Lanchote, V L; Bonato, P S; Campos, G M; Rodrigues, I

    1995-02-01

    Plasma carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZ-E) concentrations were measured in 160 epileptic patients in order to determine the effect of factors such as age, daily dosing schedule, formulation, and combination with other antiepileptic drugs on these concentrations in relation to the daily dose. The results showed that the CBZ plasma level/dose ratio was affected by all factors studied, whereas the CBZ-E plasma level/dose ratio was affected only by formulation and age. The ratio of CBZ-E to CBZ plasma levels (CBZ-E/CBZ) was affected by daily dosing schedule, age, and combination with other antiepileptic drugs. The present study demonstrated that many factors affect plasma CBZ/dose ratios, explaining the discrepancies observed in the literature. PMID:7725376

  20. Enantioselective hydrogenation. IV. Hydrogen isotope exchange in 10,11-dihydrocinchonidine and in quinoline catalyzed by platinum group metals

    SciTech Connect

    Bond, G.; Wells, P.B.

    1994-12-01

    Hydrogen isotope (H/D) exchange in the alkaloid 10,11-dihydrocinchonidine has been studied over 6.4% Pt/silica (EUROPT-1), 5% Ru/alumina, 5% Rh/alumina, and 5% Pd/alumina at 293 K using C{sub 2}H{sub 5}OD and D{sub 2} as solvent and deuterium source. Exchange was accompanied by hydrogenation. Over Pt, fast exchange occurred in the hydroxyl group followed by multiple exchange in which alkaloid molecules containing, 2, 3, 4 and 5 deuterium atoms were formed simultaneously. Mass spectrometry and {sup 1}H NMR showed that this multiple exchange occurred in the quinoline ring system and at C{sub 9}, but not in the quinuclidine ring system. The pattern of exchange in Ru was similar. Over Rh extensive hydrogenolysis of the quinuclidine ring system occurred, and over Pd the quinoline ring system was rapidly hydrogenated. Quinoline exchange and hydrogenation were also studied at 293 K; relatively rapid exchange occurred over Pt, Ru, and Rh, particularly at the 2- and 8-positions, whereas hydrogenation without significant exchange occurred over Pd. 10,11-Dihydrocinchonidine is adsorbed on Pt and Ru via the quinoline ring system and the multiple nature of the exchange indicates that the quinoline moiety is adsorbed approximately parallel to the metal surface by multicenter {pi}-bonding. An additional interaction of the alkaloid molecule with the surface occurs at carbon atom C{sub 9}, which may interpret the slower exchange in the alkaloid by comparison with that in quinoline. This study supports and enhances the model proposed to interpret the origin of enantioselectivity in pyruvate hydrogenation over Pt and Ir modified by cinchona alkaloids. The similarities of exchange over Pt and Ru suggest that enantioselective catalysis should be achievable over Ru. 28 refs., 2 figs., 2 tabs.

  1. A longitudinal study of grapheme-color synesthesia in childhood: 6/7 years to 10/11 years

    PubMed Central

    Simner, Julia; Bain, Angela E.

    2013-01-01

    Grapheme-color synesthesia is a condition characterized by enduring and consistent associations between letter/digits and colors. This study is the continuation of longitudinal research begun by Simner et al. (2009) which aimed to explore the development of this condition in real time within a childhood population. In that earlier study we randomly sampled over 600 children and tested them aged 6/7 and 7/8 years. We identified the child synesthetes within that cohort and measured their development over 1 year, in comparison to a group of non-synesthetic children with both average and superior memories. We were able to show the beginnings of a developmental progression in which synesthetic associations (e.g., A = red) mature over time from relatively chaotic pairings into a system of fixed consistent associations. In the current study we return to this same population three years later when participants are now 10/11 years. We used the same paired-association memory task to determine the synesthetic status of our participants and to also establish synesthetes' inventories of grapheme-color associations. We compared their inventories to those from age 6/7 and 7/8 years to examine how synesthesia matures over time. Together with earlier findings, our study shows that grapheme-color synesthesia emerges with a protracted trajectory, with 34% of letters/digits fixed at age 6/7 years, 48% fixed at 7/8 years and 71% fixed at 10/11 years. We also show several cases where synesthesia is not developing in the same time-frame as peers, either because it has died out at an older age, or because it was slower to develop than other cases. Our study paints the first picture of the emergence of synesthesia in real-time over four years within a randomly sampled population of child synesthetes. PMID:24312035

  2. CTC immune escape mediated by PD-L1.

    PubMed

    Wang, Xuefei; Sun, Qiang; Liu, Qiaofei; Wang, Changjun; Yao, Ru; Wang, Yimin

    2016-08-01

    Breast cancer is the most common malignant tumor in women around the world. Most breast cancer-related deaths are from CTC (circulating tumor cells) metastasis. CTC is associated with the breast cancer patients' prognosis. But recently, circulating clusters were found and its metastasis and tumor formation ability is 23-50 times as CTC. However, its mechanism has not been clarified. These days, researchers have successfully completed CTC cluster separation, CTC cell culture, and PD-L1 was found to be related with histological grading of tumor. Meanwhile, the high expression of PD-L1 in CTC surface has also been reported. Since PD-L1 can mediate Treg to play the role of immunosuppression, we propose that CTC with positive PD-L1 is easier to connect PD-L1, immune cells (Treg regulatory T cells, MDSC bone marrow inhibitory cells) and CK cytokines etc. On one hand, Treg cells can protect CTC from being attacked by the immune system through the immunosuppression, on the other hand, they can weaken CTL killing ability and trigger more MDSC. Finally, CTC formed the metastatic lesion. PMID:27372873

  3. Compressed-sensed-domain L1-PCA video surveillance

    NASA Astrophysics Data System (ADS)

    Liu, Ying; Pados, Dimitris A.

    2015-05-01

    We consider the problem of foreground and background extraction from compressed-sensed (CS) surveillance video. We propose, for the first time in the literature, a principal component analysis (PCA) approach that computes the low-rank subspace of the background scene directly in the CS domain. Rather than computing the conventional L2-norm-based principal components, which are simply the dominant left singular vectors of the CS measurement matrix, we compute the principal components under an L1-norm maximization criterion. The background scene is then obtained by projecting the CS measurement vector onto the L1 principal components followed by total-variation (TV) minimization image recovery. The proposed L1-norm procedure directly carries out low-rank background representation without reconstructing the video sequence and, at the same time, exhibits significant robustness against outliers in CS measurements compared to L2-norm PCA.

  4. Anthocyanins in berries of Maqui (Aristotelia chilensis (Mol.) Stuntz).

    PubMed

    Escribano-Bailón, María Teresa; Alcalde-Eon, Cristina; Muñoz, Orlando; Rivas-Gonzalo, Julián C; Santos-Buelga, Celestino

    2006-01-01

    The anthocyanin composition of berries of Maqui [Aristotelia chilensis (Mol.) Stuntz] was determined by HPLC with photodiode array and MS detection. Eight pigments corresponding to the 3-glucosides, 3,5-diglucosides, 3-sambubiosides and 3-sambubioside-5-glucosides of delphinidin and cyanidin were identified, the principal anthocyanin being delphinidin 3-sambubioside-5-glucoside (34% of total anthocyanins). The average total anthocyanin content was 137.6 +/- 0.4mg/100g of fresh fruit (211.9 +/- 0.6 mg/100g of dry fruit). The relative high anthocyanin content and the important presence of polar polyglycosylated derivatives makes the fruits of A. chilensis an interesting source of anthocyanin extracts for food and pharmaceutical uses. PMID:16454470

  5. Cloning and mapping of murine Nfe2L1

    SciTech Connect

    McKie, J.; Johnstone, K.; Scambler, P.

    1995-02-10

    The murine homologue of the human NFE2L1 basic leucine-zipper gene was isolated from an early embryo library. The deduced amino acid sequence shows 97% identity between the two proteins. Significant sequence similarity is also seen with the p45 subunit of NF-E2 and with the Drosophila CNC protein. Murine Nfe2l1 maps to chromosome 11DE with similar sequences at 7D1-7F1 and 2E4-2G. 14 refs., 2 figs.

  6. Lattice Green functions: the d-dimensional face-centered cubic lattice, d = 8, 9, 10, 11, 12

    NASA Astrophysics Data System (ADS)

    Hassani, S.; Koutschan, Ch; Maillard, J.-M.; Zenine, N.

    2016-04-01

    We previously reported on a recursive method to generate the expansion of the lattice Green function (LGF) of the d-dimensional face-centered cubic lattice (fcc). The method was used to generate many coefficients for d=7 and the corresponding linear differential equation has been obtained. In this paper, we show the strength and the limit of the method by producing the series and the corresponding linear differential equations for d=8,9,10,11,12. The differential Galois groups of these linear differential equations are shown to be symplectic for d=8,10,12 and orthogonal for d=9,11. The recursion relation naturally provides a two-dimensional array {t}d(n,j) where only the coefficients {t}d(n,0) correspond to the coefficients of the LGF of the d-dimensional fcc. The coefficients {t}d(n,j) are associated to D-finite bivariate series annihilated by linear partial differential equations that we analyze. Dedicated to Guttmann, for his 70th birthday.

  7. The Konya earthquakes of 10-11 September 2009 and soil conditions in Konya, Central Anatolia, Turkey

    NASA Astrophysics Data System (ADS)

    Aksoy, R.; Demiröz, A.

    2012-02-01

    Earthquakes registering magnitudes Md = 4.5 and 4.7 struck the city of Konya, Central Anatolia, on 10-11 September 2009, causing very slight damages. The earthquake epicenters were located at the east of Sille District along the Konya Fault Zone, a dip-slip fault. The nature and seismicity of the fault zone indicates that it is capable of producing earthquakes of moderate magnitudes. This paper summarizes the geologic data along the fault zone and documents groundwater conditions and analyzes borehole and geotechnical data of the Konya city. The residential area of the city covers an area of approximately 1150 square kilometers and consists almost entirely of flat land except for a small part of rugged land in the southwestern corner. Groundwater and geotechnical data were collected and analyzed to evaluate the liquefaction potential of deposits under the Konya city. This preliminary investigation indicates that areas for liquefaction are generally limited to the eastern and east central parts of the city.

  8. S-(−)-10,11-Dihydroxyfarnesoic Acid Methyl Ester Inhibits Melanin Synthesis in Murine Melanocyte Cells

    PubMed Central

    Baek, Seung-Hwa; Ahn, Jun-Won; Nam, Sung-Hee; Yoon, Cheol-Sik; Shin, Jae-Cheon; Lee, Sang-Han

    2014-01-01

    The development of antimelanogenic agents is important for the prevention of serious aesthetic problems such as melasmas, freckles, age spots, and chloasmas. In the course of screening for melanin synthesis inhibitors, we found that the culture broth from an insect morphopathogenic fungus, Beauveria bassiana CS1029, exhibits potent antimelanogenic activity. We isolated and purified an active metabolite and identified it as S-(−)-10,11-dihydroxyfarnesoic acid methyl ester (dhFAME), an insect juvenile hormone. To address whether dhFAME inhibits melanin synthesis, we first measured the size of the melanin biosynthesis inhibition zone caused by dhFAME. dhFAME also showed inhibitory activity against mushroom tyrosinase in Melan-a cells. Intracellular, dose-dependent tyrosinase inhibition activity was also confirmed by zymography. In addition, we showed that dhFAME strongly inhibits melanin synthesis in Melan-a cells. Furthermore, we compared levels of TYR, TRP-1, TRP-2, MITF, and MC1R mRNA expression by reverse-transcription polymerase chain reaction and showed that treatment of Melan-a cells with 35 μM dhFAME led to an 11-fold decrease in TYR expression, a 6-fold decrease in TRP-2 expression, and a 5-fold decrease in MITF expression. Together, these results indicate that dhFAME is a potent inhibitor of melanin synthesis that can potentially be used for cosmetic biomaterial(s). PMID:25046747

  9. Structure of low-lying states of {sup 10,11}C from proton elastic and inelastic scattering

    SciTech Connect

    Jouanne, C.; Lapoux, V.; Auger, F.; Alamanos, N.; Drouart, A.; Gillibert, A.; Lobo, G.; Musumarra, A.; Nalpas, L.; Pollacco, E.; Sida, J.-L.; Trotta, M.; Blumenfeld, Y.; Khan, E.; Suomijaervi, T.; Zerguerras, T.; Roussel-Chomaz, P.; Savajols, H.; Lagoyannis, A.; Pakou, A.

    2005-07-01

    To probe the ground state and transition densities, elastic and inelastic scattering on a proton target were measured in inverse kinematics for the unstable {sup 10}C and {sup 11}C nuclei at 45.3 and 40.6 MeV/nucleon, respectively. The detection of the recoil proton was performed by the MUST telescope array, in coincidence with a wall of scintillators for the quasiprojectile. The differential cross sections for elastic and inelastic scattering to the first excited states are compared to the optical model calculations performed within the framework of the microscopic nucleon-nucleus Jeukenne-Lejeune-Mahaux potential. Elastic scattering is sensitive to the matter-root-mean square radius found to be 2.42{+-}0.1 and 2.33{+-}0.1 fm, for {sup 10,11}C, respectively. The transition densities from cluster and mean-field models are tested, and the cluster model predicts the correct order of magnitude of cross sections for the transitions of both isotopes. Using the Bohr-Mottelson prescription, a profile for the {sup 10}C transition density from the 0{sup +} ground to the 2{sub 1}{sup +} state is deduced from the data. The corresponding neutron transition matrix element is extracted: M{sub n}=5.51{+-}1.09 fm{sup 2}.

  10. L1 adaptive output-feedback control architectures

    NASA Astrophysics Data System (ADS)

    Kharisov, Evgeny

    This research focuses on development of L 1 adaptive output-feedback control. The objective is to extend the L1 adaptive control framework to a wider class of systems, as well as obtain architectures that afford more straightforward tuning. We start by considering an existing L1 adaptive output-feedback controller for non-strictly positive real systems based on piecewise constant adaptation law. It is shown that L 1 adaptive control architectures achieve decoupling of adaptation from control, which leads to bounded away from zero time-delay and gain margins in the presence of arbitrarily fast adaptation. Computed performance bounds provide quantifiable performance guarantees both for system output and control signal in transient and steady state. A noticeable feature of the L1 adaptive controller is that its output behavior can be made close to the behavior of a linear time-invariant system. In particular, proper design of the lowpass filter can achieve output response, which almost scales for different step reference commands. This property is relevant to applications with human operator in the loop (for example: control augmentation systems of piloted aircraft), since predictability of the system response is necessary for adequate performance of the operator. Next we present applications of the L1 adaptive output-feedback controller in two different fields of engineering: feedback control of human anesthesia, and ascent control of a NASA crew launch vehicle (CLV). The purpose of the feedback controller for anesthesia is to ensure that the patient's level of sedation during surgery follows a prespecified profile. The L1 controller is enabled by anesthesiologist after he/she achieves sufficient patient sedation level by introducing sedatives manually. This problem formulation requires safe switching mechanism, which avoids controller initialization transients. For this purpose, we used an L1 adaptive controller with special output predictor initialization routine

  11. A Characterization of Banach Spaces Containing l1

    PubMed Central

    Rosenthal, Haskell P.

    1974-01-01

    It is proved that a Banach space contains a subspace isomorphic to l1 if (and only if) it has a bounded sequence with no weak-Cauchy subsequence. The proof yields that a sequence of subsets of a given set has a subsequence that is either convergent or Boolean independent. PMID:16592162

  12. The L1=L2 Hypotheses: A Reconsideration

    ERIC Educational Resources Information Center

    Ellis, Rod

    1985-01-01

    Discusses the L1=L2 hypothesis which states that, all other things except knowledge of language being equal, first language acquisition is the same as second language acquisition. Reviews the evidence for and against the hypothesis, looks at current research and considers the general distinction between formal and informal learning. (SED)

  13. L1-L2 Sentence Translation in Classroom Grammar Tests

    ERIC Educational Resources Information Center

    Salem, Ilana

    2012-01-01

    L1-L2 translation of separate sentences is one kind of task format used by mainstream EFL teachers to assess their learners' grammatical accuracy. Aimed at improving teacher-written translation items, this study analyses linguistic features potentially causing such decontextualized cues (and their target responses) to sound odd or untypical of…

  14. Discourse Connectives in L1 and L2 Argumentative Writing

    ERIC Educational Resources Information Center

    Hu, Chunyu; Li, Yuanyuan

    2015-01-01

    Discourse connectives (DCs) are multi-functional devices used to connect discourse segments and fulfill interpersonal levels of discourse. This study investigates the use of selected 80 DCs within 11 categories in the argumentative essays produced by L1 and L2 university students. The analysis is based on the International Corpus Network of Asian…

  15. Raising Learners' Awareness through L1-L2 Teacher Collaboration

    ERIC Educational Resources Information Center

    Gunning, Pamela; White, Joanna; Busque, Christine

    2016-01-01

    There is considerable interest in teacher collaboration across mother tongue and second language curricula. However, cross-curricular collaboration in reading strategy instruction has seldom been investigated. We report a two-year study involving collaboration between the French first language (L1) and English second language (L2) teachers in an…

  16. Conceptualising the Potential Role of L1 in CLIL

    ERIC Educational Resources Information Center

    Lin, Angel M. Y.

    2015-01-01

    Content and language integrated learning (CLIL) is a rapidly growing area of both research and practice in all parts of the world, especially in Europe and Asia. As a young discipline, CLIL has a good potential of distinguishing itself from monolingual L2 immersion education models by becoming more flexible and balanced about the role of L1 in…

  17. On the L1 Attrition of the Spanish Present Tense

    ERIC Educational Resources Information Center

    Cuza, Alejandro

    2010-01-01

    This study examines the potential native language (L1) attrition of the ongoing value of the Spanish present tense among long-term Spanish immigrants. Based on the assumption of second-language (L2) transfer and proposals on the permeability of interface-conditioned structures, it is hypothesized that long-term Spanish immigrants will show…

  18. New powerful thermal modelling for high-precision gravity missions with application to Pioneer 10/11

    NASA Astrophysics Data System (ADS)

    Rievers, Benny; Lämmerzahl, Claus; List, Meike; Bremer, Stefanie; Dittus, Hansjörg

    2009-11-01

    The evaluation of about 25 years of Doppler data has shown an anomalous constant deceleration of the deep space probes Pioneer 10 and 11. This observation became known as the Pioneer anomaly (PA) and has been confirmed independently by several groups. Many disturbing effects that could cause a constant deceleration of the craft have been excluded as possible source of the PA. However, a potential asymmetric heat dissipation of the spacecraft surface leading to a resulting acceleration still remains to be analysed in detail. We developed a method to calculate this force with very high precision by means of finite element (FE) modelling and ray tracing algorithms. The elaborated method is divided into two separate parts. The first part consists of the modelling of the spacecraft geometry in FE and the generation of a steady state temperature surface map of the craft. In the second part, this thermal map is used to compute the force with a ray-tracing algorithm, which gives the total momentum generated by the radiation emitted from the spacecraft surface. The modelling steps and the force computation are presented for a simplified geometry of the Pioneer 10/11 spacecraft including radioisotope thermoelectric generators (RTG), equipment/experiment section and the high gain antenna. Analysis results how that the magnitude of the forces to be expected are non-negligible with respect to the PA and that more detailed investigations are necessary. The method worked out here for the first time is not restricted to the modelling of the Pioneer spacecraft but can be used for many future fundamental physics (in particular gravitational physics) and geodesy missions like LISA, LISA Pathfinder or MICROSCOPE for which an exact disturbance modelling is crucial.

  19. Unstable nuclei in coherent dissociation of relativistic nuclei 7,9Be, 10B and 10,11C

    NASA Astrophysics Data System (ADS)

    Artemenkov, D. A.; Bradnova, V.; Firu, E.; Kornegrutsa, N. K.; Haiduc, M.; Mamatkulov, K. Z.; Kattabekov, R. R.; Neagu, A.; Rukoyatkin, P. A.; Rusakova, V. V.; Sarkisyan, V. R.; Stanoeva, R.; Zaitsev, A. A.; Zarubin, P. I.; Zarubina, I. G.

    2016-06-01

    Contribution of the unstable nuclei 7Be, 8Be and ®B into coherent dissociation events (“white” stars) of relativistic nuclei 7,9Be, 10B and 10,11C is under study on the basis of a nuclear track emulsion exposed to beams of the JINR Nuclotron. Distributions over the opening angle of α-pairs indicate to a simultaneous presence of virtual 8Beg.s. and 8Be2+ states in the ground states of the 9Be and 10C nuclei. The core 9B is manifested in the 10C nucleus with a probability of (30 ± 4)%, Selection of the 10C “white” stars accompanied by 8Beg.s. (9B) leads to the appearance in the excitation energy distribution of 2α2p “quartets” of the distinct peak with a maximum at 4.1 ± 0.3 MeV. 8Beg.s. decays are presented in 21% 2He + 2H and 19% in the 3He of the all 11C “white” stars. 9Bg.s. decays are identified in “white” stars 11C → 2He + 2H constituting 14% of the 11C “white” stars. The 9B nucleus. is manifested in the “white” stars 10B → 2He + 2H with a probability of (9 ± 1)%. For the 10B case yield of 8Beg.s. nuclei with the respect to 9B is about a factor of 3 higher than 9B.

  20. Climate Change during Marine Isotope Stages 10 & 11 based on High-Resolution Speleothem Records from Eastern North America

    NASA Astrophysics Data System (ADS)

    Buckles, J. A.; Gao, Y.; Wang, X.; Rowe, H.; Cheng, H.; Edwards, R. L.

    2014-12-01

    Two speleothems from eastern North America grew throughout Marine Isotope Stages 10 and 11. High-resolution stable isotope δ18O and δ13C, and Sr records are constrained by 16 230Th age dates. MIS 11 (374 - 424 kyr BP) is of particular interest due to the similarity of orbitally-controlled insolation conditions from this time period and the modern. While few high-resolution continental paleoclimate records exist for this time period, marine records reveal that during this prominent interglacial, sea surface temperatures were relatively stable, in contrast to those which occurred during the subsequent glacial period (MIS 10). Speleothems TNBS-8 and TNMOR2-01, from Tennessee's Blue Springs Cave and Morrell Cave, respectively, grew between 338 - 420 kyr BP and overlap for ~50 kyr. Growth rates were generally higher during MIS 11 than 10, with a higher degree of variability. Stable isotope δ18O and δ13C records (TNMOR2-01) show an overall trend towards higher values throughout the MIS 11-10 transition, with well-defined periods of depletion and enrichment. Sr concentration measured through µ-XRF reveals similar behavior as the δ13C record and serves as a proxy for moisture availability. Overlapping Sr results for both speleothems share general trends and reveal distinct intervals of increased precipitation occur throughout the record, with most coinciding with summer insolation maxima. The transitions of MIS 11.2 to 11.1 and MIS 11 to 10 are well-constrained by abrupt increases in δ18O and δ13C values along with Sr concentrations. An examination of continental proxy responses to similar orbital and climatic conditions as the modern allows for not only a greater understanding of how the climate changed during the MIS 10-11, but also allows for the examination of natural climate variability in light of the addition of anthropogenic climate forcing.

  1. A novel missense mutation in the L1CAM gene in a boy with L1 disease.

    PubMed

    Simonati, A; Boaretto, F; Vettori, A; Dabrilli, P; Criscuolo, L; Rizzuto, N; Mostacciuolo, M L

    2006-06-01

    A novel missense mutation of the L1CAM gene (Xq28) is described in an adult patient affected with severe mental retardation, spastic paraparesis, adducted thumbs, agenesis of corpus callosum and microcephaly (L1 disease). We detected a transition c2308G-->A in exon 18 that caused an amino acid change in codon 770. The patient's mother and two sisters were heterozygous for the same mutation. This newly described mutation predicts the substitution of an aspartate by asparagine (D770N) in the second fibronectin (Fn2) domain of the extracellular portion of the mature L1 protein. Even if amino acid substitution does not significantly change the physico-chemical properties of the Fn2 domain, it seems clear that the integrity of this domain is required to maintain the biological functions of the protein. The feature peculiar to this patient is the decelerated head growth post-natally, leading to microcephaly. Mutations of L1CAM associated with prolonged survival may hamper post-natal brain and head growth. PMID:16816908

  2. Singular Spectrum Analysis Based on L1-Norm

    NASA Astrophysics Data System (ADS)

    Kalantari, Mahdi; Yarmohammadi, Masoud; Hassani, Hossein

    2016-03-01

    In recent years, the singular spectrum analysis (SSA) technique has been further developed and increasingly applied to solve many practical problems. The aim of this research is to introduce a new version of SSA based on L1-norm. The performance of the proposed approach is assessed by applying it to various real and simulated time series, especially with outliers. The results are compared with those obtained using the basic version of SSA which is based on the Frobenius norm or L2-norm. Different criteria are also examined including reconstruction errors and forecasting performances. The theoretical and empirical results confirm that SSA based on L1-norm can provide better reconstruction and forecasts in comparison to basic SSA when faced with time series which are polluted by outliers.

  3. Development, validation and clinical application of an online-SPE-LC-HRMS/MS for simultaneous quantification of phenobarbital, phenytoin, carbamazepine, and its active metabolite carbamazepine 10,11-epoxide.

    PubMed

    Qu, Lihua; Fan, Yuanjie; Wang, Wenjun; Ma, Kai; Yin, Zheng

    2016-09-01

    A simple and efficient bioanalytical method for simultaneous determination of phenobarbital (PB), phenytoin (PHT), carbamazepine (CBZ), and its active metabolite carbamazepine 10,11-epoxide (CBZE) in human plasma using online solid phase extraction (SPE)-liquid chromatography (LC) coupled with high resolution mass spectrum (HRMS) under targeted MS/MS (t-MS(2)) analysis mode has been developed. The procedure integrated an automated sample clean-up of human plasma by Oasis®HLB SPE cartridge, a separation by ZORBAX SB-C18 analysis column, and a quantification by Q-Exactive Hybrid Quadrupole-Orbitrap. The total running time was 13min. The lower limit of quantification (LLOQ) of PB, PHT, CBZ, and CBZE were 0.008, 0.008, 0.0016 and 0.0016μgmL(-1) respectively and the linearities were in the range of 0.008-2.500, 0.008-2.500, 0.0016-0.500 and 0.0016-0.500μgmL(-1) respectively. The mean recovery was between 91.82% and 108.27% and the matrix effect was between 93.29% and 102.09%. The relative standard deviations of interday and intraday were less than 6.41%. The method has been successfully applied in therapeutic drug monitoring (TDM) of four Chinese epilepsy patients. This fully automated, simple, sensitive and reliable online-SPE-LC-HRMS/MS method serves well for TDM of PB, PHT, CBZ and CBZE at clinics for either single or combination treatment. PMID:27343581

  4. Programmed Death Ligand 1 (PD-L1)-targeted TRAIL combines PD-L1-mediated checkpoint inhibition with TRAIL-mediated apoptosis induction.

    PubMed

    Hendriks, Djoke; He, Yuan; Koopmans, Iris; Wiersma, Valerie R; van Ginkel, Robert J; Samplonius, Douwe F; Helfrich, Wijnand; Bremer, Edwin

    2016-08-01

    Antibodies that block PD-L1/PD-1 immune checkpoints restore the activity of functionally-impaired antitumor T cells. These antibodies show unprecedented clinical benefit in various advanced cancers, particularly in melanoma. However, only a subset of cancer patients responds to current PD-L1/PD-1-blocking strategies, highlighting the need for further advancements in PD-L1/PD-1-based immunotherapy. Here, we report on a novel approach designed to combine PD-L1 checkpoint inhibition with the tumor-selective induction of apoptosis by TNF-related Apoptosis Inducing Ligand (TRAIL). In brief, a new bi-functional fusion protein, designated anti-PD-L1:TRAIL, was constructed comprising a PD-L1-blocking antibody fragment genetically fused to the extracellular domain of the pro-apoptotic tumoricidal protein TRAIL. Treatment of PD-L1-expressing cancer cells with anti-PD-L1:TRAIL induced PD-L1-directed TRAIL-mediated cancer cell death. Treatment of T cells with anti-PD-L1:TRAIL augmented T cell activation, as evidenced by increased proliferation, secretion of IFNγ and enhanced killing of cancer cell lines and primary patient-derived cancer cells in mixed T cell/cancer cell culture experiments. Of note, elevated levels of IFNγ further upregulated PD-L1 on cancer cells and simultaneously sensitized cancer cells to TRAIL-mediated apoptosis by anti-PD-L1:TRAIL. Additionally, anti-PD-L1:TRAIL converted immunosuppressive PD-L1-expressing myeloid cells into pro-apoptotic effector cells that triggered TRAIL-mediated cancer cell death. In conclusion, combining PD-L1 checkpoint inhibition with TRAIL-mediated induction of apoptosis using anti-PD-L1:TRAIL yields promising multi-fold and mutually reinforcing anticancer activity that may be exploited to enhance the efficacy of therapeutic PD-L1/PD-1 checkpoint inhibition. PMID:27622071

  5. High electrical conductivity in Ni₃(2,3,6,7,10,11-hexaiminotriphenylene)₂, a semiconducting metal-organic graphene analogue.

    PubMed

    Sheberla, Dennis; Sun, Lei; Blood-Forsythe, Martin A; Er, Süleyman; Wade, Casey R; Brozek, Carl K; Aspuru-Guzik, Alán; Dincă, Mircea

    2014-06-25

    Reaction of 2,3,6,7,10,11-hexaaminotriphenylene with Ni(2+) in aqueous NH3 solution under aerobic conditions produces Ni3(HITP)2 (HITP = 2,3,6,7,10,11-hexaiminotriphenylene), a new two-dimensional metal-organic framework (MOF). The new material can be isolated as a highly conductive black powder or dark blue-violet films. Two-probe and van der Pauw electrical measurements reveal bulk (pellet) and surface (film) conductivity values of 2 and 40 S·cm(-1), respectively, both records for MOFs and among the best for any coordination polymer. PMID:24750124

  6. Detection of L1, infectious virions and anti-L1 antibody in domestic rabbits infected with cottontail rabbit papillomavirus.

    PubMed

    Hu, Jiafen; Budgeon, Lynn R; Cladel, Nancy M; Culp, Timothy D; Balogh, Karla K; Christensen, Neil D

    2007-12-01

    Shope papillomavirus or cottontail rabbit papillomavirus (CRPV) is one of the first small DNA tumour viruses to be characterized. Although the natural host for CRPV is the cottontail rabbit (Sylvilagus floridanus), CRPV can infect domestic laboratory rabbits (Oryctolagus cuniculus) and induce tumour outgrowth and cancer development. In previous studies, investigators attempted to passage CRPV in domestic rabbits, but achieved very limited success, leading to the suggestion that CRPV infection in domestic rabbits was abortive. The persistence of specific anti-L1 antibody in sera from rabbits infected with either virus or viral DNA led us to revisit the questions as to whether L1 and infectious CRPV can be produced in domestic rabbit tissues. We detected various levels of L1 protein in most papillomas from CRPV-infected rabbits using recently developed monoclonal antibodies. Sensitive in vitro infectivity assays additionally confirmed that extracts from these papillomas were infectious. These studies demonstrated that the CRPV/New Zealand White rabbit model could be used as an in vivo model to study natural virus infection and viral life cycle of CRPV and not be limited to studies on abortive infections. PMID:18024897

  7. Plasmids pMOL28 and pMOL30 of Cupriavidus metallidurans Are Specialized in the Maximal Viable Response to Heavy Metals▿ †

    PubMed Central

    Monchy, Sébastien; Benotmane, Mohammed A.; Janssen, Paul; Vallaeys, Tatiana; Taghavi, Safiyh; van der Lelie, Daniel; Mergeay, Max

    2007-01-01

    We fully annotated two large plasmids, pMOL28 (164 open reading frames [ORFs]; 171,459 bp) and pMOL30 (247 ORFs; 233,720 bp), in the genome of Cupriavidus metallidurans CH34. pMOL28 contains a backbone of maintenance and transfer genes resembling those found in plasmid pSym of C. taiwanensis and plasmid pHG1 of C. eutrophus, suggesting that they belong to a new class of plasmids. Genes involved in resistance to the heavy metals Co(II), Cr(VI), Hg(II), and Ni(II) are concentrated in a 34-kb region on pMOL28, and genes involved in resistance to Ag(I), Cd(II), Co(II), Cu(II), Hg(II), Pb(II), and Zn(II) occur in a 132-kb region on pMOL30. We identified three putative genomic islands containing metal resistance operons flanked by mobile genetic elements, one on pMOL28 and two on pMOL30. Transcriptomic analysis using quantitative PCR and microarrays revealed metal-mediated up-regulation of 83 genes on pMOL28 and 143 genes on pMOL30 that coded for all known heavy metal resistance proteins, some new heavy metal resistance proteins (czcJ, mmrQ, and pbrU), membrane proteins, truncated transposases, conjugative transfer proteins, and many unknown proteins. Five genes on each plasmid were down-regulated; for one of them, chrI localized on pMOL28, the down-regulation occurred in the presence of five cations. We observed multiple cross-responses (induction of specific metal resistance by other metals), suggesting that the cellular defense of C. metallidurans against heavy metal stress involves various regulons and probably has multiple stages, including a more general response and a more metal-specific response. PMID:17675385

  8. Symbolic Violence, Locality and Social Class: The Educational and Career Aspirations of 10-11-Year-Old Boys in Belfast

    ERIC Educational Resources Information Center

    Connolly, Paul; Healy, Julie

    2004-01-01

    This article is based upon a comparative, ethnographic case study of two groups of 10-11-year-old boys--one middle-class, the other working-class--living in Belfast. Drawing upon Bourdieu's related concepts of symbolic violence and habitus, it shows how locality can help to explain the very different educational and career aspirations found…

  9. Cannabidiol promotes browning in 3T3-L1 adipocytes.

    PubMed

    Parray, Hilal Ahmad; Yun, Jong Won

    2016-05-01

    Recruitment of the brown-like phenotype in white adipocytes (browning) and activation of existing brown adipocytes are currently being investigated as a means to combat obesity. Thus, a wide variety of dietary agents that contribute to browning of white adipocytes have been identified. The present study was designed to investigate the effects of cannabidiol (CBD), a major nonpsychotropic phytocannabinoid of Cannabis sativa, on induction of browning in 3T3-L1 adipocytes. CBD enhanced expression of a core set of brown fat-specific marker genes (Ucp1, Cited1, Tmem26, Prdm16, Cidea, Tbx1, Fgf21, and Pgc-1α) and proteins (UCP1, PRDM16, and PGC-1α). Increased expression of UCP1 and other brown fat-specific markers contributed to the browning of 3T3-L1 adipocytes possibly via activation of PPARγ and PI3K. In addition, CBD increased protein expression levels of CPT1, ACSL, SIRT1, and PLIN while down-regulating JNK2, SREBP1, and LPL. These data suggest possible roles for CBD in browning of white adipocytes, augmentation of lipolysis, thermogenesis, and reduction of lipogenesis. In conclusion, the current data suggest that CBD plays dual modulatory roles in the form of inducing the brown-like phenotype as well as promoting lipid metabolism. Thus, CBD may be explored as a potentially promising therapeutic agent for the prevention of obesity. PMID:27067870

  10. L1 track finding for a time multiplexed trigger

    NASA Astrophysics Data System (ADS)

    Cieri, D.; Brooke, J.; Grimes, M.; Newbold, D.; Harder, K.; Shepherd-Themistocleous, C.; Tomalin, I.; Vichoudis, P.; Reid, I.; Iles, G.; Hall, G.; James, T.; Pesaresi, M.; Rose, A.; Tapper, A.; Uchida, K.

    2016-07-01

    At the HL-LHC, proton bunches will cross each other every 25 ns, producing an average of 140 pp-collisions per bunch crossing. To operate in such an environment, the CMS experiment will need a L1 hardware trigger able to identify interesting events within a latency of 12.5 μs. The future L1 trigger will make use also of data coming from the silicon tracker to control the trigger rate. The architecture that will be used in future to process tracker data is still under discussion. One interesting proposal makes use of the Time Multiplexed Trigger concept, already implemented in the CMS calorimeter trigger for the Phase I trigger upgrade. The proposed track finding algorithm is based on the Hough Transform method. The algorithm has been tested using simulated pp-collision data. Results show a very good tracking efficiency. The algorithm will be demonstrated in hardware in the coming months using the MP7, which is a μTCA board with a powerful FPGA capable of handling data rates approaching 1 Tb/s.

  11. Acquisition of Japanese contracted sounds in L1 phonology

    NASA Astrophysics Data System (ADS)

    Tsurutani, Chiharu

    2002-05-01

    Japanese possesses a group of palatalized consonants, known to Japanese scholars as the contracted sounds, [CjV]. English learners of Japanese appear to treat them initially as consonant + glide clusters, where there is an equivalent [Cj] cluster in English, or otherwise tend to insert an epenthetic vowel [CVjV]. The acquisition of the Japanese contracted sounds by first language (L1) learners has not been widely studied compared with the consonant clusters in English with which they bear a close phonetic resemblance but have quite a different phonological status. This is a study to investigate the L1 acquisition process of the Japanese contracted sounds (a) in order to observe how the palatalization gesture is acquired in Japanese and (b) to investigate differences in the sound acquisition processes of first and second language (L2) learners: Japanese children compared with English learners. To do this, the productions of Japanese children ranging in age from 2.5 to 3.5 years were transcribed and the pattern of misproduction was observed.

  12. Getting to L1 the Hard Way: Triana's Launch Options

    NASA Technical Reports Server (NTRS)

    Houghton, Martin B.; Bauer, Frank H. (Technical Monitor)

    2002-01-01

    Over the past four years, NASA's Goddard Space Flight Center has built and tested the Triana observatory, which will be the first Earth observing science satellite to take advantage of the unique perspective offered by a Lissajous orbit about the first Earth-Sun Lagrange Point (L1). Triana was originally meant to fly on the U.S. Space Transportation System (a.k.a. the Space Shuttle), but complications with the shuttle manifest have forced Triana into a "wait and see" attitude. The observatory is currently being stored at NASA's Goddard Space Flight Center, where it waits for an appropriate launch opportunity to materialize. To that end, several possible alternatives have been considered, including variations on the nominal shuttle deployment scenario, a high inclination Delta-type launch from Vandenberg Air Force Base, a Tsyklon class vehicle launched from Baikonur, Kazakhstan, and a ride on a French Ariane vehicle out of French Guiana into a somewhat arbitrary geostationary transfer orbit (GTO). This paper chronicles and outlines the pros and cons of how each of these opportunities could be used to send Triana on its way to L1.

  13. CD274/PD-L1 gene amplification and PD-L1 protein expression are common events in squamous cell carcinoma of the oral cavity

    PubMed Central

    Straub, Melanie; Drecoll, Enken; Pfarr, Nicole; Weichert, Wilko; Langer, Rupert; Hapfelmeier, Alexander; Götz, Carolin; Wolff, Klaus-Dietrich; Kolk, Andreas; Specht, Katja

    2016-01-01

    Immunomodulatory therapies, targeting the immune checkpoint receptor-ligand complex PD-1/PD-L1 have shown promising results in early phase clinical trials in solid malignancies, including carcinomas of the head and neck. In this context, PD-L1 protein expression has been proposed as a potentially valuable predictive marker. In the present study, expression of PD-L1 and PD-1 was evaluated by immunohistochemistry in 80 patients with predominantly HPV-negative oral squamous cell carcinomas and associated nodal metastasis. In addition, CD274/PD-L1 gene copy number status was assessed by fluorescence in situ hybridization analysis. PD-L1 expression was detected in 36/80 (45%) cases and concordance of PD-L1 expression in primary tumor and corresponding nodal metastasis was present in only 20/28 (72%) cases. PD-1 expression was found in tumor-infiltrating lymphocytes (TILs) but not in tumor cells. CD274/PD-L1 gene amplification was detected in 19% of cases, with high level PD-L1 amplification present in 12/80 (15%), and low level amplification in 3/80 (4%). Interestingly, CD274/PD-L1 gene amplification was associated with positive PD-L1 immunostaining in only 73% of cases. PD-L1 copy number status was concordant in primary tumor and associated metastases. Clinically, PD-L1 tumor immunopositivity was associated with a higher risk for nodal metastasis at diagnosis, overall tumor related death und recurrence. Based on our findings we propose to include PD-L1 copy number status in addition to protein status in screening programs for future clinical trials with immunotherapeutic strategies targeting the PD-1/PD-L1 axis. PMID:26918453

  14. CD274/PD-L1 gene amplification and PD-L1 protein expression are common events in squamous cell carcinoma of the oral cavity.

    PubMed

    Straub, Melanie; Drecoll, Enken; Pfarr, Nicole; Weichert, Wilko; Langer, Rupert; Hapfelmeier, Alexander; Götz, Carolin; Wolff, Klaus-Dietrich; Kolk, Andreas; Specht, Katja

    2016-03-15

    Immunomodulatory therapies, targeting the immune checkpoint receptor-ligand complex PD-1/PD-L1 have shown promising results in early phase clinical trials in solid malignancies, including carcinomas of the head and neck. In this context, PD-L1 protein expression has been proposed as a potentially valuable predictive marker. In the present study, expression of PD-L1 and PD-1 was evaluated by immunohistochemistry in 80 patients with predominantly HPV-negative oral squamous cell carcinomas and associated nodal metastasis. In addition, CD274/PD-L1 gene copy number status was assessed by fluorescence in situ hybridization analysis. PD-L1 expression was detected in 36/80 (45%) cases and concordance of PD-L1 expression in primary tumor and corresponding nodal metastasis was present in only 20/28 (72%) cases. PD-1 expression was found in tumor-infiltrating lymphocytes (TILs) but not in tumor cells. CD274/PD-L1 gene amplification was detected in 19% of cases, with high level PD-L1 amplification present in 12/80 (15%), and low level amplification in 3/80 (4%). Interestingly, CD274/PD-L1 gene amplification was associated with positive PD-L1 immunostaining in only 73% of cases. PD-L1 copy number status was concordant in primary tumor and associated metastases. Clinically, PD-L1 tumor immunopositivity was associated with a higher risk for nodal metastasis at diagnosis, overall tumor related death und recurrence. Based on our findings we propose to include PD-L1 copy number status in addition to protein status in screening programs for future clinical trials with immunotherapeutic strategies targeting the PD-1/PD-L1 axis. PMID:26918453

  15. A new orbit for comet C/1858 L1 (Donati)

    NASA Astrophysics Data System (ADS)

    Branham, R. L., Jr.

    2014-02-01

    A new orbit for comet C/1858 L1 (Donati), based on 1036 observations in α and 971 in δ made between 7 June 1858 and 5 March 1859, is calculated using iteratively reweighted least squares. Residuals were weighted by the Welsch weighting function. The orbit represents a high eccentricity ellipse, {e=0.996265}, with large semi-major axis, a=154.8612 AU, and long period, {P=1927.22} yr. The residuals are relatively random, a 10.7 % chance of being random, but with a slight indication of % possible nongravitational forces influencing the motion. The comet will not return until the year 3759, when it will pass 0.8442 AU from the Earth.

  16. Deep Sub-micro mol{\\cdot }mol^{-1} Water-Vapor Measurement by Dual-Ball SAW Sensors for Temperature Compensation

    NASA Astrophysics Data System (ADS)

    Takeda, N.; Oizumi, T.; Tsuji, T.; Akao, S.; Takayanagi, K.; Nakaso, N.; Yamanaka, K.

    2015-12-01

    A collimated surface acoustic wave (SAW) circles around the equator of a sphere hundreds of times. Because of the long distance travel of the collimated SAW, a small change in the SAW propagation caused by the environment of the sphere can be accumulated as a measurable range in amplitude and/or in delay time. So, a spherical SAW device enables highly sensitive water-vapor measurements. In this paper, deep sub \\upmu mol{\\cdot }mol^{-1} water-vapor detection by 1 mm diameter quartz crystal ball SAW sensors is described. To measure such a low water-vapor concentration in real time, it is necessary to compensate the temperature dependence of the ball SAW sensor, which is about 20 ppm{\\cdot }°C^{-1} in delay time change. A dual-frequency burst analog detector was developed for the temperature compensation in real time. By using a harmonic SAW sensor, which was excited by 80 MHz and 240 MHz at the same time, it was confirmed that the delay time drift for a temperature range of 21.0°C ± 1.0°C became less than 0.05 ppm in delay time change. By using dual-ball SAW sensors (which included a 150 MHz sensor with a water-vapor sensitive layer and a 240 MHz sensor as a reference), water-vapor concentrations from 0.1 \\upmu mol{\\cdot }mol^{-1} to 5 \\upmu mol{\\cdot }mol^{-1} were successfully measured. It appears that the delay time change is proportional to the square root of the water-vapor concentration. The detection limit determined by the electrical noise of the system was estimated at 0.01 \\upmu mol{\\cdot }mol^{-1}.

  17. Permanent monitoring of alpine slope instabilities with L1-GPS

    NASA Astrophysics Data System (ADS)

    Limpach, Philippe; Geiger, Alain; Su, Zhenzhong; Beutel, Jan; Gruber, Stephan

    2013-04-01

    Since winter 2010/2011, a network of permanent GPS stations is being set up in the Matter Valley (Swiss Alps). The aim is to monitor the time variable movement of potentially instable rock glaciers. The network has been established in the framework of the X-Sense project, currently totaling more than 20 stations. X-Sense is an interdisciplinary project for monitoring alpine mass movements at multiple scales, funded by the Swiss federal program Nano-Tera within the Swiss Science Foundation. The X-Sense stations consist of low-cost L1 GPS receivers coupled with inclinometers. A part of the stations allow for on-line data transmission. The data of the X-Sense L1 GPS network is operationally processed on a daily basis with Bernese GPS software, in a fully automated processing chain. In addition, real-time solutions are computed for the on-line stations. The geodetic potential of low-cost GPS receivers for the precise monitoring of slope instabilities in mountain areas was previously investigated in a feasibility study. It is shown that low-cost GPS units are able to provide reliable and continuous time series of surface displacements at cm-level accuracy in harsh environment, using adequate differential processing techniques. Enhanced algorithms were developed to derive accurate time series of surface velocities based on the GPS displacements. It was shown that the low-cost GPS receivers allow to reliably observe surface velocities even below 1 cm/day, as well as to detect small and short-term velocity changes. In addition, the time series of more than 2 years obtained reveal the capability to detect seasonal velocity variations, as well as inter-annual variations of the velocity pattern. By providing continuous observations of surface motion, the GPS-based permanent monitoring contributes to the understanding of processes linked to permafrost-related slope instabilities.

  18. The 3T3-L1 adipocyte glycogen proteome

    PubMed Central

    2013-01-01

    Background Glycogen is a branched polysaccharide of glucose residues, consisting of α-1-4 glycosidic linkages with α-1-6 branches that together form multi-layered particles ranging in size from 30 nm to 300 nm. Glycogen spatial conformation and intracellular organization are highly regulated processes. Glycogen particles interact with their metabolizing enzymes and are associated with a variety of proteins that intervene in its biology, controlling its structure, particle size and sub-cellular distribution. The function of glycogen in adipose tissue is not well understood but appears to have a pivotal role as a regulatory mechanism informing the cells on substrate availability for triacylglycerol synthesis. To provide new molecular insights into the role of adipocyte glycogen we analyzed the glycogen-associated proteome from differentiated 3T3-L1-adipocytes. Results Glycogen particles from 3T3-L1-adipocytes were purified using a series of centrifugation steps followed by specific elution of glycogen bound proteins using α-1,4 glucose oligosaccharides, or maltodextrins, and tandem mass spectrometry. We identified regulatory proteins, 14-3-3 proteins, RACK1 and protein phosphatase 1 glycogen targeting subunit 3D. Evidence was also obtained for a regulated subcellular distribution of the glycogen particle: metabolic and mitochondrial proteins were abundant. Unlike the recently analyzed hepatic glycogen proteome, no endoplasmic proteins were detected, along with the recently described starch-binding domain protein 1. Other regulatory proteins which have previously been described as glycogen-associated proteins were not detected, including laforin, the AMPK beta-subunit and protein targeting to glycogen (PTG). Conclusions These data provide new molecular insights into the regulation of glycogen-bound proteins that are associated with the maintenance, organization and localization of the adipocyte glycogen particle. PMID:23521774

  19. MAD1L1 Arg558His and MAD2L1 Leu84Met interaction with smoking increase the risk of colorectal cancer

    PubMed Central

    Zhong, Rong; Chen, Xiaohua; Chen, Xueqin; Zhu, Beibei; Lou, Jiao; Li, Jiaoyuan; Shen, Na; Yang, Yang; Gong, Yajie; Zhu, Ying; Yuan, Jing; Xia, Xiaoping; Miao, Xiaoping

    2015-01-01

    The spindle assembly checkpoint (SAC) has been established as an important mechanism of driving aneuploidy, which occurs at a high frequency in the colorectal tumorigenesis. Two important components of SAC are MAD1L1 and MAD2L1, which function together in an interactive manner to initiate the checkpoint signal. We hypothesize that genetic variants in the binding domains of MAD1L1 and MAD2L1 may modulate protein structures and eventually contribute to CRC susceptibility. A case-control study including 710 CRC cases and 735 controls was performed to examine MAD1L1 Arg558His and MAD2L1 Leu84Met’s conferring susceptibility to CRC. Cytokinesis-block micronucleus cytome assays were applied to assess the effect of two functional variants on chromosomal instability (CIN). Significant associations with CRC risk were observed for MAD1L1 Arg558His (OR = 1.38,95% CI: 1.09–1.75) and MAD2L1 Leu84Met in a dominant model (OR = 1.48,95% CI: 1.09–2.01). Moreover, significant multiplicative gene-smoking interactions were found in MAD1L1 Arg558His (P = 0.019) and MAD2L184 Leu/Met (P = 0.016) to enhance CRC risk. Additionally, the frequencies of lymphocytic micro-nucleated binucleated cells for MAD1L1 Arg558His polymorphism were significantly different in the exposed group (P = 0.013), but not in the control group. The study emphasized that MAD1L1 Arg558His and MAD2L1 Leu84Met can significantly interact with smoking to enhance CRC risk, and the genetic effects of MAD1L1Arg558His on CIN need to be further clarified in follow-up studies. PMID:26183163

  20. L1 cell adhesion molecule as a therapeutic target in cancer.

    PubMed

    Yu, Xinzhe; Yang, Feng; Fu, De-Liang; Jin, Chen

    2016-03-01

    L1 cell adhesion molecule (L1CAM) is the prototype member of the L1-family of closely related neural adhesion molecules. L1CAM is differentially expressed in the normal nervous system as well as pathological tissues and displays a wide range of biological activities. In human malignancies, L1CAM plays a vital role in tumor growth, invasion and metastasis. Recently, increasing evidence has suggested that L1CAM exerts a variety of functions at different steps of tumor progression through a series of signaling pathways. In addition, L1CAM has been identified as a promising target for cancer therapy by using synthetic and natural inhibitors. In this review, we provide an up-to-date overview of the role of L1CAM involved in cancers and the rationale for L1CAM as a novel molecular target for cancer therapy. PMID:26781307

  1. High Electrical Conductivity in Ni3(2,3,6,7,10,11-hexaiminotriphenylene)2, a Semiconducting Metal-Organic Graphene Analogue

    SciTech Connect

    Sheberla, Dennis; Sun, Lei; Blood-Forsythe, Martin A.; Er, Süleyman; Wade, Casey R.; Brozek, Carl K.; Aspuru-Guzik, Alán; Dinc,; #259; Mircea,

    2014-09-22

    Reaction of 2,3,6,7,10,11-hexaaminotriphenylene with Ni2+ in aqueous NH3 solution under aerobic conditions produces Ni3(HITP)2 (HITP = 2,3,6,7,10,11-hexaiminotriphenylene), a new two-dimensional metal–organic framework (MOF). The new material can be isolated as a highly conductive black powder or dark blue-violet films. Two-probe and van der Pauw electrical measurements reveal bulk (pellet) and surface (film) conductivity values of 2 and 40 S·cm–1, respectively, both records for MOFs and among the best for any coordination polymer.

  2. Immunogenicity of a Trivalent Human Papillomavirus L1 DNA-Encapsidated, Non-Replicable Baculovirus Nanovaccine

    PubMed Central

    Heo, Yoon-Ki; Cho, Yeondong; Gwon, Yong-Dae; Kim, Mi-Gyeong; Park, Ki Hoon; Oh, Yu-Kyoung; Kim, Young Bong

    2014-01-01

    Previously, we developed a non-replicating recombinant baculovirus coated with human endogenous retrovirus envelope protein (AcHERV) for enhanced cellular delivery of human papillomavirus (HPV) 16L1 DNA. Here, we report the immunogenicity of an AcHERV-based multivalent HPV nanovaccine in which the L1 segments of HPV 16, 18, and 58 genes were inserted into a single baculovirus genome of AcHERV. To test whether gene expression levels were affected by the order of HPV L1 gene insertion, we compared the efficacy of bivalent AcHERV vaccines with the HPV 16L1 gene inserted ahead of the 18L1 gene (AcHERV-HP16/18L1) with that of AcHERV with the HPV 18L1 gene inserted ahead of the 16L1 gene (AcHERV-HP18/16L1). Regardless of the order, the bivalent AcHERV DNA vaccines retained the immunogenicity of monovalent AcHERV-HP16L1 and AcHERV-HP18L1 DNA vaccines. Moreover, the immunogenicity of bivalent AcHERV-HP16/18L1 was not significantly different from that of AcHERV-HP18/16L1. In challenge tests, both bivalent vaccines provided complete protection against HPV 16 and 18 pseudotype viruses. Extending these results, we found that a trivalent AcHERV nanovaccine encoding HPV 16L1, 18L1, and 58L1 genes (AcHERV-HP16/18/58L1) provided high levels of humoral and cellular immunogenicity against all three subtypes. Moreover, mice immunized with the trivalent AcHERV-based nanovaccine were protected from challenge with HPV 16, 18, and 58 pseudotype viruses. These results suggest that trivalent AcHERV-HPV16/18/58L1 could serve as a potential prophylactic baculoviral nanovaccine against concurrent infection with HPV 16, 18, and 58. PMID:24759938

  3. GridMol: a grid application for molecular modeling and visualization.

    PubMed

    Sun, Yanhua; Shen, Bin; Lu, Zhonghua; Jin, Zhong; Chi, Xuebin

    2008-02-01

    In this paper we present GridMol, an extensible tool for building a high performance computational chemistry platform in the grid environment. GridMol provides computational chemists one-stop service for molecular modeling, scientific computing and molecular information visualization. GridMol is not only a visualization and modeling tool but also simplifies control of remote Grid software that can access high performance computing resources. GridMol has been successfully integrated into China National Grid, the most powerful Chinese Grid Computing platform. In Section "Grid computing" of this paper, a computing example is given to show the availability and efficiency of GridMol. GridMol is coded using Java and Java3D for portability and cross-platform compatibility (Windows, Linux, MacOS X and UNIX). GridMol can run not only as a stand-alone application, but also as an applet through web browsers. In this paper, we will present the techniques for molecular visualization, molecular modeling and grid computing. GridMol is available free of charge under the GNU Public License (GPL) from our website: http://www.sccas.cn/~syh/GridMol/index.html. PMID:18231861

  4. Development of phonological awareness in English-Mandarin bilinguals: a comparison of English-L1 and Mandarin-L1 kindergarten children.

    PubMed

    Yeong, Stephanie H M; Rickard Liow, Susan J

    2012-06-01

    Phoneme awareness is critical for literacy acquisition in English, but relatively little is known about the early development of phonological awareness in ESL (English as a second language) bilinguals when their two languages have different phonological structures. Using parallel tasks in English and Mandarin, we tracked the development of L1 (first language) and L2 (second language) syllable and phoneme awareness longitudinally in English-L1 and Mandarin-L1 prereaders (n=70, 4- and 5-year-olds) across three 6-month intervals. In English, the English-L1 children's performance was better in phoneme awareness at all three time points, but the Mandarin-L1 children's syllable awareness was equivalent to the English-L1 children's syllable awareness by Time 3. In Mandarin, the English-L1 children's phoneme awareness, but not their syllable awareness, was also significantly better than that of the Mandarin-L1 children at all three time points. Cross-lagged correlations revealed that only the English-L1 children applied their L1 syllable and phoneme awareness to their L2 (Mandarin) processing by Time 2 and that the Mandarin-L1 children seemed to require exposure to English (L2) before they developed phoneme awareness in either language. The data provide further evidence that phonological awareness is a language-general ability but that cross-language application depends on the similarity between the phonological structures of a child's L1 and L2. Implications for classroom teaching are briefly discussed. PMID:22382048

  5. Enhanced expression of soluble human papillomavirus L1 through coexpression of molecular chaperonin in Escherichia coli.

    PubMed

    Pan, Dong; Zha, Xiao; Yu, Xianghui; Wu, Yuqing

    2016-04-01

    The major recombinant capsid protein L1 of human papillomavirus (HPV) is widely used to produce HPV prophylactic vaccines. However, the quality of soluble and active expression of L1 in Escherichia coli was below the required amount. Coexpression with the chaperonin GroEL/ES enhanced L1 expression. Overexpressing GroEL/ES increased the soluble expression level of glutathione S-transferase-fused L1 (GST-L1) by approximately ∼3 fold. The yield of HPV type 16 L1 pentamer (L1-p) was ∼2 fold higher than that in a single expression system after purification through size-exclusion chromatograph. The expression and purification conditions were then optimized. The yield of L1-p was enhanced by ∼5 fold, and those of HPV types 18 and 58 L1-p increased by ∼3 and ∼2 folds, respectively, compared with that in the single expression system. Coexpressing the mono-site mutant HPV16 L1 L469A with GroEL/ES increased L1-p yield by ∼7 fold compared with strains expressing the wild-type L1 gene. L1-p was then characterized using circular dichroism spectra, UV-vis cloud point, dynamic light scattering and transmission electron microscope analyses. Results indicated that the conformation and biological characteristics of L1-p were identical to that of native L1. Hence, overexpressing chaperonin in E. coli can increase the expression level of GST-L1 and L1-p production after purification. This finding may contribute to the development of a platform for prophylactic HPV vaccines. PMID:26732286

  6. Reviving the Dead: History and Reactivation of an Extinct L1

    PubMed Central

    Yang, Lei; Brunsfeld, John; Scott, LuAnn; Wichman, Holly

    2014-01-01

    Although L1 sequences are present in the genomes of all placental mammals and marsupials examined to date, their activity was lost in the megabat family, Pteropodidae, ∼24 million years ago. To examine the characteristics of L1s prior to their extinction, we analyzed the evolutionary history of L1s in the genome of a megabat, Pteropus vampyrus, and found a pattern of periodic L1 expansion and quiescence. In contrast to the well-characterized L1s in human and mouse, megabat genomes have accommodated two or more simultaneously active L1 families throughout their evolutionary history, and major peaks of L1 deposition into the genome always involved multiple families. We compared the consensus sequences of the two major megabat L1 families at the time of their extinction to consensus L1s of a variety of mammalian species. Megabat L1s are comparable to the other mammalian L1s in terms of adenosine content and conserved amino acids in the open reading frames (ORFs). However, the intergenic region (IGR) of the reconstructed element from the more active family is dramatically longer than the IGR of well-characterized human and mouse L1s. We synthesized the reconstructed element from this L1 family and tested the ability of its components to support retrotransposition in a tissue culture assay. Both ORFs are capable of supporting retrotransposition, while the IGR is inhibitory to retrotransposition, especially when combined with either of the reconstructed ORFs. We dissected the inhibitory effect of the IGR by testing truncated and shuffled versions and found that length is a key factor, but not the only one affecting inhibition of retrotransposition. Although the IGR is inhibitory to retrotransposition, this inhibition does not account for the extinction of L1s in megabats. Overall, the evolution of the L1 sequence or the quiescence of L1 is unlikely the reason of L1 extinction. PMID:24968166

  7. Reviving the dead: history and reactivation of an extinct l1.

    PubMed

    Yang, Lei; Brunsfeld, John; Scott, LuAnn; Wichman, Holly

    2014-06-01

    Although L1 sequences are present in the genomes of all placental mammals and marsupials examined to date, their activity was lost in the megabat family, Pteropodidae, ∼24 million years ago. To examine the characteristics of L1s prior to their extinction, we analyzed the evolutionary history of L1s in the genome of a megabat, Pteropus vampyrus, and found a pattern of periodic L1 expansion and quiescence. In contrast to the well-characterized L1s in human and mouse, megabat genomes have accommodated two or more simultaneously active L1 families throughout their evolutionary history, and major peaks of L1 deposition into the genome always involved multiple families. We compared the consensus sequences of the two major megabat L1 families at the time of their extinction to consensus L1s of a variety of mammalian species. Megabat L1s are comparable to the other mammalian L1s in terms of adenosine content and conserved amino acids in the open reading frames (ORFs). However, the intergenic region (IGR) of the reconstructed element from the more active family is dramatically longer than the IGR of well-characterized human and mouse L1s. We synthesized the reconstructed element from this L1 family and tested the ability of its components to support retrotransposition in a tissue culture assay. Both ORFs are capable of supporting retrotransposition, while the IGR is inhibitory to retrotransposition, especially when combined with either of the reconstructed ORFs. We dissected the inhibitory effect of the IGR by testing truncated and shuffled versions and found that length is a key factor, but not the only one affecting inhibition of retrotransposition. Although the IGR is inhibitory to retrotransposition, this inhibition does not account for the extinction of L1s in megabats. Overall, the evolution of the L1 sequence or the quiescence of L1 is unlikely the reason of L1 extinction. PMID:24968166

  8. Gamma radiation increases endonuclease-dependent L1 retrotransposition in a cultured cell assay.

    PubMed

    Farkash, Evan A; Kao, Gary D; Horman, Shane R; Prak, Eline T Luning

    2006-01-01

    Long Interspersed Elements (LINE-1s, L1s) are the most active mobile elements in the human genome and account for a significant fraction of its mass. The propagation of L1 in the human genome requires disruption and repair of DNA at the site of integration. As Barbara McClintock first hypothesized, genotoxic stress may contribute to the mobilization of transposable elements, and conversely, element mobility may contribute to genotoxic stress. We tested the ability of genotoxic agents to increase L1 retrotransposition in a cultured cell assay. We observed that cells exposed to gamma radiation exhibited increased levels of L1 retrotransposition. The L1 retrotransposition frequency was proportional to the number of phosphorylated H2AX foci, an indicator of genotoxic stress. To explore the role of the L1 endonuclease in this context, endonuclease-deficient tagged L1 constructs were produced and tested for their activity in irradiated cells. The activity of the endonuclease-deficient L1 was very low in irradiated cells, suggesting that most L1 insertions in irradiated cells still use the L1 endonuclease. Consistent with this interpretation, DNA sequences that flank L1 insertions in irradiated cells harbored target site duplications. These results suggest that increased L1 retrotransposition in irradiated cells is endonuclease dependent. The mobilization of L1 in irradiated cells potentially contributes to genomic instability and could be a driving force for secondary mutations in patients undergoing radiation therapy. PMID:16507671

  9. Recombination Creates Novel L1 (Line-1) Elements in Rattus Norvegicus

    PubMed Central

    Hayward, B. E.; Zavanelli, M.; Furano, A. V.

    1997-01-01

    Mammalian L1 (long interspersed repeated DNA, LINE-1) retrotransposons consist of a 5' untranslated region (UTR) with regulatory properties, two protein encoding regions (ORF I, ORF II, which encodes a reverse transcriptase) and a 3' UTR. L1 elements have been evolving in mammals for >100 million years and this process continues to generate novel L1 subfamilies in modern species. Here we characterized the youngest known subfamily in Rattus norvegicus, L1(mlvi2), and unexpectedly found that this element has a dual ancestry. While its 3' UTR shares the same lineage as its nearest chronologically antecedent subfamilies, L1(3) and L1(4), its ORF I sequence does not. The L1(mlvi2) ORF I was derived from an ancestral ORF I sequence that was the evolutionary precursor of the L1(3) and L1(4) ORF I. We suggest that an ancestral ORF I sequence was recruited into the modern L1(mlvi2) subfamily by recombination that possibly could have resulted from template strand switching by the reverse transcriptase during L1 replication. This mechanism could also account for some of the structural features of rodent L1 5' UTR and ORF I sequences including one of the more dramatic features of L1 evolution in mammals, namely the repeated acquisition of novel 5' UTRs. PMID:9178013

  10. PD-L1 expression in human cancers and its association with clinical outcomes.

    PubMed

    Wang, Xin; Teng, Feifei; Kong, Li; Yu, Jinming

    2016-01-01

    PD-L1 is an immunoinhibitory molecule that suppresses the activation of T cells, leading to the progression of tumors. Overexpression of PD-L1 in cancers such as gastric cancer, hepatocellular carcinoma, renal cell carcinoma, esophageal cancer, pancreatic cancer, ovarian cancer, and bladder cancer is associated with poor clinical outcomes. In contrast, PD-L1 expression correlates with better clinical outcomes in breast cancer and merkel cell carcinoma. The prognostic value of PD-L1 expression in lung cancer, colorectal cancer, and melanoma is controversial. Blocking antibodies that target PD-1 and PD-L1 have achieved remarkable response rates in cancer patients who have PD-L1-overexpressing tumors. However, using PD-L1 as an exclusive predictive biomarker for cancer immunotherapy is questionable due to the low accuracy of PD-L1 immunohistochemistry staining. Factors that affect the accuracy of PD-L1 immunohistochemistry staining are as follows. First, antibodies used in different studies have different sensitivity. Second, in different studies, the cut-off value of PD-L1 staining positivity is different. Third, PD-L1 expression in tumors is not uniform, and sampling time and location may affect the results of PD-L1 staining. Therefore, better understanding of tumor microenvironment and use of other biomarkers such as gene marker and combined index are necessary to better identify patients who will benefit from PD-1/PD-L1 checkpoint blockade therapy. PMID:27574444

  11. The RGD integrin binding site in human L1-CAM is important for nuclear signaling

    SciTech Connect

    Gast, Daniela; Riedle, Svenja; Kiefel, Helena; Mueerkoester, Susanne Sebens; Schaefer, Heiner; Schaefer, Michael K.E.; Altevogt, Peter

    2008-08-01

    L1 cell adhesion molecule (L1-CAM) is a transmembrane cell adhesion molecule initially defined as a promigratory molecule in the developing nervous system. L1 is also overexpressed in a variety of human carcinomas and is associated with bad prognosis. In carcinoma cell lines L1 augments cell motility and metastasis, tumor growth in nude mice and induces expression of L1-dependent genes. It is not known whether L1-signaling requires ligand binding. The RGD motif in the sixth Ig domain of L1 is a binding site for integrins. In the present study we analyzed the role of RGDs in L1-signaling using site-directed mutagenesis combined with antibody blocking studies. We observed that L1-RGE expressing HEK293 cells showed reduced cell-cell binding, cell motility, invasiveness and tumor growth in NOD/SCID mice. The RGE-mutation impaired L1-dependent gene regulation and antibodies to {alpha}v{beta}5 integrin had similar effects. Mutant L1 was unable to translocate to the nucleus. Our findings highlight the importance of the RGD site in L1 for human tumors and suggest that nuclear signaling of L1 is dependent on integrins.

  12. PD-L1 expression in human cancers and its association with clinical outcomes

    PubMed Central

    Wang, Xin; Teng, Feifei; Kong, Li; Yu, Jinming

    2016-01-01

    PD-L1 is an immunoinhibitory molecule that suppresses the activation of T cells, leading to the progression of tumors. Overexpression of PD-L1 in cancers such as gastric cancer, hepatocellular carcinoma, renal cell carcinoma, esophageal cancer, pancreatic cancer, ovarian cancer, and bladder cancer is associated with poor clinical outcomes. In contrast, PD-L1 expression correlates with better clinical outcomes in breast cancer and merkel cell carcinoma. The prognostic value of PD-L1 expression in lung cancer, colorectal cancer, and melanoma is controversial. Blocking antibodies that target PD-1 and PD-L1 have achieved remarkable response rates in cancer patients who have PD-L1-overexpressing tumors. However, using PD-L1 as an exclusive predictive biomarker for cancer immunotherapy is questionable due to the low accuracy of PD-L1 immunohistochemistry staining. Factors that affect the accuracy of PD-L1 immunohistochemistry staining are as follows. First, antibodies used in different studies have different sensitivity. Second, in different studies, the cut-off value of PD-L1 staining positivity is different. Third, PD-L1 expression in tumors is not uniform, and sampling time and location may affect the results of PD-L1 staining. Therefore, better understanding of tumor microenvironment and use of other biomarkers such as gene marker and combined index are necessary to better identify patients who will benefit from PD-1/PD-L1 checkpoint blockade therapy. PMID:27574444

  13. Status of the ESA L1 mission candidate ATHENA

    NASA Astrophysics Data System (ADS)

    Rando, N.; Martin, D.; Lumb, D.; Verhoeve, P.; Oosterbroek, T.; Bavdaz, M.; Fransen, S.; Linder, M.; Peyrou-Lauga, R.; Voirin, T.; Braghin, M.; Mangunsong, S.; van Pelt, M.; Wille, E.

    2012-09-01

    ATHENA (Advanced Telescope for High Energy Astrophysics) was an L class mission candidate within the science programme Cosmic Vision 2015-2025 of the European Space Agency, with a planned launch by 2022. ATHENA was conceived as an ESA-led project, open to the possibility of focused contributions from JAXA and NASA. By allowing astrophysical observations between 100 eV and 10 keV, it would represent the new generation X-ray observatory, following the XMM-Newton, Astro-H and Chandra heritage. The main scientific objectives of ATHENA include the study of large scale structures, the evolution of black holes, strong gravity effects, neutron star structure as well as investigations into dark matter. The ATHENA mission concept would be based on focal length of 12m achieved via a rigid metering tube and a twoaperture, x-ray telescope. Two identical x-ray mirrors would illuminate fixed focal plane instruments: a cryogenic imaging spectrometer (XMS) and a wide field imager (WFI). The S/C is designed to be fully compatible with Ariane 5 ECA. The observatory would operate at SE-L2, with a nominal lifetime of 5 yr. This paper provides a summary of the reformulation activities, completed in December 2011. An overview of the spacecraft design and of the payload is provided, including both telescope and instruments. Following the ESA Science Programme Committee decision on the L1 mission in May 2012, ATHENA was not selected to enter Definition Phase.

  14. Robust Gaussian Graphical Modeling via l1 Penalization

    PubMed Central

    Sun, Hokeun; Li, Hongzhe

    2012-01-01

    Summary Gaussian graphical models have been widely used as an effective method for studying the conditional independency structure among genes and for constructing genetic networks. However, gene expression data typically have heavier tails or more outlying observations than the standard Gaussian distribution. Such outliers in gene expression data can lead to wrong inference on the dependency structure among the genes. We propose a l1 penalized estimation procedure for the sparse Gaussian graphical models that is robustified against possible outliers. The likelihood function is weighted according to how the observation is deviated, where the deviation of the observation is measured based on its own likelihood. An efficient computational algorithm based on the coordinate gradient descent method is developed to obtain the minimizer of the negative penalized robustified-likelihood, where nonzero elements of the concentration matrix represents the graphical links among the genes. After the graphical structure is obtained, we re-estimate the positive definite concentration matrix using an iterative proportional fitting algorithm. Through simulations, we demonstrate that the proposed robust method performs much better than the graphical Lasso for the Gaussian graphical models in terms of both graph structure selection and estimation when outliers are present. We apply the robust estimation procedure to an analysis of yeast gene expression data and show that the resulting graph has better biological interpretation than that obtained from the graphical Lasso. PMID:23020775

  15. Brain abnormality segmentation based on l1-norm minimization

    NASA Astrophysics Data System (ADS)

    Zeng, Ke; Erus, Guray; Tanwar, Manoj; Davatzikos, Christos

    2014-03-01

    We present a method that uses sparse representations to model the inter-individual variability of healthy anatomy from a limited number of normal medical images. Abnormalities in MR images are then defined as deviations from the normal variation. More precisely, we model an abnormal (pathological) signal y as the superposition of a normal part ~y that can be sparsely represented under an example-based dictionary, and an abnormal part r. Motivated by a dense error correction scheme recently proposed for sparse signal recovery, we use l1- norm minimization to separate ~y and r. We extend the existing framework, which was mainly used on robust face recognition in a discriminative setting, to address challenges of brain image analysis, particularly the high dimensionality and low sample size problem. The dictionary is constructed from local image patches extracted from training images aligned using smooth transformations, together with minor perturbations of those patches. A multi-scale sliding-window scheme is applied to capture anatomical variations ranging from fine and localized to coarser and more global. The statistical significance of the abnormality term r is obtained by comparison to its empirical distribution through cross-validation, and is used to assign an abnormality score to each voxel. In our validation experiments the method is applied for segmenting abnormalities on 2-D slices of FLAIR images, and we obtain segmentation results consistent with the expert-defined masks.

  16. Forward looking GPR sidelobe reduction using L1-norm minimization

    NASA Astrophysics Data System (ADS)

    Burns, Brian

    2012-06-01

    Ground Penetrating Radar (GPR) has been applied for several years to the problem of detecting both anti-personnel and anti-tank landmines. One area of research is using Forward Looking GPR (FLGPR) to detect mines. While FLGPR has the advantage of standoff versus downward looking GPR, the responses from buried targets generally decrease while the responses from clutter increase. One source of clutter is from sidelobes and grating lobes caused by off-road clutter. As it is not possible to get a narrow beamwidth at the low frequencies required to get ground penetration, FLGPR receives responses from both on and off the road. Off-road clutter responses are often much stronger than the responses from buried mines. These off-road clutter objects can produce sidelobes that overlap with and obscure the responses from inroad targets. This becomes especially problematic if the antenna array spacing is not fine enough and grating lobes are formed. To reduce both the sidelobes and grating lobes, a technique using L1-norm minimization was tested. One advantage of this technique is it only requires a single aperture. The resulting image retains phase information which allows the images to be then coherently summed, resulting in better quality images. In this paper a description of the algorithm is provided. The algorithm was applied to a FLGPR data set to show its ability to reduce both sidelobes and grating lobes. Resulting images are shown.

  17. Antibody Fragments Directed against Different Portions of the Human Neural Cell Adhesion Molecule L1 Act as Inhibitors or Activators of L1 Function

    PubMed Central

    Wang, Yan; Loers, Gabriele; Pan, Hong-Chao; Gouveia, Ricardo; Zhao, Wei-Jiang; Shen, Yan-Qin; Kleene, Ralf; Costa, Julia; Schachner, Melitta

    2012-01-01

    The neural cell adhesion molecule L1 plays important roles in neuronal migration and survival, neuritogenesis and synaptogenesis. L1 has also been found in tumors of different origins, with levels of L1 expression correlating positively with the metastatic potential of tumors. To select antibodies targeting the varied functions of L1, we screened the Tomlinson library of recombinant human antibody fragments to identify antibodies binding to recombinant human L1 protein comprising the entire extracellular domain of human L1. We obtained four L1 binding single-chain variable fragment antibodies (scFvs), named I4, I6, I13, and I27 and showed by enzyme-linked immunosorbent assay (ELISA) that scFvs I4 and I6 have high affinity to the immunoglobulin-like (Ig) domains 1–4 of L1, while scFvs I13 and I27 bind strongly to the fibronectin type III homologous (Fn) domains 1–3 of L1. Application of scFvs I4 and I6 to human SK-N-SH neuroblastoma cells reduced proliferation and transmigration of these cells. Treatment of SK-N-SH cells with scFvs I13 and I27 enhanced cell proliferation and migration, neurite outgrowth, and protected against the toxic effects of H2O2 by increasing the ratio of Bcl-2/Bax. In addition, scFvs I4 and I6 inhibited and scFvs I13 and I27 promoted phosphorylation of src and Erk. Our findings indicate that scFvs reacting with the immunoglobulin-like domains 1–4 inhibit L1 functions, whereas scFvs interacting with the fibronectin type III domains 1–3 trigger L1 functions of cultured neuroblastoma cells. PMID:23272240

  18. Induction of L1 and L2 β-Lactamases of Stenotrophomonas maltophilia▿

    PubMed Central

    Hu, Rouh-Mei; Huang, Kuang-Jay; Wu, Lii-Tzu; Hsiao, Ying-Ju; Yang, Tsuey-Ching

    2008-01-01

    Isogenic L1 and L2 gene knockout mutants of Stenotrophomonas maltophilia KJ (KJΔL1 and KJΔL2, respectively) were constructed by xylE gene replacement. Induction kinetics of the L1 and L2 genes were evaluated by testing catechol 2,3-dioxygenase activity in the mutants. The results suggested that the induction of the L1 and L2 genes was differentially regulated. PMID:18086856

  19. L1 adhesion molecule on mouse leukocytes: regulation and involvement in endothelial cell binding.

    PubMed

    Hubbe, M; Kowitz, A; Schirrmacher, V; Schachner, M; Altevogt, P

    1993-11-01

    L1 is a cell surface glycoprotein of the immunoglobulin superfamily which was initially shown to mediate adhesion between neural cells. Recently we have reported that L1 is expressed by bone marrow cells and the majority of mature lymphocytes (Kowitz et al., Eur. J. Immunol. 1992. 22: 1199-1205). To analyze the function of L1 on leukocytes we studied its regulation following cell activation. In vitro activation of B lymphocytes with lipopolysaccharide or T lymphocytes with phorbol 12-myristate 13-acetate/Ca2+ ionophore, concanavalin A or anti-CD3 monoclonal antibody as well as in vivo activation of V beta 8+ T cells with staphylococcal enterotoxin B (SEB) revealed a down-regulation of L1 within 48 h. A rapid loss of L1 expression was seen when mouse neutrophils were activated with PMA alone. This rapid loss paralleled the shedding of L-selectin. We also studied a possible role of L1 in the binding of leukocytes to endothelial cells. ESb-MP lymphoma cells with a high expression of L1 (L1hi) could bind to bend3 endothelioma cells without prior activation with inflammatory cytokines. The interaction was inhibited by anti-L1 antibodies. In contrast, ESb-MP cells with low L1 expression (L1lo) were only marginally bound. Latex beads coated with affinity-isolated L1 antigen were also able to bind to the endothelioma cells in a specific fashion. The binding of ESb-MP lymphoma cells required Ca2+ and Mg2+ ions and was sensitive to cold temperature. Since the endothelioma cells did not express L1 the binding mechanism studied here is distinct from the established L1-L1 homotypic interaction. It is possible that the novel L1-mediated adhesion pathway involves an unidentified ligand and could play a role in leukocyte migration. PMID:8223869

  20. Synthesis and Characterization of a Cyclobutane Duocarmycin Derivative Incorporating the CbBI (1,2,10,11-tetrahydro-9H-cyclobuta[c]benzo[e]indol-4-one) Alkylation Subunit

    PubMed Central

    Lajiness, James P.; Boger, Dale L.

    2010-01-01

    The synthesis of 1,2,10,11-tetrahydro-9H-cyclobuta[c]benzo[e]indol-4- one (17, CbBI), containing a deep-seated fundamental structural modification in the CC-1065 and duocarmycin alkylation subunit with the incorporation of a ring expanded fused cyclobutane (vs cyclopropane), its chemical and structural characterization, and its incorporation into a key analogue of the natural products are detailed. The approach to the preparation of CbBI was based on a precedented (Ar-3′ and Ar-5′), but previously unknown Ar-4′ spirocyclization of a phenol onto a tethered alkyl halide to form the desired cyclobutane. The conditions required for the implementation of the Ar-4′ spirocyclization indicate that the entropy of activation substantially impacts the rate of reaction relative to the much more facile Ar-3′ spirocyclization, while the higher enthalpy of activation slows the reaction relative to an Ar-5′ spirocyclization. The characterization of the CbBI-based agents revealed their exceptional stability and exquisite reaction regioselectivity, and a single crystal X-ray structure analysis of N-Boc-CbBI (13) revealed their structural origins. The reaction regioselectivity may be attributed to the stereoelectronic alignment of the two available cyclobutane bonds with the cyclohexadienone π-system, which resides in the bond that extends to the less substituted cyclobutane carbon for 13. The remarkable stability of N-Boc-CbBI (stable even at pH 1) relative to N-Boc-CBI (t1/2 = 133 h at pH 3) containing a cyclopropane may be attributed to a combination of the increased extent of vinylogous amide conjugation, the non-optimal geometric alignment of the cyclobutane with the activating cyclohexadienone, and the intrinsic but modestly lower strain energy (1.8 kcal/mol) of a cyclobutane versus cyclopropane. PMID:20839806

  1. An L1-Script-Transfer-Effect Fallacy: A Rejoinder to Wang et al

    ERIC Educational Resources Information Center

    Yamada, Jun

    2004-01-01

    Do different L1 (first language) writing systems differentially affect word identification in English as a second language (ESL)? Wang, Koda, and Perfetti [Cognition 87 (2003) 129] answered yes by examining Chinese students with a logographic L1 background and Korean students with an alphabetic L1 background for their phonological and orthographic…

  2. Does Reading in Shallow L1 Orthography Slow Attrition of Language-Specific Morphological Structures?

    ERIC Educational Resources Information Center

    Zaretsky, Elena; Bar-Shalom, Eva G.

    2010-01-01

    This study looks at the relationship between L1 (Russian) attrition and L1 reading ability in Russian-English-speaking bilingual children. Ten Russian-English bilingual children and 10 adults participated in this study. Nine out of 10 children participants were born in the US and used L1 as their primary language of interaction within the family,…

  3. L1 Use during L2 Writing: An Empirical Study of a Complex Phenomenon

    ERIC Educational Resources Information Center

    van Weijen, Daphne; van den Bergh, Huub; Rijlaarsdam, Gert; Sanders, Ted

    2009-01-01

    This study examined writers' use of their first language (L1) while writing in their second language (L2). Twenty students each wrote four short argumentative essays in their L1 (Dutch) and four in their L2 (English) under think-aloud conditions. We analysed whether L1 use varied between writers and tasks, and whether it was related to general…

  4. 26 CFR 1.401(l)-1 - Permitted disparity in employer-provided contributions or benefits.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... contributions or benefits. 1.401(l)-1 Section 1.401(l)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT... Plans, Etc. § 1.401(l)-1 Permitted disparity in employer-provided contributions or benefits. (a... section 401(l). Thus, if a plan satisfies section 401(l), permitted disparities in...

  5. 26 CFR 36.3121(l)(1)-2 - Amendment of agreement.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

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  6. 26 CFR 36.3121(l)(1)-3 - Effect of agreement.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

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  7. 26 CFR 31.3402(l)-1 - Determination and disclosure of marital status.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

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  8. 26 CFR 36.3121(l)(1)-3 - Effect of agreement.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 15 2011-04-01 2011-04-01 false Effect of agreement. 36.3121(l)(1)-3 Section 36.3121(l)(1)-3 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED... SUBSIDIARIES § 36.3121(l)(1)-3 Effect of agreement. (a) Liability for amounts equivalent to tax—(1) In...

  9. 26 CFR 1.401(l)-1 - Permitted disparity in employer-provided contributions or benefits.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... contributions or benefits. 1.401(l)-1 Section 1.401(l)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT..., Stock Bonus Plans, Etc. § 1.401(l)-1 Permitted disparity in employer-provided contributions or benefits... permitted under section 401(l). Thus, if a plan satisfies section 401(l), permitted disparities in...

  10. 26 CFR 36.3121(l)(1)-3 - Effect of agreement.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 15 2013-04-01 2013-04-01 false Effect of agreement. 36.3121(l)(1)-3 Section 36.3121(l)(1)-3 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED... SUBSIDIARIES § 36.3121(l)(1)-3 Effect of agreement. (a) Liability for amounts equivalent to tax—(1) In...

  11. 17 CFR 275.203(l)-1 - Venture capital fund defined.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    .... 275.203(l)-1 Section 275.203(l)-1 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) RULES AND REGULATIONS, INVESTMENT ADVISERS ACT OF 1940 § 275.203(l)-1 Venture capital fund defined. (a) Venture capital fund defined. For purposes of section 203(l) of the Act (15...

  12. 26 CFR 31.3402(l)-1 - Determination and disclosure of marital status.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    .... 31.3402(l)-1 Section 31.3402(l)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... COLLECTION OF INCOME TAX AT SOURCE Collection of Income Tax at Source § 31.3402(l)-1 Determination and... married person. (c) Determination of marital status. For the purposes of section 3402(l)(2) and...

  13. 26 CFR 31.3402(l)-1 - Determination and disclosure of marital status.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    .... 31.3402(l)-1 Section 31.3402(l)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... COLLECTION OF INCOME TAX AT SOURCE Collection of Income Tax at Source § 31.3402(l)-1 Determination and... married person. (c) Determination of marital status. For the purposes of section 3402(l)(2) and...

  14. 26 CFR 31.3402(l)-1 - Determination and disclosure of marital status.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    .... 31.3402(l)-1 Section 31.3402(l)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... COLLECTION OF INCOME TAX AT SOURCE Collection of Income Tax at Source § 31.3402(l)-1 Determination and... married person. (c) Determination of marital status. For the purposes of section 3402(l)(2) and...

  15. 17 CFR 275.203(l)-1 - Venture capital fund defined.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    .... 275.203(l)-1 Section 275.203(l)-1 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) RULES AND REGULATIONS, INVESTMENT ADVISERS ACT OF 1940 § 275.203(l)-1 Venture capital fund defined. (a) Venture capital fund defined. For purposes of section 203(l) of the Act (15...

  16. 26 CFR 1.401(l)-1 - Permitted disparity in employer-provided contributions or benefits.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... contributions or benefits. 1.401(l)-1 Section 1.401(l)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT..., Stock Bonus Plans, Etc. § 1.401(l)-1 Permitted disparity in employer-provided contributions or benefits... permitted under section 401(l). Thus, if a plan satisfies section 401(l), permitted disparities in...

  17. 26 CFR 1.401(l)-1 - Permitted disparity in employer-provided contributions or benefits.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... contributions or benefits. 1.401(l)-1 Section 1.401(l)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT..., Stock Bonus Plans, Etc. § 1.401(l)-1 Permitted disparity in employer-provided contributions or benefits... permitted under section 401(l). Thus, if a plan satisfies section 401(l), permitted disparities in...

  18. 26 CFR 36.3121(l)(1)-2 - Amendment of agreement.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 15 2013-04-01 2013-04-01 false Amendment of agreement. 36.3121(l)(1)-2 Section 36.3121(l)(1)-2 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED... SUBSIDIARIES § 36.3121(l)(1)-2 Amendment of agreement. (a) An agreement entered into by a domestic...

  19. 26 CFR 36.3121(l)(1)-2 - Amendment of agreement.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 15 2014-04-01 2014-04-01 false Amendment of agreement. 36.3121(l)(1)-2 Section 36.3121(l)(1)-2 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED... SUBSIDIARIES § 36.3121(l)(1)-2 Amendment of agreement. (a) An agreement entered into by a domestic...

  20. 26 CFR 36.3121(l)(1)-3 - Effect of agreement.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 15 2014-04-01 2014-04-01 false Effect of agreement. 36.3121(l)(1)-3 Section 36.3121(l)(1)-3 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED... SUBSIDIARIES § 36.3121(l)(1)-3 Effect of agreement. (a) Liability for amounts equivalent to tax—(1) In...

  1. A Study of Relationships between L1 Pragmatic Transfer and L2 Proficiency

    ERIC Educational Resources Information Center

    Bu, Jiemin

    2012-01-01

    Studies in interlanguage pragmatics have shown that L2 learners' proficiency has an influence on the occurrences of L1 pragmatic transfer. However, questions remain whether the relationship between L1 pragmatic transfer and L2 proficiency is positive or negative. This paper is designed to study L1 pragmatic transfer in requests made by Chinese…

  2. 17 CFR 275.203(l)-1 - Venture capital fund defined.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    .... 275.203(l)-1 Section 275.203(l)-1 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) RULES AND REGULATIONS, INVESTMENT ADVISERS ACT OF 1940 § 275.203(l)-1 Venture capital fund defined. (a) Venture capital fund defined. For purposes of section 203(l) of the Act (15...

  3. 26 CFR 36.3121(l)(1)-3 - Effect of agreement.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 15 2012-04-01 2012-04-01 false Effect of agreement. 36.3121(l)(1)-3 Section 36.3121(l)(1)-3 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED... SUBSIDIARIES § 36.3121(l)(1)-3 Effect of agreement. (a) Liability for amounts equivalent to tax—(1) In...

  4. 26 CFR 36.3121(l)(1)-2 - Amendment of agreement.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Amendment of agreement. 36.3121(l)(1)-2 Section 36.3121(l)(1)-2 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED... SUBSIDIARIES § 36.3121(l)(1)-2 Amendment of agreement. (a) An agreement entered into by a domestic...

  5. 26 CFR 1.401(l)-1 - Permitted disparity in employer-provided contributions or benefits.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... contributions or benefits. 1.401(l)-1 Section 1.401(l)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT..., Stock Bonus Plans, Etc. § 1.401(l)-1 Permitted disparity in employer-provided contributions or benefits... permitted under section 401(l). Thus, if a plan satisfies section 401(l), permitted disparities in...

  6. 26 CFR 31.3402(l)-1 - Determination and disclosure of marital status.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    .... 31.3402(l)-1 Section 31.3402(l)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... COLLECTION OF INCOME TAX AT SOURCE Collection of Income Tax at Source § 31.3402(l)-1 Determination and... married person. (c) Determination of marital status. For the purposes of section 3402(l)(2) and...

  7. 26 CFR 36.3121(l)(1)-2 - Amendment of agreement.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 15 2012-04-01 2012-04-01 false Amendment of agreement. 36.3121(l)(1)-2 Section 36.3121(l)(1)-2 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED... SUBSIDIARIES § 36.3121(l)(1)-2 Amendment of agreement. (a) An agreement entered into by a domestic...

  8. English Teachers' Use of Learners' L1 (Arabic) in College Classrooms in Kuwait

    ERIC Educational Resources Information Center

    Alrabah, Sulaiman; Wu, Shu-hua; Alotaibi, Abdullah M.; Aldaihani, Hussein A.

    2016-01-01

    This study investigated English teachers' use of learners' L1 (Arabic) in college classrooms in Kuwait. The purpose of the study was three-fold: (1) to describe the functions for which L1 was employed by the teachers, (2) to explore the affective, sociolinguistic, and psycholinguistic factors that may have led teachers to use L1 in L2 teaching,…

  9. CALL versus Paper: In Which Context Are L1 Glosses More Effective?

    ERIC Educational Resources Information Center

    Taylor, Alan M.

    2013-01-01

    CALL glossing in first language (L1) or second language (L2) texts has been shown by previous studies to be more effective than traditional, paper-and-pen L1 glossing. Using a pool of studies with much more statistical power and more accurate results, this meta-analysis demonstrates more precisely the degree to which CALL L1 glossing can be more…

  10. HackaMol: An Object-Oriented Modern Perl Library for Molecular Hacking on Multiple Scales.

    PubMed

    Riccardi, Demian; Parks, Jerry M; Johs, Alexander; Smith, Jeremy C

    2015-04-27

    HackaMol is an open source, object-oriented toolkit written in Modern Perl that organizes atoms within molecules and provides chemically intuitive attributes and methods. The library consists of two components: HackaMol, the core that contains classes for storing and manipulating molecular information, and HackaMol::X, the extensions that use the core. The core is well-tested, well-documented, and easy to install across computational platforms. The goal of the extensions is to provide a more flexible space for researchers to develop and share new methods. In this application note, we provide a description of the core classes and two extensions: HackaMol::X::Calculator, an abstract calculator that uses code references to generalize interfaces with external programs, and HackaMol::X::Vina, a structured class that provides an interface with the AutoDock Vina docking program. PMID:25793330

  11. An Introduction to Using the Method of Levels (MOL) Therapy to Work with People Experiencing Psychosis.

    PubMed

    Tai, Sara J

    2016-01-01

    This paper provides a basic introduction to using method of levels (MOL) therapy with people experiencing psychosis. As MOL is a direct application of perceptual control theory (PCT), a brief overview of the three main theoretical principles of this theory--control, conflict, and reorganization will be outlined in relation to understanding psychosis. In particular, how these principles form the basis of problem conceptualisation and determine what an MOL therapist is required to do during therapy will be illustrated. A practical description of MOL will be given, using case examples and short excerpts of therapeutic interactions. Some direct contrasts will also be made with cognitive behaviour therapy for psychosis (CBTp) and psychodynamic approaches (PA) in order to help illustrate the theory and practice of MOL. PMID:27052610

  12. The L2 Acquisition of Spanish Rhotics by L1 English Speakers: The Effect of L1 Articulatory Routines and Phonetic Context for Allophonic Variation

    ERIC Educational Resources Information Center

    Olsen, Michael K.

    2012-01-01

    This article offers a fine-grained investigation of how first-language (L1) phonetics involving English rhotics affect Spanish rhotic production by second-language (L2) learners. Specifically, this study investigates how different L1 English rhotic articulatory routines (retroflex-like and bunched-like) and the phonetic context that produces…

  13. Quantifying the Quality Difference between L1 and L2 Essays: A Rating Procedure with Bilingual Raters and L1 and L2 Benchmark Essays

    ERIC Educational Resources Information Center

    Tillema, Marion; van den Bergh, Huub; Rijlaarsdam, Gert; Sanders, Ted

    2013-01-01

    It is the consensus that, as a result of the extra constraints placed on working memory, texts written in a second language (L2) are usually of lower quality than texts written in the first language (L1) by the same writer. However, no method is currently available for quantifying the quality difference between L1 and L2 texts. In the present…

  14. Do L2 Writing Courses Affect the Improvement of L1 Writing Skills via Skills Transfer from L2 to L1?

    ERIC Educational Resources Information Center

    Gonca, Altmisdort

    2016-01-01

    This study investigates the relationship of second language (L2) writing skills proficiency with the first language (L1) writing skills, in light of the language transfer. The study aims to analyze the positive effects of L2 writing proficiency on L1 writing proficiency. Forty native Turkish-speaking university students participated in the study.…

  15. AnL1 smoothing spline algorithm with cross validation

    NASA Astrophysics Data System (ADS)

    Bosworth, Ken W.; Lall, Upmanu

    1993-08-01

    We propose an algorithm for the computation ofL1 (LAD) smoothing splines in the spacesWM(D), with . We assume one is given data of the formyiD(f(ti) +ɛi, iD1,...,N with {itti}iD1N ⊂D, theɛi are errors withE(ɛi)D0, andf is assumed to be inWM. The LAD smoothing spline, for fixed smoothing parameterλ?;0, is defined as the solution,sλ, of the optimization problem (1/N)∑iD1N yi-g(ti +λJM(g), whereJM(g) is the seminorm consisting of the sum of the squaredL2 norms of theMth partial derivatives ofg. Such an LAD smoothing spline,sλ, would be expected to give robust smoothed estimates off in situations where theɛi are from a distribution with heavy tails. The solution to such a problem is a "thin plate spline" of known form. An algorithm for computingsλ is given which is based on considering a sequence of quadratic programming problems whose structure is guided by the optimality conditions for the above convex minimization problem, and which are solved readily, if a good initial point is available. The "data driven" selection of the smoothing parameter is achieved by minimizing aCV(λ) score of the form .The combined LAD-CV smoothing spline algorithm is a continuation scheme in λ↘0 taken on the above SQPs parametrized inλ, with the optimal smoothing parameter taken to be that value ofλ at which theCV(λ) score first begins to increase. The feasibility of constructing the LAD-CV smoothing spline is illustrated by an application to a problem in environment data interpretation.

  16. Stabilizing l1-norm prediction models by supervised feature grouping.

    PubMed

    Kamkar, Iman; Gupta, Sunil Kumar; Phung, Dinh; Venkatesh, Svetha

    2016-02-01

    Emerging Electronic Medical Records (EMRs) have reformed the modern healthcare. These records have great potential to be used for building clinical prediction models. However, a problem in using them is their high dimensionality. Since a lot of information may not be relevant for prediction, the underlying complexity of the prediction models may not be high. A popular way to deal with this problem is to employ feature selection. Lasso and l1-norm based feature selection methods have shown promising results. But, in presence of correlated features, these methods select features that change considerably with small changes in data. This prevents clinicians to obtain a stable feature set, which is crucial for clinical decision making. Grouping correlated variables together can improve the stability of feature selection, however, such grouping is usually not known and needs to be estimated for optimal performance. Addressing this problem, we propose a new model that can simultaneously learn the grouping of correlated features and perform stable feature selection. We formulate the model as a constrained optimization problem and provide an efficient solution with guaranteed convergence. Our experiments with both synthetic and real-world datasets show that the proposed model is significantly more stable than Lasso and many existing state-of-the-art shrinkage and classification methods. We further show that in terms of prediction performance, the proposed method consistently outperforms Lasso and other baselines. Our model can be used for selecting stable risk factors for a variety of healthcare problems, so it can assist clinicians toward accurate decision making. PMID:26689771

  17. Fluence estimation by deconvolution via l1-norm minimization

    NASA Astrophysics Data System (ADS)

    García Hernández, J. C.; Lazaro-Ponthus, D.; Gmar, M.; Barthe, J.

    2011-03-01

    Advances in radiotherapy irradiation techniques have led to very complex treatments requiring for a more stringent control. The dosimetric properties of electronic portal imaging devices (EPID) encouraged their use for treatment verification. Two main approaches have been proposed: the forward approach, where measured portal dose images are compared to predicted dose images and the backward approach, where EPID images are used to estimate the dose delivered to the patient. Both approaches need EPID images to be converted into a fluence distribution by deconvolution. However, deconvolution is an ill-posed problem which is very sensitive to small variations on input data. This study presents the application of a deconvolution method based on l1-norm minimization; this is a method known for being very stable while working with noisy data. The algorithm was first evaluated on synthetic images with different noise levels, the results were satisfactory. Deconvolution algorithm was then applied to experimental portal images; the required EPID response kernel and energy fluence images were computed by Monte-Carlo calculation, accelerator treatment head and EPID models had already been commissioned in a previous work. The obtained fluence images were in good agreement with simulated fluence images. This deconvolution algorithm may be generalized to an inverse problem with a general operator, where image formation is not longer modeled by a convolution but by a linear operation that might be seen as a position-dependent convolution. Moreover, this procedure would be detector independent and could be used for any detector type provided its response function is known.

  18. De Par en Par, 10 & 11. (Wide Open, 10 & 11.)

    ERIC Educational Resources Information Center

    De Par en Par, 1997

    1997-01-01

    These two magazines, written entirely in Spanish, are designed for classroom use in the elementary grades. Number 10, focuses on ecology, discussing such topics as the greenhouse effect, endangered species, protecting the natural environment, tree planting, earthworms, natural waste, books on environmental subjects, saving the earth, and…

  19. Characterization of the Biosynthetic Genes for 10,11-Dehydrocurvularin, a Heat Shock Response-Modulating Anticancer Fungal Polyketide from Aspergillus terreus

    PubMed Central

    Xu, Yuquan; Espinosa-Artiles, Patricia; Schubert, Vivien; Xu, Ya-ming; Zhang, Wei; Lin, Min; Gunatilaka, A. A. Leslie; Süssmuth, Roderich

    2013-01-01

    10,11-Dehydrocurvularin is a prevalent fungal phytotoxin with heat shock response and immune-modulatory activities. It features a dihydroxyphenylacetic acid lactone polyketide framework with structural similarities to resorcylic acid lactones like radicicol or zearalenone. A genomic locus was identified from the dehydrocurvularin producer strain Aspergillus terreus AH-02-30-F7 to reveal genes encoding a pair of iterative polyketide synthases (A. terreus CURS1 [AtCURS1] and AtCURS2) that are predicted to collaborate in the biosynthesis of 10,11-dehydrocurvularin. Additional genes in this locus encode putative proteins that may be involved in the export of the compound from the cell and in the transcriptional regulation of the cluster. 10,11-Dehydrocurvularin biosynthesis was reconstituted in Saccharomyces cerevisiae by heterologous expression of the polyketide synthases. Bioinformatic analysis of the highly reducing polyketide synthase AtCURS1 and the nonreducing polyketide synthase AtCURS2 highlights crucial biosynthetic programming differences compared to similar synthases involved in resorcylic acid lactone biosynthesis. These differences lead to the synthesis of a predicted tetraketide starter unit that forms part of the 12-membered lactone ring of dehydrocurvularin, as opposed to the penta- or hexaketide starters in the 14-membered rings of resorcylic acid lactones. Tetraketide N-acetylcysteamine thioester analogues of the starter unit were shown to support the biosynthesis of dehydrocurvularin and its analogues, with yeast expressing AtCURS2 alone. Differential programming of the product template domain of the nonreducing polyketide synthase AtCURS2 results in an aldol condensation with a different regiospecificity than that of resorcylic acid lactones, yielding the dihydroxyphenylacetic acid scaffold characterized by an S-type cyclization pattern atypical for fungal polyketides. PMID:23335766

  20. Cancer Treatment with Anti-PD-1/PD-L1 Agents: Is PD-L1 Expression a Biomarker for Patient Selection?

    PubMed

    Festino, Lucia; Botti, Gerardo; Lorigan, Paul; Masucci, Giuseppe V; Hipp, Jason D; Horak, Christine E; Melero, Ignacio; Ascierto, Paolo A

    2016-06-01

    Strategies to help improve the efficacy of the immune system against cancer represent an important innovation, with recent attention having focused on anti-programmed death (PD)-1/PD-ligand 1 (L1) monoclonal antibodies. Clinical trials have shown objective clinical activity of these agents (e.g., nivolumab, pembrolizumab) in several malignancies, including melanoma, non-small-cell lung cancer, bladder cancer, squamous head and neck cancer, renal cell cancer, ovarian cancer, microsatellite-unstable colorectal cancer, and Hodgkin's lymphoma. Expression of PD-L1 in the tumor microenvironment appears to be crucial for therapeutic activity, and initial trials suggested positive PD-L1 tumor expression was associated with higher response rates. However, subsequent observations have questioned the prospect of using PD-L1 expression as a biomarker for selecting patients for therapy, especially since many patients considered PD-L1-negative experience a benefit from treatment. Importantly, there is not yet a definitive test for determination of PD-L1 and a cut-off reference for PD-L1-positive status has not been established. Immunohistochemistry with different antibodies and different thresholds has been used to define PD-L1 positivity (1-50 %), with no clear superiority of one threshold over another for identifying which patients respond. Moreover, the type of cells on which PD-L1 expression is most relevant is not yet clear, with immune infiltrate cells and tumor cells both being used. In conclusion, while PD-L1 expression is often a predictive factor for treatment response, it must be complemented by other biomarkers or histopathologic features, such as the composition and amount of inflammatory cells in the tumor microenvironment and their functional status. Multi-parameter quantitative or semi-quantitative algorithms may become useful and reliable tools to guide patient selection. PMID:27229745

  1. Study to define low voltage and low temperature operating limits of the Pioneer 10/11 Meteoroid Detection Equipment (MDE) system

    NASA Technical Reports Server (NTRS)

    Parker, C. D.

    1975-01-01

    The Pioneer 10/11 meteoroid detection equipment (MDE) pressure cells were tested at liquid nitrogen (LN2) and liquid helium (LHe) temperatures with the excitation voltage controlled as a parameter. The cells failed by firing because of pressurizing gas condensation as the temperature was lowered from LN2 to LHe temperature and when raised from LHe temperature. A study was conducted to determine cell pressure as a function of temperature, and cell failure was estimated as a function of temperature and excitation voltage. The electronic system was also studied, and a profile of primary spacecraft voltage (nominally 28 Vdc) and temperature corresponding to electronic system failure was determined experimentally.

  2. A humanized antibody for imaging immune checkpoint ligand PD-L1 expression in tumors

    PubMed Central

    Gabrielson, Matthew; Lisok, Ala; Wharram, Bryan; Sysa-Shah, Polina; Azad, Babak Behnam; Pomper, Martin G.; Nimmagadda, Sridhar

    2016-01-01

    Antibodies targeting the PD-1/PD-L1 immune checkpoint lead to tumor regression and improved survival in several cancers. PD-L1 expression in tumors may be predictive of response to checkpoint blockade therapy. Because tissue samples might not always be available to guide therapy, we developed and evaluated a humanized antibody for non-invasive imaging of PD-L1 expression in tumors. Radiolabeled [111In]PD-L1-mAb and near-infrared dye conjugated NIR-PD-L1-mAb imaging agents were developed using the mouse and human cross-reactive PD-L1 antibody MPDL3280A. We tested specificity of [111In]PD-L1-mAb and NIR-PD-L1-mAb in cell lines and in tumors with varying levels of PD-L1 expression. We performed SPECT/CT imaging, biodistribution and blocking studies in NSG mice bearing tumors with constitutive PD-L1 expression (CHO-PDL1) and in controls (CHO). Results were confirmed in triple negative breast cancer (TNBC) (MDAMB231 and SUM149) and non-small cell lung cancer (NSCLC) (H2444 and H1155) xenografts with varying levels of PD-L1 expression. There was specific binding of [111In]PD-L1-mAb and NIR-PD-L1-mAb to tumor cells in vitro, correlating with PD-L1 expression levels. In mice bearing subcutaneous and orthotopic tumors, there was specific and persistent high accumulation of signal intensity in PD-L1 positive tumors (CHO-PDL1, MDAMB231, H2444) but not in controls. These results demonstrate that [111In]PD-L1-mAb and NIR-PD-L1-mAb can detect graded levels of PD-L1 expression in human tumor xenografts in vivo. As a humanized antibody, these findings suggest clinical translation of radiolabeled versions of MPDL3280A for imaging. Specificity of NIR-PD-L1-mAb indicates the potential for optical imaging of PD-L1 expression in tumors in relevant pre-clinical as well as clinical settings. PMID:26848870

  3. An L1-script-transfer-effect fallacy: a rejoinder to Wang et al. (2003).

    PubMed

    Yamada, Jun

    2004-09-01

    Do different L1 (first language) writing systems differentially affect word identification in English as a second language (ESL)? Wang, Koda, and Perfetti [Cognition 87 (2003) 129] answered yes by examining Chinese students with a logographic L1 background and Korean students with an alphabetic L1 background for their phonological and orthographic processing skills on English word identification. Such a conclusion is premature, however. We propose that the L1 phonological system (rather than the L1 writing system) of the learner largely accounts for cognitive processes in learning to read a second language (L2). PMID:15147932

  4. Ezetimibe-sensitive cholesterol uptake by NPC1L1 protein does not require endocytosis

    PubMed Central

    Johnson, Tory A.; Pfeffer, Suzanne R.

    2016-01-01

    Human NPC1L1 protein mediates cholesterol absorption in the intestine and liver and is the target of the drug ezetimibe, which is used to treat hypercholesterolemia. Previous studies concluded that NPC1L1-GFP protein trafficking is regulated by cholesterol binding and that ezetimibe blocks NPC1L1-GFP function by inhibiting its endocytosis. We used cell surface biotinylation to monitor NPC1L1-GFP endocytosis and show that ezetimibe does not alter the rate of NPC1L1-GFP endocytosis in cultured rat hepatocytes grown under normal growth conditions. As expected, NPC1L1-GFP endocytosis depends in part on C-terminal, cytoplasmically oriented sequences, but endocytosis does not require cholesterol binding to NPC1L1’s N-terminal domain. In addition, two small- molecule inhibitors of general (and NPC1L1-GFP) endocytosis failed to inhibit the ezetimibe-sensitive uptake of [3H]cholesterol from taurocholate micelles. These experiments demonstrate that cholesterol uptake by NPC1L1 does not require endocytosis; moreover, ezetimibe interferes with NPC1L1’s cholesterol adsorption activity without blocking NPC1L1 internalization in RH7777 cells. PMID:27075173

  5. Endothelial deficiency of L1 reduces tumor angiogenesis and promotes vessel normalization

    PubMed Central

    Magrini, Elena; Villa, Alessandra; Angiolini, Francesca; Doni, Andrea; Mazzarol, Giovanni; Rudini, Noemi; Maddaluno, Luigi; Komuta, Mina; Topal, Baki; Prenen, Hans; Schachner, Melitta; Confalonieri, Stefano; Dejana, Elisabetta; Bianchi, Fabrizio; Mazzone, Massimiliano; Cavallaro, Ugo

    2014-01-01

    While tumor blood vessels share many characteristics with normal vasculature, they also exhibit morphological and functional aberrancies. For example, the neural adhesion molecule L1, which mediates neurite outgrowth, fasciculation, and pathfinding, is expressed on tumor vasculature. Here, using an orthotopic mouse model of pancreatic carcinoma, we evaluated L1 functionality in cancer vessels. Tumor-bearing mice specifically lacking L1 in endothelial cells or treated with anti-L1 antibodies exhibited decreased angiogenesis and improved vascular stabilization, leading to reduced tumor growth and metastasis. In line with these dramatic effects of L1 on tumor vasculature, the ectopic expression of L1 in cultured endothelial cells (ECs) promoted phenotypical and functional alterations, including proliferation, migration, tubulogenesis, enhanced vascular permeability, and endothelial-to-mesenchymal transition. L1 induced global changes in the EC transcriptome, altering several regulatory networks that underlie endothelial pathophysiology, including JAK/STAT-mediated pathways. In particular, L1 induced IL-6–mediated STAT3 phosphorylation, and inhibition of the IL-6/JAK/STAT signaling axis prevented L1-induced EC proliferation and migration. Evaluation of patient samples revealed that, compared with that in noncancerous tissue, L1 expression is specifically enhanced in blood vessels of human pancreatic carcinomas and in vessels of other tumor types. Together, these data indicate that endothelial L1 orchestrates multiple cancer vessel functions and represents a potential target for tumor vascular-specific therapies. PMID:25157817

  6. L1 CELL ADHESION MOLECULE SIGNALING IS INHIBITED BY ETHANOL IN VIVO

    PubMed Central

    Littner, Yoav; Tang, Ningfeng; He, Min; Bearer, Cynthia F.

    2012-01-01

    Background Fetal alcohol spectrum disorder is an immense public health problem. In vitro studies support the hypothesis that L1 cell adhesion molecule (L1) is a target for ethanol developmental neurotoxicity. L1 is critical for the development of the central nervous system. It functions through signal transduction leading to phosphorylation and dephosphorylation of tyrosines on its cytoplasmic domain. The function of L1 is also dependent on trafficking through lipid rafts. Our hypothesis is that L1 is a target for ethanol neurotoxicity in vivo. Our objective is to demonstrate changes in L1 phosphorylation/dephosphorylation and lipid raft association in vivo. Methods Rat pups on postnatal day 6 are administered 4.5, 5.25 and 6 g/kg of ethanol divided into 2 doses 2 hours apart, then sacrificed. Cerebella are rapidly frozen for assay. Blood is analyzed for blood ethanol concentration. L1 tyrosine phosphorylation is determined by immunoprecipitation and dephosphorylation of tyrosine 1176 determined by immunoblot. Lipid rafts are isolated by sucrose density gradient and the distribution of L1 in lipid rafts is determined. Results Ethanol at all doses reduced the relative amount of Y1176 dephosphorylation as well as the relative amount of L1 phosphorylated on other tyrosines. The proportion of L1 present in lipid rafts is significantly increased in pups who received 6 g/kg ethanol compared to intubated controls. Conclusions L1 is a target for ethanol developmental neurotoxicity in vivo. PMID:23050935

  7. Ezetimibe-sensitive cholesterol uptake by NPC1L1 protein does not require endocytosis.

    PubMed

    Johnson, Tory A; Pfeffer, Suzanne R

    2016-06-01

    Human NPC1L1 protein mediates cholesterol absorption in the intestine and liver and is the target of the drug ezetimibe, which is used to treat hypercholesterolemia. Previous studies concluded that NPC1L1-GFP protein trafficking is regulated by cholesterol binding and that ezetimibe blocks NPC1L1-GFP function by inhibiting its endocytosis. We used cell surface biotinylation to monitor NPC1L1-GFP endocytosis and show that ezetimibe does not alter the rate of NPC1L1-GFP endocytosis in cultured rat hepatocytes grown under normal growth conditions. As expected, NPC1L1-GFP endocytosis depends in part on C-terminal, cytoplasmically oriented sequences, but endocytosis does not require cholesterol binding to NPC1L1's N-terminal domain. In addition, two small- molecule inhibitors of general (and NPC1L1-GFP) endocytosis failed to inhibit the ezetimibe-sensitive uptake of [(3)H]cholesterol from taurocholate micelles. These experiments demonstrate that cholesterol uptake by NPC1L1 does not require endocytosis; moreover, ezetimibe interferes with NPC1L1's cholesterol adsorption activity without blocking NPC1L1 internalization in RH7777 cells. PMID:27075173

  8. Vaccine potential of recombinant pro- and mature cathepsinL1 against fasciolosis gigantica in mice.

    PubMed

    Kueakhai, Pornanan; Changklungmoa, Narin; Chaichanasak, Pannigan; Jaikua, Wipaphorn; Itagaki, Tadashi; Sobhon, Prasert

    2015-10-01

    In Fasciola gigantica cathepsin L1 (CatL1) is a family of predominant proteases that is expressed in caecal epithelial cells and secreted into the excretory-secretory products (ES). CatL1 isotypes are expressed in both early and late stages of the life cycle and the parasites use them for migration and digestion. Therefore, CatL1 is a plausible target for vaccination against this parasite. Recombinant pro-F.gigantica CatL1 (rproFgCatL1) and recombinant mature F.gigantica CatL1 (rmatFgCatL1) were expressed in Escherichia coli BL21. The vaccination was performed in Imprinting Control Region (ICR) mice (n=10) by subcutaneous injection with 50μg of rproFgCatL1 and rmatFgCatL1 combined with Freund's adjuvant. Two weeks after the second boost, mice were infected with 15 metacercariae by the oral route. The level of protection of rproFgCatL1 and rmatFgCatL1 vaccines was estimated to be 39.1, 41.7% and 44.9, 47.2% when compared with non vaccinated-infected and adjuvant-infected controls, respectively. Antibodies in the immune sera of vaccinated mice were shown by immuno-blotting to react with the native FgCatL1 in the extract of newly excysted juveniles (NEJ), 4-week-old juveniles and the ES products of 4 week-old juveniles. By determining the levels of IgG1 and IgG2a in the immune sera, which are indicative of Th2 and Th1 immune response, respectively, it was found that both Th1 and Th2 responses were significantly increased in rproFgCatL1- and rmatFgCatL1-immunized groups compared with the control groups, with higher levels of Th2 (IgG1) than Th1 (IgG2a). The levels of serum aspartate aminotransferase (AST) and alanine transaminase (ALT) in rmatFgCatL1-immunized group showed a significant decrease when compared to rproFgCatL1-immunized group, indicating that rmatFgCatL1-vaccinated mice had reduced liver parenchyma damage. The pathological lesions of liver in vaccinated groups were significantly decreased when compared with control groups. This study indicates that rFgCatL

  9. Fotoexcitación de Moléculas Pequeñas

    NASA Astrophysics Data System (ADS)

    González Díaz, P. F.

    El modelo estocástico no puede justificar la excitación multi-fotónica de moléculas pequeñas o muy simétricas. Basándonos en un escenario de interacción radiación-molécula cooperativo para la absorción de N-1 fotones IR por un sistema de N niveles, se especula que un posible mecanismo para la excitación no estocástica de moléculas pudiera ser la generación de procesos caóticos intra-moleculares.

  10. PD-L1 Expression Is Increased in a Subset of Basal Type Breast Cancer Cells

    PubMed Central

    Soliman, Hatem; Khalil, Farah; Antonia, Scott

    2014-01-01

    Background Tumor cells express programmed death ligand 1 (PD-L1) and is a key immune evasion mechanism. PD-L1 expression in multiple breast cancer cell lines was evaluated to identify intrinsic differences that affect their potential for immune evasion. Methods PD-L1 expression was analyzed in six breast cancer cell lines: AU565&MCF7 (luminal), BT20&HCC1143 (basal A), MDA231&HCC38 (basal B). Surface and intracellular PD-L1 expression +/− interferon γ for 48 hours was measured by flow cytometry. PD-L1 gene expression data for all breast cancer cell lines in the Comprehensive Cell Line Encyclopedia (CCLE) was analyzed. Correlation between PD-L1 levels and clinicopathologic parameters was analyzed within Oncomine datasets. A tissue microarray containing 61 invasive breast cancer primary tumor cores was stained for PD-L1 expression and analyzed. Results Basal breast cancer cells constitutively express the highest levels of PD-L1. All cell lines increased PD-L1 expression with interferon γ, but basal B cells (MDA-231 and HCC38) demonstrated the largest increases. There were no differences in protein localization between cell lines. In the CCLE data, basal cell lines demonstrated higher mean PD-L1 expression compared to luminal cell lines. High PD-L1 expressing basal cell lines over-express genes involved in invasion, proliferation, and chemoresistance compared to low PD-L1 basal cell lines. High PD-L1 basal cell lines had lower expression of IRF2BP2 and higher STAT1 levels compared to low PD-L1 expressing cell lines. Within Oncomine datasets PDL1 mRNA levels were higher in basal type tumors. The TMA analysis demonstrated that lymph node positive cases had higher levels of PD-L1 protein expression compared to lymph node negative cases. Conclusions Basal type breast cancer (especially basal B) express greater levels of PD-L1 constitutively and with IFN γ. High PD-L1 basal cells over-express genes involved in invasion, motility, and chemoresistance. Targeting PD-L1

  11. A New CCD Camera at the Molėtai Observatory

    NASA Astrophysics Data System (ADS)

    Zdanavičius, J.; Zdanavičius, K.

    The results of the first testing of a new CCD camera of the Molėtai Observatory are given. The linearity and the flat field corrections of good accuracy are determined by using shifted star field exposures.

  12. L1 retrotransposition: The snap-velcro model and its consequences.

    PubMed

    Viollet, Sébastien; Monot, Clément; Cristofari, Gaël

    2014-01-01

    LINE-1 (L1) elements are the only active and autonomous transposable elements in humans. The core retrotransposition machinery is a ribonucleoprotein particle (RNP) containing the L1 mRNA, with endonuclease and reverse transcriptase activities. It initiates reverse transcription directly at genomic target sites upon endonuclease cleavage. Recently, using a direct L1 extension assay (DLEA), we systematically tested the ability of native L1 RNPs to extend DNA substrates of various sequences and structures. We deduced from these experiments the general rules guiding the initiation of L1 reverse transcription, referred to as the snap-velcro model. In this model, L1 target choice is not only mediated by the sequence specificity of the endonuclease, but also through base-pairing between the L1 mRNA and the target site, which permits the subsequent L1 reverse transcription step. In addition, L1 reverse transcriptase efficiently primes L1 DNA synthesis only when the 3' end of the DNA substrate is single-stranded, suggesting so-far unrecognized DNA processing steps at the integration site. PMID:24818067

  13. PD-L1 expression as predictive biomarker in patients with NSCLC: a pooled analysis

    PubMed Central

    Natoli, Clara; Rizzo, Sergio; Galvano, Antonio; Listì, Angela; Cicero, Giuseppe; Rolfo, Christian; Santini, Daniele; Russo, Antonio

    2016-01-01

    Background Clinical trials of immune checkpoints modulators, including both programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors, have recently shown promising activity and tolerable toxicity in pre-treated NSCLC patients. However the predictive role of PD-L1 expression is still controversial. This pooled analysis aims to clarify the association of clinical objective responses to anti PD-1/PD-L1 monoclonal antibodies (MoAbs) and tumor PD-L1 expression in pre-treated NSCLC patients. Methods Data from published studies, that evaluated efficacy and safety of PD-1/PD-L1 inhibitors in pre-treated NSCLC patients, stratified by tumor PD-L1 expression status (immunohistochemistry, cut-off point 1%), were collected by searching in PubMed, Cochrane Library, American Society of Clinical Oncology, European Society of Medical Oncology and World Conference of Lung Cancer, meeting proceedings. Pooled Odds ratio (OR) and 95% confidence intervals (95% CIs) were calculated for the Overall Response Rate (ORR) (as evaluated by Response Evaluation Criteria in Solid Tumors, version 1.1), according to PD-L1 expression status. Results A total of seven studies, with 914 patients, were eligible. Pooled analysis showed that patients with PD-L1 positive tumors (PD-L1 tumor cell staining ≥1%), had a significantly higher ORR, compared to patients with PD-L1 negative tumors (OR: 2.44; 95% CIs: 1.61-3.68). Conclusions PD-L1 tumor over-expression seems to be associated with higher clinical activity of anti PD-1/PD-L1 MoAbs, in pre-treated NSCLC patients, suggesting a potential role of PD-L1 expression, IHC cut-off point 1%, as predictive biomarker for the selection of patients to treat with immune-checkpoint inhibitors. PMID:26918451

  14. L1 Interaction Domains of Papillomavirus L2 Necessary for Viral Genome Encapsidation

    PubMed Central

    Okun, Martin M.; Day, Patricia M.; Greenstone, Heather L.; Booy, Frank P.; Lowy, Douglas R.; Schiller, John T.; Roden, Richard B. S.

    2001-01-01

    BPHE-1 cells, which harbor 50 to 200 viral episomes, encapsidate viral genome and generate infectious bovine papillomavirus type 1 (BPV1) upon coexpression of capsid proteins L1 and L2 of BPV1, but not coexpression of BPV1 L1 and human papillomavirus type 16 (HPV16) L2. BPV1 L2 bound in vitro via its C-terminal 85 residues to purified L1 capsomers, but not with intact L1 virus-like particles in vitro. However, when the efficiency of BPV1 L1 coimmunoprecipitation with a series of BPV1 L2 deletion mutants was examined in vivo, the results suggested that residues 129 to 246 and 384 to 460 contain independent L1 interaction domains. An L2 mutant lacking the C-terminal L1 interaction domain was impaired for encapsidation of the viral genome. Coexpression of BPV1 L1 and a chimeric L2 protein composed of HPV16 L2 residues 1 to 98 fused to BPV1 L2 residues 99 to 469 generated infectious virions. However, inefficient encapsidation was seen when L1 was coexpressed with either BPV1 L2 with residues 91 to 246 deleted or with BPV1 L2 with residues 1 to 225 replaced with HPV16 L2. Impaired genome encapsidation did not correlate closely with impairment of the L2 proteins either to localize to promyelocytic leukemia oncogenic domains (PODs) or to induce localization of L1 or E2 to PODs. We conclude that the L1-binding domain located near the C terminus of L2 may bind L1 prior to completion of capsid assembly, and that both L1-binding domains of L2 are required for efficient encapsidation of the viral genome. PMID:11287582

  15. Vaccine potential of recombinant cathepsinL1G against Fasciola gigantica in mice.

    PubMed

    Changklungmoa, Narin; Phoinok, Natthacha; Yencham, Chonthicha; Sobhon, Prasert; Kueakhai, Pornanan

    2016-08-15

    In this study, we characterized and investigated the vaccine potential of FgCatL1G against Fasciola gigantica infection in mice. Recombinant mature FgCatL1G (rmFgCatL1G) was expressed in Escherichia coli BL21. The vaccination was performed in Imprinting Control Region (ICR) mice (n=10) by subcutaneous injection with 50μg of rmFgCatL1G combined with Freund's adjuvant. Two weeks after the second boost, mice were infected with 15 metacercariae by the oral route. The percents of protection of rmFgCatL1G vaccine were estimated to be 56.5% and 58.3% when compared with non vaccinated-infected and adjuvant-infected controls, respectively. Antibodies in the immune sera of vaccinated mice were shown by immunoblot to react with the native FgCatL1s in the extract of all stages of parasites and rmFgCatL1H, recombinant pro - FgCatL1 (rpFgCatL1). By immunohistochemistry, the immune sera also reacted with FgCatL1s in the caecal epithelial cells of the parasites. The levels of IgG1 and IgG2a in the immune sera, which are indicative of Th2 and Th1 immune responses, were also increased with IgG1 predominating. The levels of serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) in rmFgCatL1G-immunized group showed no significant difference from the control groups, but pathological lesions of livers in rmFgCatL1G-immunized group showed significant decrease when compared to the control groups. This study indicates that rmFgCatL1G has a vaccine potential against F. gigantica in mice, and this potential will be tested in larger livestock animals. PMID:27514897

  16. Protective cell-mediated immunity by DNA vaccination against Papillomavirus L1 capsid protein in the Cottontail Rabbit Papillomavirus model.

    PubMed

    Hu, Jiafen; Cladel, Nancy M; Budgeon, Lynn R; Reed, Cynthia A; Pickel, Martin D; Christensen, Neil D

    2006-01-01

    Papillomavirus major capsid protein L1 has successfully stimulated protective immunity against virus infection by induction of neutralizing antibodies in animal models and in clinical trials. However, the potential impact of L1-induced protective cell-mediated immune (CMI) responses is difficult to measure in vivo because of the coincidence of anti-L1 antibody. In this study, we tested the hypothesis that L1 could activate CMI, using the Cottontail Rabbit Papillomavirus (CRPV)-rabbit model. A unique property of this model is that infections can be initiated with viral DNA, thus bypassing all contributions to protection via neutralizing anti-L1 antibody. DNA vaccines containing either CRPV L1, or subfragments of L1 (amino-terminal two-thirds of L1 [L1N] and the carboxylterminal two-thirds of L1 [L1C]), were delivered intracutaneously into rabbits, using a gene gun. After three booster immunizations, the rabbits were challenged with several viral DNA constructs: wild-type CRPV, CRPV L1ATGko (an L1 ATG knockout mutation), and CRPV-ROPV hybrid (CRPV with a replacement L1 from Rabbit Oral Papillomavirus). Challenge of L1 DNA-vaccinated rabbits with wild-type CRPV resulted in significantly fewer papillomas when compared with challenge with CRPV L1ATGko DNA. Significantly smaller papillomas were found in CRPV L1-, L1N-, and L1C-vaccinated rabbits. In addition, rabbits vaccinated with either L1 or L1N grew significantly fewer and smaller papillomas when challenged with CRPV-ROPV hybrid DNA. Therefore, CRPV L1 DNA vaccination induced CMI responses to CRPV DNA infections that can contribute to protective immunity. Cross-protective immunity against CRPV L1 and ROPV L1 was elicited in these CRPV L1- and subfragment-vaccinated rabbits. PMID:16987067

  17. Crystal structure of 1,4,5,6,7,8,9,10,11,12,13-undeca-hydro-cyclo-dodeca[c]pyrazol-3-ol.

    PubMed

    Raymond, Casey C; Knopp, Michael A

    2015-10-01

    The title compound, C13H22N2O, crystallized as a pyrazolol tautomer. The 12-membered macrocycle has a distorted chair conformation. In the crystal, mol-ecules are linked via pairs of O-H⋯N hydrogen bonds, forming inversion dimers. The dimers are linked via N-H⋯π and C-H⋯π inter-actions, forming slabs parallel to the bc plane. PMID:26594458

  18. Crystal structure of 1,4,5,6,7,8,9,10,11,12,13-undeca­hydro­cyclo­dodeca[c]pyrazol-3-ol

    PubMed Central

    Raymond, Casey C.; Knopp, Michael A.

    2015-01-01

    The title compound, C13H22N2O, crystallized as a pyrazolol tautomer. The 12-membered macrocycle has a distorted chair conformation. In the crystal, mol­ecules are linked via pairs of O—H⋯N hydrogen bonds, forming inversion dimers. The dimers are linked via N—H⋯π and C—H⋯π inter­actions, forming slabs parallel to the bc plane. PMID:26594458

  19. The clinical utility of PD-L1 testing in selecting non-small cell lung cancer patients for PD1/PD-L1-directed therapy.

    PubMed

    Villaruz, L C; Socinski, M A

    2016-09-01

    Lung cancer is the leading cause of cancer mortality in the United States and worldwide. Long thought to be nonimmunogenic, immunotherapy in lung cancer has historically been met with disappointing results. Programmed death-1 (PD-1), and the PD-1 ligand, PD-L1, are immune checkpoint proteins that fine-tune the antigen-specific T-cell response after stimulation of the T-cell receptor and are crucial for self-tolerance. This pathway in particular is co-opted by tumors through expression of PD-L1 on the tumor cell surface and within the tumor microenvironment, allowing for direct suppression of antitumor cytolytic T-cell activity by the tumor. Indeed, induction of the PD1/PD-L1 pathway represents an adaptive immune resistance mechanism exerted by tumor cells in response to endogenous antitumor activity. In 2015, the US Food and Drug Administration (FDA) approved two immuno-oncology agents, the PD-1 inhibitors nivolumab and pembrolizumab, for the treatment of previously treated advanced non-small cell lung cancer (NSCLC). Coincident with the clinical trials that led to these regulatory approvals has been the development of several immunohistochemistry (IHC) tests of PD-L1 expression, which may serve to select patients who will derive the most benefit from PD1- or PD-L1-directed therapy. The PD-L1 IHC assays are distinct in their methods and interpretation, which poses a challenge to clinicians selecting patients for these therapies. PMID:27090296

  20. A hot L1 retrotransposon evades somatic repression and initiates human colorectal cancer.

    PubMed

    Scott, Emma C; Gardner, Eugene J; Masood, Ashiq; Chuang, Nelson T; Vertino, Paula M; Devine, Scott E

    2016-06-01

    Although human LINE-1 (L1) elements are actively mobilized in many cancers, a role for somatic L1 retrotransposition in tumor initiation has not been conclusively demonstrated. Here, we identify a novel somatic L1 insertion in the APC tumor suppressor gene that provided us with a unique opportunity to determine whether such insertions can actually initiate colorectal cancer (CRC), and if so, how this might occur. Our data support a model whereby a hot L1 source element on Chromosome 17 of the patient's genome evaded somatic repression in normal colon tissues and thereby initiated CRC by mutating the APC gene. This insertion worked together with a point mutation in the second APC allele to initiate tumorigenesis through the classic two-hit CRC pathway. We also show that L1 source profiles vary considerably depending on the ancestry of an individual, and that population-specific hot L1 elements represent a novel form of cancer risk. PMID:27197217

  1. Crystal structure of ribosomal protein L1 from the bacterium Aquifex aeolicus

    NASA Astrophysics Data System (ADS)

    Nikonova, E. Yu.; Tishchenko, S. V.; Gabdulkhakov, A. G.; Shklyaeva, A. A.; Garber, M. B.; Nikonov, S. V.; Nevskaya, N. A.

    2011-07-01

    The crystal structure of ribosomal protein L1 from the bacterium Aquifex aeolicus was solved by the molecular-replacement method and refined to R cryst = 19.4% and R free = 25.1% at 2.1 Å protein consists of two domains linked together by a flexible hinge region. In the structure under consideration, the domains are in close proximity and adopt a closed conformation. Earlier, this conformation has been found in the structure of protein L1 from the bacterium Thermus thermophilus, whereas the structures of archaeal L1 proteins and the structures of all L1 proteins in the RNA-bound form have an open conformation. The fact that a closed conformation was found in the structures of two L1 proteins which crystallize in different space groups and belong to different bacteria suggests that this conformation is a characteristic feature of L1 bacterial proteins in the free form.

  2. “CRASH”ing with the worm – insights into L1CAM functions and mechanisms

    PubMed Central

    Chen, Lihsia; Zhou, Shan

    2011-01-01

    The L1 family of cell adhesion molecules (L1CAMs) in vertebrates has long been studied for its roles in nervous system development and function. Members of this family have been associated with distinct neurological disorders that include CRASH, autism, 3p syndrome, and schizophrenia. The conservation of L1CAMs in Drosophila and C. elegans allows the opportunity to take advantage of these simple model organisms and their accessible genetic manipulations to dissect L1CAM functions and mechanisms of action. This review summarizes the discoveries of L1CAMs made in C. elegans, showcasing this simple model organism as a powerful system to uncover L1CAM mechanisms and roles in healthy and diseased states. PMID:20225255

  3. Green Tea (-)-Epigallotocatechin-3-Gallate Induces PGC-1α Gene Expression in HepG2 Cells and 3T3-L1 Adipocytes.

    PubMed

    Lee, Mak-Soon; Lee, Seohyun; Doo, Miae; Kim, Yangha

    2016-03-01

    Green tea (Camellia sinensis) is one of the most popular beverages in the world and has been acknowledged for centuries as having significant health benefits. (-)-Epigallocatechin-3-gallate (EGCG) is the most abundant catechin in green tea, and it has been reported to have health benefit effects. Peroxisome proliferator-activated receptor γ coactivator (PGC)-1α is a crucial regulator of mitochondrial biogenesis and hepatic gluconeogenesis. The objective of this study was to investigate whether EGCG from green tea can affect the ability of transcriptional regulation on PGC-1α mRNA expression in HepG2 cells and 3T3-L1 adipocytes. To study the molecular mechanism that allows EGCG to control PGC-1α expression, the promoter activity levels of PGC-1α were examined. The PGC-1α mRNA level was measured using quantitative real-time PCR. The -970/+412 bp of PGC-1α promoter was subcloned into the pGL3-Basic vector that includes luciferase as a reporter gene. EGCG was found to up-regulate the PGC-1α mRNA levels significantly with 10 μmol/L of EGCG in HepG2 cells and differentiated 3T3-L1 adipocytes. PGC-1α promoter activity was also increased by treatment with 10 μmol/L of EGCG in both cells. These results suggest that EGCG may induce PGC-1α gene expression, potentially through promoter activation. PMID:27069908

  4. Green Tea (−)-Epigallotocatechin-3-Gallate Induces PGC-1α Gene Expression in HepG2 Cells and 3T3-L1 Adipocytes

    PubMed Central

    Lee, Mak-Soon; Lee, Seohyun; Doo, Miae; Kim, Yangha

    2016-01-01

    Green tea (Camellia sinensis) is one of the most popular beverages in the world and has been acknowledged for centuries as having significant health benefits. (−)-Epigallocatechin-3-gallate (EGCG) is the most abundant catechin in green tea, and it has been reported to have health benefit effects. Peroxisome proliferator-activated receptor γ coactivator (PGC)-1α is a crucial regulator of mitochondrial biogenesis and hepatic gluconeogenesis. The objective of this study was to investigate whether EGCG from green tea can affect the ability of transcriptional regulation on PGC-1α mRNA expression in HepG2 cells and 3T3-L1 adipocytes. To study the molecular mechanism that allows EGCG to control PGC-1α expression, the promoter activity levels of PGC-1α were examined. The PGC-1α mRNA level was measured using quantitative real-time PCR. The −970/+412 bp of PGC-1α promoter was subcloned into the pGL3-Basic vector that includes luciferase as a reporter gene. EGCG was found to up-regulate the PGC-1α mRNA levels significantly with 10 μmol/L of EGCG in HepG2 cells and differentiated 3T3-L1 adipocytes. PGC-1α promoter activity was also increased by treatment with 10 μmol/L of EGCG in both cells. These results suggest that EGCG may induce PGC-1α gene expression, potentially through promoter activation. PMID:27069908

  5. Differential induction of PD-1/PD-L1 in Neuroimmune cells by drug of abuse.

    PubMed

    Mishra, Vikas; Schuetz, Heather; Haorah, James

    2015-01-01

    Interaction of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) plays a critical role in regulating the delicate balance between protective immunity and tolerance. Human neuroimmune cells express very low or undetectable levels of PD-1/PD-L1 in normal physiological condition.We seek to examine if exposure of these cells to drug of abuse such as methamphetamine (METH) alters the profile of PD-1/PD-L1 levels, thereby dampens the innate immune response of the host cells. Thus, we assessed the changes in the levels of PD-1/PD-L1 in primary human macrophages, brain endothelial cells (hBECs), astrocytes, microglia, and neurons after exposure to METH. We observed that stimulation of these neuroimmune cells by METH responded differentially to PD-1/PD-L1 expression. Stimulation of macrophage culture with 50 μM of METH exhibited immediate gradual upregulation of PD-L1, while increase in PD-1 took 2-4 hours later than PD-L1. The response of hBECs to PD-1/PD-L1 induction occurred at 24 hours, while increase of PD-1/PD-L1 levels in neurons and microglia was immediate following METH exposure. We found that astrocytes expressed moderate levels of endogenous PD-1/PD-L1, which was diminished by METH exposure. Our findings show a differential expression of PD-1/PD-L1 in neuroimmune cells in response to METH stimulation, suggesting that PD-1/PD-L1 interplay in these cell types could orchestrate the intercellular interactive communication for neuronal death or protection in the brain environment. PMID:26330898

  6. Clinical and prognostic significance of PD-1 and PD-L1 expression in sarcomas.

    PubMed

    Paydas, Semra; Bagir, Emine Kilic; Deveci, Mehmet Ali; Gonlusen, Gulfiliz

    2016-08-01

    Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) are new targets in cancer immunotherapy in recent years. The aim of this study is to evaluate the PD-1/PD-L1 expressions in sarcomas and to determine association between PD-1/PD-L1 expressions and clinical/pathological properties in some sarcoma subtypes. Formalin-fixed, paraffin-embedded tissue samples from 65 cases with sarcomas were analyzed. Immunohistochemical staining was performed to detect the PD-1 and PD-L1 expressions in tumor tissue and microenvironment, separately. PD-1 expression in tumor tissue and microenvironment was detected in 11 (17 %) and 8 (12 %) cases, respectively. PD-L1 expression in tumor tissue and microenvironment was detected in 19 (29 %) and 20 cases (30 %), respectively. None of the 5 Ewing sarcomas involving bone showed PD-1/PD-L1 expression, while 2 of 3 cases with Ewing sarcomas involving soft tissue showed PD-1 and PD-L1 expression. Among 5 cases with Kaposi sarcoma, four showed PD-1 and/or PD-L1 expression in tumor or microenvironment. PD-1/PD-L1 expressions were detected 3 of 6 cases with pleomorphic sarcoma, 2 of 4 cases with peripheral nerve sheath tumors and 1 of 4 cases with synovial sarcoma. Interestingly, strongest PD-1/PD-L1 expressions in our study group were detected in 2 sarcoma cases with the history of giant cell tumor. PD-1 and PD-L1 expressions are up to 30 % of the cases with sarcomas. It may be rational to target programmed death pathway in Kaposi sarcoma, pleomorphic sarcoma and peripheral nerve sheath tumors. Strong expression of PD-1/PD-L1 in cases with previous giant cell bone tumor has been found to be interesting and must be studied in giant cell tumor samples. PMID:27421997

  7. The Impact of PD-L1 Expression in Patients with Metastatic GEP-NETs

    PubMed Central

    Kim, Seung Tae; Ha, Sang Yun; Lee, Sujin; Ahn, Soomin; Lee, Jeeyun; Park, Se Hoon; Park, Joon Oh; Lim, Ho Yeong; Kang, Won Ki; Kim, Kyoung-Mee; Park, Young Suk

    2016-01-01

    Programmed death-ligand 1 (PD-L1), which is expressed on many cancer cells, interacts with PD1 expressed on the surface of T cells, inhibiting the T cells and blocking the antitumor immune response. Expression of PD-L1 in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has not been studied. We investigated the impact of PD-L1 expression in 32 patients with metastatic GEP-NET. The expression of PD-L1 was evaluated using an anti-PD-L1 immunohistochemistry (IHC) antibody optimized for staining of formalin-fixed paraffin-embedded (FFPE) tissue samples. The correlation between PD-L1 and clinicopathological data including survival and response to systemic treatments was analyzed. Primary sites were 24 foregut-derived GEP-NETs, including stomach (n=1), duodenum (n=2), biliary tract (n=7), and pancreas (n=14), and 8 hindgut-derived GEP-NETs of the distal colon and rectum. Among the 32 patients with metastatic GEP-NET analyzed in this study, 7 (21.9%) had expression of PD-L1 in tumor tissues. Expression of PD-L1 was significantly associated with high-grade WHO classification (grade 3) (p=0.008) but not with gender, primary site, and number of metastatic sites (p>0.05). The status of PD-L1 expression was statistically associated with progression-free survival (PFS) for first-line systemic treatment (p=0.047). Moreover, the status of PD-L1 expression could significantly predict overall survival (p=0.037). The expression of PD-L1 was associated with higher WHO tumor grade (grade 3) in metastatic GEP-NETs. PD-L1 expression had both predictive and prognostic value for survival of patients with metastatic GEP-NETs. PMID:26958083

  8. In Vitro Screening for Compounds That Enhance Human L1 Mobilization

    PubMed Central

    Terasaki, Natsuko; Goodier, John L.; Cheung, Ling E.; Wang, Yue J.; Kajikawa, Masaki; Kazazian, Haig H.; Okada, Norihiro

    2013-01-01

    The Long interspersed element 1 (LINE1 or L1) retrotransposon constitutes 17% of the human genome. There are currently 80–100 human L1 elements that are thought to be active in any diploid human genome. These elements can mobilize into new locations of the genome, resulting in changes in genomic information. Active L1s are thus considered to be a type of endogenous mutagen, and L1 insertions can cause disease. Certain stresses, such as gamma radiation, oxidative stress, and treatment with some agents, can induce transcription and/or mobilization of retrotransposons. In this study, we used a reporter gene assay in HepG2 cells to screen compounds for the potential to enhance the transcription of human L1. We assessed 95 compounds including genotoxic agents, substances that induce cellular stress, and commercially available drugs. Treatment with 15 compounds increased the L1 promoter activity by >1.5-fold (p<0.05) after 6 or 24 hours of treatment. In particular, genotoxic agents (benzo[a]pyrene, camptothecin, cytochalasin D, merbarone, and vinblastine), PPARα agonists (bezafibrate and fenofibrate), and non-steroidal anti-inflammatory drugs (diflunisal, flufenamic acid, salicylamide, and sulindac) induced L1 promoter activity. To examine their effects on L1 retrotransposition, we developed a high-throughput real-time retrotransposition assay using a novel secreted Gaussia luciferase reporter cassette. Three compounds (etomoxir, WY-14643, and salicylamide) produced a significant enhancement in L1 retrotransposition. This is the first study to report the effects of a wide variety of compounds on L1 transcription and retrotransposition. These results suggest that certain chemical- and drug-induced stresses might have the potential to cause genomic mutations by inducing L1 mobilization. Thus, the risk of induced L1 transcription and retrotransposition should be considered during drug safety evaluation and environmental risk assessments of chemicals. PMID:24040300

  9. Heterozygous L1-deficient mice express an autism-like phenotype.

    PubMed

    Sauce, Bruno; Wass, Christopher; Netrakanti, Meera; Saylor, Joshua; Schachner, Melitta; Matzel, Louis D

    2015-10-01

    The L1CAM (L1) gene encodes a cell adhesion molecule that contributes to several important processes in the developing and adult nervous system, including neuronal migration, survival, and plasticity. In humans and mice, mutations in the X chromosome-linked gene L1 cause severe neurological defects in males. L1 heterozygous female mice with one functional copy of the L1 gene show complex morphological features that are different from L1 fully-deficient and wild-type littermate mice. However, almost no information is available on the behavior of L1 heterozygous mice and humans. Here, we investigated the behavior of heterozygous female mice in which the L1 gene is constitutively inactivated. These mice were compared to wild-type littermate females. Animals were assessed in five categories of behavioral tests: five tests for anxiety/stress/exploration, four tests for motor abilities, two tests for spatial learning, three tests for social behavior, and three tests for repetitive behavior. We found that L1 heterozygous mice express an autism-like phenotype, comprised of reduced social behaviors and excessive self-grooming (a repetitive behavior also typical in animal models of autism). L1 heterozygous mice also exhibited an increase in sensitivity to light, assessed by a reluctance to enter the lighted areas of novel environments. However, levels of anxiety, stress, motor abilities, and spatial learning in L1 heterozygous mice were similar to those of wild-type mice. These observations raise the possibility that using molecules known to trigger L1 functions may become valuable in the treatment of autism in humans. PMID:26079769

  10. Targeted Disruption of the Intracellular Domain of Receptor FgfrL1 in Mice

    PubMed Central

    Bluteau, Gilles; Zhuang, Lei; Amann, Ruth; Trueb, Beat

    2014-01-01

    FgfrL1 is the fifth member of the fibroblast growth factor receptor (Fgfr) family. Studies with FgfrL1 deficient mice have demonstrated that the gene plays an important role during embryonic development. FgfrL1 knock-out mice die at birth as they have a malformed diaphragm and lack metanephric kidneys. Similar to the classical Fgfrs, the FgfrL1 protein contains an extracellular part composed of three Ig-like domains that interact with Fgf ligands and heparin. However, the intracellular part of FgfrL1 is not related to the classical receptors and does not possess any tyrosine kinase activity. Curiously enough, the amino acid sequence of this domain is barely conserved among different species, with the exception of three motifs, namely a dileucine peptide, a tandem tyrosine-based motif YXXΦ and a histidine-rich sequence. To investigate the function of the intracellular domain of FgfrL1, we have prepared genetically modified mice that lack the three conserved sequence motifs, but instead contain a GFP cassette (FgfrL1ΔC-GFP). To our surprise, homozygous FgfrL1ΔC-GFP knock-in mice are viable, fertile and phenotypically normal. They do not exhibit any alterations in the diaphragm or the kidney, except for a slight reduction in the number of glomeruli that does not appear to affect life expectancy. In addition, the pancreas of both FgfrL1ΔC-GFP knock-in and FgfrL1 knock-out mice do not show any disturbances in the production of insulin, in contrast to what has been suggested by recent studies. Thus, the conserved motifs of the intracellular FgfrL1 domain are dispensable for organogenesis and normal life. We conclude that the extracellular domain of the protein must conduct the vital functions of FgfrL1. PMID:25126760

  11. Adult ESL Korean Readers' Responses about Their Reading in L1 Korean and L2 English

    ERIC Educational Resources Information Center

    Kim, Misun

    2010-01-01

    In this research study I explore: (a) beliefs Korean ESL readers have about reading in L1 and L2 prior to the Retrospective Miscue Analysis (RMA) sessions, (b) how their beliefs about reading affect the way they read in L1 and L2 and their evaluation of themselves as readers in L1 and L2 reading, and (c) change of their beliefs about reading and…

  12. The Effects of L2 Reading Skills on L1 Reading Skills through Transfer

    ERIC Educational Resources Information Center

    Altmisdort, Gonca

    2016-01-01

    This study investigated whether transfer from L2 to L1 in reading occurs, and if so, which reading sub-skills are transferred into L1 reading. The aim is to identify the role of second language reading skills in L1 reading skills by means of transfer. In addition, the positive effects of the second language transfer to the first language in the…

  13. Differential induction of PD-1/PD-L1 in Neuroimmune cells by drug of abuse

    PubMed Central

    Mishra, Vikas; Schuetz, Heather; Haorah, James

    2015-01-01

    Interaction of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) plays a critical role in regulating the delicate balance between protective immunity and tolerance. Human neuroimmune cells express very low or undetectable levels of PD-1/PD-L1 in normal physiological condition.We seek to examine if exposure of these cells to drug of abuse such as methamphetamine (METH) alters the profile of PD-1/PD-L1 levels, thereby dampens the innate immune response of the host cells. Thus, we assessed the changes in the levels of PD-1/PD-L1 in primary human macrophages, brain endothelial cells (hBECs), astrocytes, microglia, and neurons after exposure to METH. We observed that stimulation of these neuroimmune cells by METH responded differentially to PD-1/PD-L1 expression. Stimulation of macrophage culture with 50 μM of METH exhibited immediate gradual upregulation of PD-L1, while increase in PD-1 took 2-4 hours later than PD-L1. The response of hBECs to PD-1/PD-L1 induction occurred at 24 hours, while increase of PD-1/PD-L1 levels in neurons and microglia was immediate following METH exposure. We found that astrocytes expressed moderate levels of endogenous PD-1/PD-L1, which was diminished by METH exposure. Our findings show a differential expression of PD-1/PD-L1 in neuroimmune cells in response to METH stimulation, suggesting that PD-1/PD-L1 interplay in these cell types could orchestrate the intercellular interactive communication for neuronal death or protection in the brain environment. PMID:26330898

  14. Apolipoprotein L1 Variant Associated with Increased Susceptibility to Trypanosome Infection

    PubMed Central

    Cuypers, Bart; Lecordier, Laurence; Meehan, Conor J.; Van den Broeck, Frederik; Imamura, Hideo; Büscher, Philippe; Dujardin, Jean-Claude; Laukens, Kris; Schnaufer, Achim; Dewar, Caroline; Lewis, Michael; Balmer, Oliver; Azurago, Thomas; Kyei-Faried, Sardick; Ohene, Sally-Ann; Duah, Boateng; Homiah, Prince; Mensah, Ebenezer Kofi; Anleah, Francis; Franco, Jose Ramon; Pays, Etienne

    2016-01-01

    ABSTRACT African trypanosomes, except Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, which cause human African trypanosomiasis, are lysed by the human serum protein apolipoprotein L1 (ApoL1). These two subspecies can resist human ApoL1 because they express the serum resistance proteins T. b. gambiense glycoprotein (TgsGP) and serum resistance-associated protein (SRA), respectively. Whereas in T. b. rhodesiense, SRA is necessary and sufficient to inhibit ApoL1, in T. b. gambiense, TgsGP cannot protect against high ApoL1 uptake, so different additional mechanisms contribute to limit this uptake. Here we report a complex interplay between trypanosomes and an ApoL1 variant, revealing important insights into innate human immunity against these parasites. Using whole-genome sequencing, we characterized an atypical T. b. gambiense infection in a patient in Ghana. We show that the infecting trypanosome has diverged from the classical T. b. gambiense strains and lacks the TgsGP defense mechanism against human serum. By sequencing the ApoL1 gene of the patient and subsequent in vitro mutagenesis experiments, we demonstrate that a homozygous missense substitution (N264K) in the membrane-addressing domain of this ApoL1 variant knocks down the trypanolytic activity, allowing the trypanosome to avoid ApoL1-mediated immunity. PMID:27073096

  15. The increase of circulating PD-L1-expressing CD68(+) macrophage in ovarian cancer.

    PubMed

    Qu, Qiu-Xia; Huang, Qin; Shen, Yu; Zhu, Yi-Bei; Zhang, Xue-Guang

    2016-04-01

    Tumor-associated macrophages (TAMs) have been characterized as a critical population of immunosuppressive cells in a variety of tumor types. PD-L1 (also termed B7-H1) has been described to exert co-inhibitory and immune regulatory functions. Here, in ovarian cancer, PD-L1 is selectively overexpressed on some TAM compared that of benign ovarian disease. When expanding the data in peripheral blood, the proportion of PD-L1(+)CD68(+) cell among CD68(+) cells and the intensity of PD-L1 staining on CD68(+) cell in healthy group were similar to that observed in ovarian cyst group; instead, these two measures were significantly higher in ovarian cancer group, thereafter related to TNM stage. Interestingly, intracellular levels of IL-10, IL-6, TNF-α, and IFN-γ in PD-L1(+)CD68(+) macrophage were higher than those in PD-L1(-)CD68(+) macrophage, especially IL-6 expression. Based on the PD-L1 receptor PD-1 expression on tumor-infiltrating cytotoxic cells, our data supported that expression of PD-L1 on TAM promoted apoptosis of T cells via interaction with PD-1 on CD8(+)T cells. Taken together, these results suggested that PD-L1-expressing macrophage represents a novel suppressor cell population in ovarian cancer, which contributes immune escape of ovarian cancer. PMID:26541760

  16. SCWRL and MolIDE: Computer programs for side-chain conformation prediction and homology modeling

    PubMed Central

    Wang, Qiang; Canutescu, Adrian A.; Dunbrack, Roland L.

    2009-01-01

    SCWRL and MolIDE are software applications for prediction of protein structures. SCWRL is designed specifically for the task of prediction of side-chain conformations given a fixed backbone usually obtained from an experimental structure determined by X-ray crystallography or NMR. SCWRL is a command-line program that typically runs in a few seconds. MolIDE provides a graphical interface for basic comparative (homology) modeling using SCWRL and other programs. MolIDE takes an input target sequence, and uses PSI-BLAST to identify and align templates for comparative modeling of the target. The sequence alignment to any template can be manually modified within a graphical window of the target-template alignment and visualization of the alignment on the template structure. MolIDE builds the model of the target structure based on the template backbone, predicted side-chain conformations with SCWRL, and a loop-modeling program for insertion-deletion regions with user-selected sequence segments. SCWRL and MolIDE can be obtained at http://dunbrack.fccc.edu/Software.php. PMID:18989261

  17. Real-Time PyMOL Visualization for Rosetta and PyRosetta

    PubMed Central

    Baugh, Evan H.; Lyskov, Sergey; Weitzner, Brian D.; Gray, Jeffrey J.

    2011-01-01

    Computational structure prediction and design of proteins and protein-protein complexes have long been inaccessible to those not directly involved in the field. A key missing component has been the ability to visualize the progress of calculations to better understand them. Rosetta is one simulation suite that would benefit from a robust real-time visualization solution. Several tools exist for the sole purpose of visualizing biomolecules; one of the most popular tools, PyMOL (Schrödinger), is a powerful, highly extensible, user friendly, and attractive package. Integrating Rosetta and PyMOL directly has many technical and logistical obstacles inhibiting usage. To circumvent these issues, we developed a novel solution based on transmitting biomolecular structure and energy information via UDP sockets. Rosetta and PyMOL run as separate processes, thereby avoiding many technical obstacles while visualizing information on-demand in real-time. When Rosetta detects changes in the structure of a protein, new coordinates are sent over a UDP network socket to a PyMOL instance running a UDP socket listener. PyMOL then interprets and displays the molecule. This implementation also allows remote execution of Rosetta. When combined with PyRosetta, this visualization solution provides an interactive environment for protein structure prediction and design. PMID:21857909

  18. Diffuse High Intensity PD-L1 Staining in Thymic Epithelial Tumors

    PubMed Central

    Padda, Sukhmani K.; Riess, Jonathan W.; Schwartz, Erich J.; Lu, Tian; Kohrt, Holbrook E.; Neal, Joel W.; West, Robert B.; Wakelee, Heather A.

    2016-01-01

    Introduction Blockade of the immune checkpoint programmed death receptor ligand-1 (PD-L1)/PD-1 pathway has well-established clinical activity across many tumor types. PD-L1 protein expression by immunohistochemistry (IHC) is emerging as a predictive biomarker of response to these therapies. Here, we examine PD-L1 expression in a thymic epithelial tumor (TET) tissue microarray (TMA). Methods The TMA contained 69 TETs and 17 thymic controls, with each case represented by triplicate cores. The TMA was stained with rabbit monoclonal antibody (clone 15, Sino Biological) to human PD-L1. PD-L1 staining was scored based on intensity as follows: 0=none, 1=equivocal/uninterpretable, 2=weak, and 3=intermediate-strong. Those cases with all cores scoring 3 in the epithelial component were categorized as PD-L1high and the remaining as PD-L1low. Results PD-L1high scores were more frequent in TETs than controls (68.1% vs. 17.6%, p=0.0036). PD-L1 scores and histology were significantly correlated, with higher intensity staining in WHO B2/B3/C TETs. Only 14.8% of TETs had PD-L1 staining of associated lymphocytes. In an adjusted analysis (age/gender), PD-L1high TETs had a significantly worse overall survival (HR 5.40, 95% CI 1.13-25.89, p=0.035) and a trend for worse event-free survival (HR 2.94, 95% CI 0.94-9.24, p=0.064). Conclusions PD-L1 expression was present in all cases of TETs within the epithelial component but only in a minority in the lymphocytic component. TETs stained more intensely for PD-L1 than controls, and PD-L1high TETs were associated with more aggressive histology and worse prognosis. This study lends rationale to a clinical trial with anti-PD1/PD-L1 therapy in this rare tumor type. PMID:25402569

  19. Clinical Neuropathology mini-review 6-2015: PD-L1: emerging biomarker in glioblastoma?

    PubMed Central

    Preusser, Matthias; Berghoff, Anna S.; Wick, Wolfgang; Weller, Michael

    2015-01-01

    Programmed death 1 (PD-1, CD279) and programmed death ligand 1 (PD-L1, CD274) are involved in generating tumor-associated immunosuppression by suppression of T-cell proliferation and interleukin 2 (IL-2) production and immune checkpoint inhibitors targeting these molecules are showing compelling activity against a variety of human cancers. PD-L1 expression has shown a positive association with response to PD-1 inhibition in non-central nervous system (CNS) tumors, e.g., melanoma or non-small cell lung cancer, and is discussed as a potential predictive biomarker for patient selection in these tumor types. This review summarizes current knowledge and potential clinical implications of PD-L1 expression in glioblastoma. At present, the following conclusions are drawn: (a) functional data support a role for PD-1/PD-L1 in tumor-associated immunosuppression in glioblastoma; (b) the incidence of PD-L1-expressing glioblastomas seems to be relatively high in comparison to other tumor types, however, the reported rates of glioblastomas with PD-L1 protein expression vary and range from 61 to 88%; (c) there is considerable variability in the methodology of PD-L1 assessment in glioblastoma across studies with heterogeneity in utilized antibodies, tissue sampling strategies, immunohistochemical staining protocols, cut-off definitions, and evaluated staining patterns; (d) there are conflicting data on the prognostic role and so far no data on the predictive role of PD-L1 gene and protein expression in glioblastoma. In summary, the ongoing clinical studies evaluating the activity of PD-1/PD-L1 inhibitors in glioblastoma need to be complemented with well designed and stringently executed studies to understand the influence of PD-1/PD-L1 expression on therapy response or failure and to develop robust means of PD-L1 assessment for meaningful biomarker development. PMID:26501438

  20. Effects of MAPK and PI3K Pathways on PD-L1 Expression in Melanoma

    PubMed Central

    Atefi, Mohammad; Avramis, Earl; Lassen, Amanda; Wong, Deborah; Robert, Lidia; Foulad, David; Cerniglia, Michael; Titz, Bjoern; Chodon, Thinle; Graeber, Thomas G.; Comin-Anduix, Begonya; Ribas, Antoni

    2014-01-01

    Purpose PD-L1 is the main ligand for the immune inhibitory receptor PD-1. This ligand is frequently expressed by melanoma cells. In this study we investigated whether PD-L1 expression is controlled by melanoma driver mutations and modified by oncogenic signaling inhibition. Experimental Design Expression of PD-L1 was investigated in a panel of 51 melanoma cell lines containing different oncogenic mutations, including cell lines with innate and acquired resistance to BRAF inhibitors. The effects of targeted therapy drugs on expression of PD-L1 by melanoma cells were investigated. Results No association was found between the level of PD-L1 expression and mutations in BRAF, NRAS, PTEN or amplification of AKT. Resistance to vemurafenib due to the activation of alternative signaling pathways was accompanied with the induction of PD-L1 expression, while the resistance due to the reactivation of the MAPK pathway had no effect on PD-L1 expression. In melanoma cell lines the effects of BRAF, MEK and PI3K inhibitors on expression of PD-L1 were variable from reduction to induction, particularly in the presence of INFγ. In PD-L1-exposed lymphocytes, vemurafenib paradoxically restored activity of the MAPK pathway and increased the secretion of cytokines. Conclusions In melanoma cell lines, including BRAF inhibitor-resistant cells, PD-L1 expression is variably regulated by oncogenic signaling pathways. PD-L1-exposed lymphocytes decrease MAPK signaling, which is corrected by exposure to vemurafenib, providing potential benefits of combining this drug with immunotherapies. PMID:24812408

  1. Aberrant PD-L1 expression through 3'-UTR disruption in multiple cancers.

    PubMed

    Kataoka, Keisuke; Shiraishi, Yuichi; Takeda, Yohei; Sakata, Seiji; Matsumoto, Misako; Nagano, Seiji; Maeda, Takuya; Nagata, Yasunobu; Kitanaka, Akira; Mizuno, Seiya; Tanaka, Hiroko; Chiba, Kenichi; Ito, Satoshi; Watatani, Yosaku; Kakiuchi, Nobuyuki; Suzuki, Hiromichi; Yoshizato, Tetsuichi; Yoshida, Kenichi; Sanada, Masashi; Itonaga, Hidehiro; Imaizumi, Yoshitaka; Totoki, Yasushi; Munakata, Wataru; Nakamura, Hiromi; Hama, Natsuko; Shide, Kotaro; Kubuki, Yoko; Hidaka, Tomonori; Kameda, Takuro; Masuda, Kyoko; Minato, Nagahiro; Kashiwase, Koichi; Izutsu, Koji; Takaori-Kondo, Akifumi; Miyazaki, Yasushi; Takahashi, Satoru; Shibata, Tatsuhiro; Kawamoto, Hiroshi; Akatsuka, Yoshiki; Shimoda, Kazuya; Takeuchi, Kengo; Seya, Tsukasa; Miyano, Satoru; Ogawa, Seishi

    2016-06-16

    Successful treatment of many patients with advanced cancer using antibodies against programmed cell death 1 (PD-1; also known as PDCD1) and its ligand (PD-L1; also known as CD274) has highlighted the critical importance of PD-1/PD-L1-mediated immune escape in cancer development. However, the genetic basis for the immune escape has not been fully elucidated, with the exception of elevated PD-L1 expression by gene amplification and utilization of an ectopic promoter by translocation, as reported in Hodgkin and other B-cell lymphomas, as well as stomach adenocarcinoma. Here we show a unique genetic mechanism of immune escape caused by structural variations (SVs) commonly disrupting the 3' region of the PD-L1 gene. Widely affecting multiple common human cancer types, including adult T-cell leukaemia/lymphoma (27%), diffuse large B-cell lymphoma (8%), and stomach adenocarcinoma (2%), these SVs invariably lead to a marked elevation of aberrant PD-L1 transcripts that are stabilized by truncation of the 3'-untranslated region (UTR). Disruption of the Pd-l1 3'-UTR in mice enables immune evasion of EG7-OVA tumour cells with elevated Pd-l1 expression in vivo, which is effectively inhibited by Pd-1/Pd-l1 blockade, supporting the role of relevant SVs in clonal selection through immune evasion. Our findings not only unmask a novel regulatory mechanism of PD-L1 expression, but also suggest that PD-L1 3'-UTR disruption could serve as a genetic marker to identify cancers that actively evade anti-tumour immunity through PD-L1 overexpression. PMID:27281199

  2. The Specificity and Flexibility of L1 Reverse Transcription Priming at Imperfect T-Tracts

    PubMed Central

    Viollet, Sébastien; Mir, Ashfaq Ali; Gabus, Caroline; Darlix, Jean-Luc; Cristofari, Gaël

    2013-01-01

    L1 retrotransposons have a prominent role in reshaping mammalian genomes. To replicate, the L1 ribonucleoprotein particle (RNP) first uses its endonuclease (EN) to nick the genomic DNA. The newly generated DNA end is subsequently used as a primer to initiate reverse transcription within the L1 RNA poly(A) tail, a process known as target-primed reverse transcription (TPRT). Prior studies demonstrated that most L1 insertions occur into sequences related to the L1 EN consensus sequence (degenerate 5′-TTTT/A-3′ sites) and frequently preceded by imperfect T-tracts. However, it is currently unclear whether—and to which degree—the liberated 3′-hydroxyl extremity on the genomic DNA needs to be accessible and complementary to the poly(A) tail of the L1 RNA for efficient priming of reverse transcription. Here, we employed a direct assay for the initiation of L1 reverse transcription to define the molecular rules that guide this process. First, efficient priming is detected with as few as 4 matching nucleotides at the primer 3′ end. Second, L1 RNP can tolerate terminal mismatches if they are compensated within the 10 last bases of the primer by an increased number of matching nucleotides. All terminal mismatches are not equally detrimental to DNA extension, a C being extended at higher levels than an A or a G. Third, efficient priming in the context of duplex DNA requires a 3′ overhang. This suggests the possible existence of additional DNA processing steps, which generate a single-stranded 3′ end to allow L1 reverse transcription. Based on these data we propose that the specificity of L1 reverse transcription initiation contributes, together with the specificity of the initial EN cleavage, to the distribution of new L1 insertions within the human genome. PMID:23675310

  3. The specificity and flexibility of l1 reverse transcription priming at imperfect T-tracts.

    PubMed

    Monot, Clément; Kuciak, Monika; Viollet, Sébastien; Mir, Ashfaq Ali; Gabus, Caroline; Darlix, Jean-Luc; Cristofari, Gaël

    2013-05-01

    L1 retrotransposons have a prominent role in reshaping mammalian genomes. To replicate, the L1 ribonucleoprotein particle (RNP) first uses its endonuclease (EN) to nick the genomic DNA. The newly generated DNA end is subsequently used as a primer to initiate reverse transcription within the L1 RNA poly(A) tail, a process known as target-primed reverse transcription (TPRT). Prior studies demonstrated that most L1 insertions occur into sequences related to the L1 EN consensus sequence (degenerate 5'-TTTT/A-3' sites) and frequently preceded by imperfect T-tracts. However, it is currently unclear whether--and to which degree--the liberated 3'-hydroxyl extremity on the genomic DNA needs to be accessible and complementary to the poly(A) tail of the L1 RNA for efficient priming of reverse transcription. Here, we employed a direct assay for the initiation of L1 reverse transcription to define the molecular rules that guide this process. First, efficient priming is detected with as few as 4 matching nucleotides at the primer 3' end. Second, L1 RNP can tolerate terminal mismatches if they are compensated within the 10 last bases of the primer by an increased number of matching nucleotides. All terminal mismatches are not equally detrimental to DNA extension, a C being extended at higher levels than an A or a G. Third, efficient priming in the context of duplex DNA requires a 3' overhang. This suggests the possible existence of additional DNA processing steps, which generate a single-stranded 3' end to allow L1 reverse transcription. Based on these data we propose that the specificity of L1 reverse transcription initiation contributes, together with the specificity of the initial EN cleavage, to the distribution of new L1 insertions within the human genome. PMID:23675310

  4. Bilingual lexical access during L1 sentence reading: The effects of L2 knowledge, semantic constraint, and L1-L2 intermixing.

    PubMed

    Titone, Debra; Libben, Maya; Mercier, Julie; Whitford, Veronica; Pivneva, Irina

    2011-11-01

    Libben and Titone (2009) recently observed that cognate facilitation and interlingual homograph interference were attenuated by increased semantic constraint during bilingual second language (L2) reading, using eye movement measures. We now investigate whether cross-language activation also occurs during first language (L1) reading as a function of age of L2 acquisition and task demands (i.e., inclusion of L2 sentences). In Experiment 1, participants read high and low constraint English (L1) sentences containing interlingual homographs, cognates, or control words. In Experiment 2, we included French (L2) filler sentences to increase salience of the L2 during L1 reading. The results suggest that bilinguals reading in their L1 show nonselective activation to the extent that they acquired their L2 early in life. Similar to our previous work on L2 reading, high contextual constraint attenuated cross-language activation for cognates. The inclusion of French filler items promoted greater cross-language activation, especially for late stage reading measures. Thus, L1 bilingual reading is modulated by L2 knowledge, semantic constraint, and task demands. PMID:21767061

  5. [Expression of the cathepsin L1 gene of Fasciola hepatica eucaryotic cells].

    PubMed

    Kuk, Salih; Kaplan, Mustafa; Kalkan, Ahmet; Ozdarendeli, Aykut

    2006-01-01

    The parasitic trematode Fasciola hepatica is the causative agent of fasciolosis that is common in ruminants especially sheep and cattle and is occasionally found in humans. Fasciolosis has a worldwide distribution including Turkey and causes major economic losses in agricultural industry. Cathepsin L1 is one of the major molecules in the excretory-secretory products of F. hepatica and is involved in tissue penetration, immune evasion and feeding and therefore may be used in vaccination and serological diagnosis. The aim of this study was to evaluate cloning and expression of the cathepsin L1 gene of F. hepatica eucaryotic cells. For this purpose, total RNA was extracted from adult F. hepatica. Cathepsin L1 DNA amplicons were obtained with the reverse transcription polymerase chain reaction (RT-PCR). The 981 base-coding gene region of cathepsin L1 was amplified using specific primers to the cathepsin L1 gene. Then, the cathepsin L1 gene was cloned into the pCI-neo mammalian expression vector. The presence of the cathepsin L1 gene was confirmed by PCR screening and enzyme digestion assays. So, the resulting recombinant plasmid was named pFhCL1. Afterwards, the pFhCL1 vector was transiently transfected into Vero cells. The presence of the cathepsin L1 proteins was shown by Western immunoblotting. PMID:17106850

  6. The Implications of Cognitive Models in L1 and L2 Writing.

    ERIC Educational Resources Information Center

    Railey, Kevin; And Others

    A study investigated one dimension of metacognition--the knowledge of cognition--in first language (L1) and second language (L2) writing. Subjects were 20 students (10 L1 and 10 L2) in a first level college writing course. A questionnaire elicited subjects' definitions of good writing, their notions of the constituent features of the writing…

  7. Task Response and Text Construction across L1 and L2 Writing

    ERIC Educational Resources Information Center

    Kobayashi, Hiroe; Rinnert, Carol

    2008-01-01

    This exploratory study, undertaken from a socio-cognitive perspective, aims to investigate the effects of intensive preparatory high school training in L1 and/or L2 essay writing for university entrance exams. The analysis focuses on the task response and structural features in L1 (Japanese) and L2 (English) essays written by first-year Japanese…

  8. Rate of Acquiring and Processing L2 Color Words in Relation to L1 Phonological Awareness

    ERIC Educational Resources Information Center

    Hu, Chieh-Fang

    2008-01-01

    This study examined the effect of first language (L1) phonological awareness on the rate of learning new second language (L2) color terms and the rate of processing old color terms. Two groups of 37 children participated; they differed on L1 phonological awareness measured at Grade 3. At Grade 5, over multiple trials, the children learned new L2…

  9. The Relationship between L1 Fluency and L2 Fluency Development

    ERIC Educational Resources Information Center

    Derwing, Tracey M.; Munro, Murray J.; Thomson, Ronald I.; Rossiter, Marian J.

    2009-01-01

    A fundamental question in the study of second language (L2) fluency is the extent to which temporal characteristics of speakers' first language (L1) productions predict the same characteristics in the L2. A close relationship between a speaker's L1 and L2 temporal characteristics would suggest that fluency is governed by an underlying trait. This…

  10. Use of L1 in L2 Reading Comprehension among Tertiary ESL Learners

    ERIC Educational Resources Information Center

    Seng, Goh Hock; Hashim, Fatimah

    2006-01-01

    This study is an attempt to provide insights into the extent of first language (L1) use while reading second language (L2) texts in a collaborative situation among tertiary ESL learners. Through the identification of reading strategies utilized by the subjects, the study is also aimed at discovering possible reasons for the use of L1 while…

  11. The Status of the Auxiliary "Do" in L1 and L2 English Negative Clauses

    ERIC Educational Resources Information Center

    Perales, Susana

    2010-01-01

    This paper addresses the issue of whether negative sentences containing auxiliary "do" in L1 and L2 English share the same underlying syntactic representation. To this end, I compare the negative sentences produced by 77 bilingual (Spanish/Basque) L2 learners of English with the corresponding data available for L1 acquirers reported on in Schutze…

  12. Activation of individual L1 retrotransposon instances is restricted to cell-type dependent permissive loci

    PubMed Central

    Philippe, Claude; Vargas-Landin, Dulce B; Doucet, Aurélien J; van Essen, Dominic; Vera-Otarola, Jorge; Kuciak, Monika; Corbin, Antoine; Nigumann, Pilvi; Cristofari, Gaël

    2016-01-01

    LINE-1 (L1) retrotransposons represent approximately one sixth of the human genome, but only the human-specific L1HS-Ta subfamily acts as an endogenous mutagen in modern humans, reshaping both somatic and germline genomes. Due to their high levels of sequence identity and the existence of many polymorphic insertions absent from the reference genome, the transcriptional activation of individual genomic L1HS-Ta copies remains poorly understood. Here we comprehensively mapped fixed and polymorphic L1HS-Ta copies in 12 commonly-used somatic cell lines, and identified transcriptional and epigenetic signatures allowing the unambiguous identification of active L1HS-Ta copies in their genomic context. Strikingly, only a very restricted subset of L1HS-Ta loci - some being polymorphic among individuals - significantly contributes to the bulk of L1 expression, and these loci are differentially regulated among distinct cell lines. Thus, our data support a local model of L1 transcriptional activation in somatic cells, governed by individual-, locus-, and cell-type-specific determinants. DOI: http://dx.doi.org/10.7554/eLife.13926.001 PMID:27016617

  13. Collocational Links in the L2 Mental Lexicon and the Influence of L1 Intralexical Knowledge

    ERIC Educational Resources Information Center

    Wolter, Brent; Gyllstad, Henrik

    2011-01-01

    This article assesses the influence of L1 intralexical knowledge on the formation of L2 intralexical collocations. Two tests, a primed lexical decision task (LDT) and a test of receptive collocational knowledge, were administered to a group of non-native speakers (NNSs) (L1 Swedish), with native speakers (NSs) of English serving as controls on the…

  14. Concatenative and Nonconcatenative Plural Formation in L1, L2, and Heritage Speakers of Arabic

    ERIC Educational Resources Information Center

    Albirini, Abdulkafi; Benmamoun, Elabbas

    2014-01-01

    This study compares Arabic L1, L2, and heritage speakers' (HS) knowledge of plural formation, which involves concatenative and nonconcatenative modes of derivation. Ninety participants (divided equally among L1, L2, and heritage speakers) completed two oral tasks: a picture naming task (to measure proficiency) and a plural formation task. The…

  15. Developmental Word Recognition: A Study of L1 English Readers of L2 Japanese

    ERIC Educational Resources Information Center

    Chikamatsu, Nobuko

    2006-01-01

    This study focused on developmental word recognition strategies used by first language (L1) English readers of second language (L2) Japanese. There were two proficiency groups of Japanese learners. The study considered whether or not word recognition strategies are developmental and whether or not L1 orthographic interference (i.e., involvement of…

  16. Perception of Mandarin Tones: The Effect of L1 Background and Training

    ERIC Educational Resources Information Center

    Wang, Xinchun

    2013-01-01

    This study investigates whether native Hmong speakers' first language (L1) lexical tone experience facilitates or interferes with their perception of Mandarin tones and whether training is effective for perceptual learning of second (L2) tones. In Experiment 1, 3 groups of beginning level learners of Mandarin with different L1 prosodic background…

  17. Threshold to Transfer Writing Skills from L1 to L2

    ERIC Educational Resources Information Center

    Ito, Fumihiko

    2009-01-01

    Background: It has been hypothesized that L2 (second language) readers are not able to draw on their L1 (first language) reading skills for the successful development of L2 reading skills until they develop a certain proficiency in L2 because a lack of proficiency blocks transfer of L1 reading skills to the reading of L2 texts. This minimum degree…

  18. Individual Differences in L2 Learning and Long-Term L1-L2 Relationships

    ERIC Educational Resources Information Center

    Sparks, Richard L.

    2012-01-01

    In this article, I describe studies conducted over 25 years with secondary and post-secondary L2 learners in the United States. The evidence from these studies shows that there are important connections between students' early L1 skills and their L2 aptitude and L2 proficiency and that individual differences in students' L1 skills in elementary…

  19. L1 and L2 Distance Effects in Learning L3 Dutch

    ERIC Educational Resources Information Center

    Schepens, Job J.; der Slik, Frans; Hout, Roeland

    2016-01-01

    Many people speak more than two languages. How do languages acquired earlier affect the learnability of additional languages? We show that linguistic distances between speakers' first (L1) and second (L2) languages and their third (L3) language play a role. Larger distances from the L1 to the L3 and from the L2 to the L3 correlate with lower…

  20. The Diglossic Foreign-Language Classroom: Learners' Views on L1 and L2 Functions.

    ERIC Educational Resources Information Center

    Chavez, Monika

    This study examined the views of college learners of German regarding desired degrees of first language (L1) versus second language (L2) use, how desired language use related to observed language use for students and teachers, gaps between desired and observed language, tasks for which students expressed strong preference for L1 and for L2, how…

  1. Reading Attitudes in L1 and L2, and Their Influence on L2 Extensive Reading

    ERIC Educational Resources Information Center

    Yamashita, Junko

    2004-01-01

    This study examines the relationship between both first language (L1) and second language (L2) reading attitudes, and learners' performance in L2 extensive reading. Four reading attitude variables were identified (Comfort, Anxiety, Value, Self-perception), both in L1 and L2, according to learners' responses to a questionnaire. Results of analyses…

  2. Enhanced expression of PD L1 in cervical intraepithelial neoplasia and cervical cancers.

    PubMed

    Mezache, Louisa; Paniccia, Bernard; Nyinawabera, Angelique; Nuovo, Gerard J

    2015-12-01

    Programmed death ligand 1 (PD L1) expression can reduce the immune response in both infectious diseases and cancers. We thus examined PD L1 expression in cervical intraepithelial neoplasias (CINs) and cancers since they each reflect infection by human papillomavirus (HPV). PD L1 protein was not evident by immunohistochemistry in histologically normal cervical epithelia (0/55) even when adjacent to CIN or cancer. PD L1 expression was much increased in CINs (20/21=95%) and cervical squamous cell cancer (56/70=80%) and localized to the dysplastic/neoplastic squamous cells and mononuclear cells, respectively. There was also a significant increase (each P<0.001) in PD L1 detection in mononuclear cells when comparing cervical squamous cell cancers to endometrial (22/115=19%) and ovarian adenocarcinomas (5/40=13%). Co-expression analyses showed that the primary inflammatory cell that contained PD L1 was the CD8+ lymphocyte that strongly concentrated around the dysplastic CIN cells and nests of invasive squamous cancer cells. These data show that PD L1 is a solid biomarker of productive HPV infection of the cervix and that it is significantly upregulated in both the carcinoma and surrounding inflammatory cells in cervical cancer when compared with other gynecologic malignancies. This suggests that anti-PD L1 therapy may have a role in the treatment of cervical cancer. PMID:26403783

  3. Effects of Age of L2 Acquisition on L1 Event Conceptualization Patterns

    ERIC Educational Resources Information Center

    Bylund, Emanuel

    2009-01-01

    This study explores the effects that the age of onset (AO) of second language (L2) acquisition exerts on the attrition of first language (L1) event conceptualization patterns. The subjects studied are L1 Spanish-L2 Swedish bilinguals living in Sweden. The specific research questions addressed in the study concern the role of AO in endpoint…

  4. Code-Switching: L1-Coded Mediation in a Kindergarten Foreign Language Classroom

    ERIC Educational Resources Information Center

    Lin, Zheng

    2012-01-01

    This paper is based on a qualitative inquiry that investigated the role of teachers' mediation in three different modes of coding in a kindergarten foreign language classroom in China (i.e. L2-coded intralinguistic mediation, L1-coded cross-lingual mediation, and L2-and-L1-mixed mediation). Through an exploratory examination of the varying effects…

  5. L1 retrotransposition in neurons is modulated by MeCP2.

    PubMed

    Muotri, Alysson R; Marchetto, Maria C N; Coufal, Nicole G; Oefner, Ruth; Yeo, Gene; Nakashima, Kinichi; Gage, Fred H

    2010-11-18

    Long interspersed nuclear elements-1 (LINE-1 or L1s) are abundant retrotransposons that comprise approximately 20% of mammalian genomes. Active L1 retrotransposons can impact the genome in a variety of ways, creating insertions, deletions, new splice sites or gene expression fine-tuning. We have shown previously that L1 retrotransposons are capable of mobilization in neuronal progenitor cells from rodents and humans and evidence of massive L1 insertions was observed in adult brain tissues but not in other somatic tissues. In addition, L1 mobility in the adult hippocampus can be influenced by the environment. The neuronal specificity of somatic L1 retrotransposition in neural progenitors is partially due to the transition of a Sox2/HDAC1 repressor complex to a Wnt-mediated T-cell factor/lymphoid enhancer factor (TCF/LEF) transcriptional activator. The transcriptional switch accompanies chromatin remodelling during neuronal differentiation, allowing a transient stimulation of L1 transcription. The activity of L1 retrotransposons during brain development can have an impact on gene expression and neuronal function, thereby increasing brain-specific genetic mosaicism. Further understanding of the molecular mechanisms that regulate L1 expression should provide new insights into the role of L1 retrotransposition during brain development. Here we show that L1 neuronal transcription and retrotransposition in rodents are increased in the absence of methyl-CpG-binding protein 2 (MeCP2), a protein involved in global DNA methylation and human neurodevelopmental diseases. Using neuronal progenitor cells derived from human induced pluripotent stem cells and human tissues, we revealed that patients with Rett syndrome (RTT), carrying MeCP2 mutations, have increased susceptibility for L1 retrotransposition. Our data demonstrate that L1 retrotransposition can be controlled in a tissue-specific manner and that disease-related genetic mutations can influence the frequency of neuronal L

  6. Microwave sintering of ZrO{sub 2}-12 mol% CeO{sub 2}

    SciTech Connect

    Janney, M.A.; Jackson, M.L.; Kimrey, H.D.

    1993-12-31

    Sintering of ZrO{sub 2}-12 mol% CeO{sub 2} was accelerated by microwave processing at 2.45 GHz as compared with conventional firing. However, the size of the ``microwave effect`` was significantly smaller than that which was previously observed for microwave sintering of ZrO{sub 2}-8 mol% Y{sub 2}O{sub 3}. The difference in the effect that the microwave field had on the two zirconia systems is interpreted in terms of their ionic conductivities.

  7. XmMol: an X11 and motif program for macromolecular visualization and modeling.

    PubMed

    Tufféry, P

    1995-02-01

    XmMol is a desktop tool designed to provide both interactive molecular graphics on X11 displays and easy interface with external applications. A kernel provides an interactive wire-frame display of macromolecules. It supports depth cueing, 3D clipping, and stereo. Various representations, coloring, and labeling modes are proposed. Docking and interactive backbone deformation tools are also supported. Communication protocols allow the user to develop new external features or to use XmMol as a visualization tool for external numerical programs. PMID:7794836

  8. The Lunar L1 Gateway: Portal to the Stars and Beyond

    NASA Technical Reports Server (NTRS)

    Lo, Martin; Ross, Shane

    2001-01-01

    Our Solar System is interconnected by a vast system of winding tunnels generated by the Lagrange Points of all the planets and their moons. These passageways are identified by portals around L1 and L2, the halo orbits. By passing through a halo orbit portal, one enters the ancient and colossal labyrinth of the Sun. This natural Interplanetary Supher highway System (IPS) provides ultra-low energy transport throughout the Earth's Neighborhood, the region between Earth's L1 and L2. This is enabled by an accident: the current energy levels of the Earth L1 and L2 Lagrange points differ from that of the Earth-Moon by only about 50 rn/s (as measured by AV). The significance of this happy coincidence to the development of space cannot be overstated. For example, this implies that Lunar L1 halo orbits are connected to halo orbits around Earth's L1 or L2 via low energy pathways...

  9. Widespread somatic L1 retrotransposition occurs early during gastrointestinal cancer evolution

    PubMed Central

    Ewing, Adam D.; Gacita, Anthony; Wood, Laura D.; Ma, Florence; Xing, Dongmei; Kim, Min-Sik; Manda, Srikanth S.; Abril, Gabriela; Pereira, Gavin; Makohon-Moore, Alvin; Looijenga, Leendert H.J.; Gillis, Ad J.M.; Hruban, Ralph H.; Anders, Robert A.; Romans, Katharine E.; Pandey, Akhilesh; Iacobuzio-Donahue, Christine A.; Vogelstein, Bert; Kinzler, Kenneth W.; Kazazian, Haig H.; Solyom, Szilvia

    2015-01-01

    Somatic L1 retrotransposition events have been shown to occur in epithelial cancers. Here, we attempted to determine how early somatic L1 insertions occurred during the development of gastrointestinal (GI) cancers. Using L1-targeted resequencing (L1-seq), we studied different stages of four colorectal cancers arising from colonic polyps, seven pancreatic carcinomas, as well as seven gastric cancers. Surprisingly, we found somatic L1 insertions not only in all cancer types and metastases but also in colonic adenomas, well-known cancer precursors. Some insertions were also present in low quantities in normal GI tissues, occasionally caught in the act of being clonally fixed in the adjacent tumors. Insertions in adenomas and cancers numbered in the hundreds, and many were present in multiple tumor sections, implying clonal distribution. Our results demonstrate that extensive somatic insertional mutagenesis occurs very early during the development of GI tumors, probably before dysplastic growth. PMID:26260970

  10. COOMET.QM-K93 (COOMET 615/RU/13): key comparison in the field of measuring of the ethanol amount fraction in nitrogen (120 μmol/mol)

    NASA Astrophysics Data System (ADS)

    Konopelko, L. A.; Efremova, O. V.; Fatina, O. V.; Orshanskaia, A. A.; Rozhnov, M. S.; Melnyk, D. M.; Petryshyn, P. V.

    2016-01-01

    The relevance of the COOMET.QM-K93 comparison is founded on paying particular attention to reliability of measurements which are performed during the medical examination of drivers of vehicles in order to assess the degree of alcoholic intoxication. Standard gas mixtures of ethanol in nitrogen in cylinders under pressure play a key role in providing metrological assurance of breath-alcohol analyzers. Participating laboratories: VNIIM and Ukrmetrteststandart. This comparison was carried out in 2014-2015. This supplementary comparison supports CMC claims for: ethanol in the range 50-500 μmol/mol in a matrix of either nitrogen or synthetic air. Results: The results are consistent with the reference values. Main text To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

  11. Immune biomarkers PD-1/PD-L1 and TLR3 in malignant pleural mesotheliomas.

    PubMed

    Combaz-Lair, Christelle; Galateau-Sallé, Françoise; McLeer-Florin, Anne; Le Stang, Nolwenn; David-Boudet, Laurence; Duruisseaux, Mickael; Ferretti, Gilbert R; Brambilla, Elisabeth; Lebecque, Serge; Lantuejoul, Sylvie

    2016-06-01

    Malignant pleural mesothelioma (MPM) is an aggressive tumor with no effective therapy. However PD-L1/PD-1 immunity checkpoint therapies gave encouraging results; TLR3 is a programmed death factor, which triggering up-regulates PD-L1. As PD-1/PD-L1 blocking antibodies could restore antitumor immune responses alone or in combination with TLR3 agonists, we investigated PD-L1/PD-1 and TLR3 expressions in MPM to select patients for immunotherapy. Sixty-eight pleural surgical specimens, including 58 MPM (epithelioid, n = 34; biphasic, n = 11; sarcomatoid, n = 13) and 10 benign lesions, were studied. PD-L1 expression was assessed using E1L3N and SP142 clones in tumor cells (TCs) and in tumor-infiltrating lymphocytes (TILs) (positivity threshold of 1%), and compared with overall survival. PD-1, CD3 and CD8 expression by TILs, and TLR3 expression by TCs were analyzed concomitantly. PD-L1 was more expressed by sarcomatoid subtype than by other MPM (62% versus 23% and 9% for E1L3N; 38% versus 11% for SP142) (P = .01 and .04, respectively). Specificity and sensitivity of E1L3N and SP142 were of 53% and 98%, and 90% and 86%, respectively. PD-L1 expression by TILs and TCs correlated for SP142 (P = .023), and PD-L1 SP142 expression by TCs was associated with shorter overall survival (P = .016). TLR3 was expressed in most MPM, but weakly in sarcomatoid MPM. We confirm by comparing two commercially available antibodies that PD-L1 expression is higher in sarcomatoid MPM and correlates with a shorter survival. Whereas TLR3 agonists could be tested in MPM expressing TLR3, the sarcomatoid subtype could benefit from anti-PD-L1/PD-1 therapies alone or in combination. PMID:26980049

  12. PD-L1 and Survival in Solid Tumors: A Meta-Analysis

    PubMed Central

    Li, Lijun; Chai, Ying; Huang, Jian

    2015-01-01

    Background Numerous agents targeting PD-L1/PD-1 check-point are in clinical development. However, the correlation between PD-L1expression and prognosis of solid tumor is still in controversial. Here, we elicit a systematic review and meta-analysis to investigate the potential value of PD-L1 in the prognostic prediction in human solid tumors. Methods Electronic databases were searched for studies evaluating the expression of PD-L1 and overall survival (OS) of patients with solid tumors. Odds ratios (ORs) from individual studies were calculated and pooled by using a random-effect model, and heterogeneity and publication bias analyses were also performed. Results A total of 3107 patients with solid tumor from 28 published studies were included in the meta-analysis. The median percentage of solid tumors with PD-L1 overexpression was 52.5%. PD-L1 overexpression was associated with worse OS at both 3 years (OR = 2.43, 95% confidence interval (CI) = 1.60 to 3.70, P < 0.0001) and 5 years (OR = 2.23, 95% CI = 1.40 to 3.55, P = 0.0008) of solid tumors. Among the tumor types, PD-L1 was associated with worse 3 year-OS of esophageal cancer, gastric cancer, hepatocellular carcinoma, and urothelial cancer, and 5 year-OS of esophageal cancer, gastric cancer and colorectal cancer. Conclusions These results suggest that expression of PD-L1 is associated with worse survival in solid tumors. However, the correlations between PD-L1 and prognosis are variant among different tumor types. More studies are needed to investigate the clinical value of PD-L1 expression in prognostic prediction and treatment option. PMID:26114883

  13. Study of Li 2TiO 3 + 5 mol% TiO 2 lithium ceramics after long-term neutron irradiation

    NASA Astrophysics Data System (ADS)

    Chikhray, Y.; Shestakov, V.; Maksimkin, O.; Turubarova, L.; Osipov, I.; Kulsartov, T.; Kuykabayeba, A.; Tazhibayeva, I.; Kawamura, H.; Tsuchiya, K.

    2009-04-01

    Given work presents the results of complex material-science studies of 1 mm diameter ceramic pebbles manufactured of Li 2TiO 3 + 5 mol% TiO 2 ceramics before and after long-time neutron irradiation. Ceramic samples were placed in specially ampoules (six items) made of stainless steel Cr18Ni10Ti which were vacuumized and filled with helium. Irradiation of ampoules was carried out in the loop channel of WWRK reactor (Almaty, Kazakhstan) during 223 days at 6 MW power. After irradiation light-colored pebbles became grey-colored due to structure changes which generation of grey-colored inclusions (lithium oxide) with low density and microhardness. There is a radiation softening of lithium ceramic and that effect is higher for lower irradiation temperature 760 K than for 920 K. The value of maximum permissible load (pebble crash limit) at that is low and comprises ˜37.9 N. The content of residual tritium is higher for ceramic irradiated at 760 K (6.6 ± 0.6 × 10 11 Bq/kg) than for ceramic irradiated at 920 K (17 ± 3 × 10 10 Bq/kg). The size change indicates that pebble increase more after irradiation at 760 K than at 920 K where the bigger portion of tritium leaves the pebble. X-ray analysis shows radiation modification of Li 2TiO 3 + 5 mol% TiO 2 phase composition and generation of new phases: LiTi 2O 4, LiTiO 2 and Li 4Ti 5O 12.

  14. Plasmid Location and Molecular Heterogeneity of the L1 and L2 β-Lactamase Genes of Stenotrophomonas maltophilia

    PubMed Central

    Avison, Matthew B.; Higgins, Catherine S.; von Heldreich, Charlotte J.; Bennett, Peter M.; Walsh, Timothy R.

    2001-01-01

    An approximately 200-kb plasmid has been purified from clinical isolates of Stenotrophomonas maltophilia. This plasmid was found in all of the 10 isolates examined and contains both the L1 and the L2 β-lactamase genes. The location of L1 and L2 on a plasmid makes it more likely that they could spread to other gram-negative bacteria, potentially causing clinical problems. Sequence analysis of the 10 L1 genes revealed three novel genes, L1c, L1d, and L1e, with 8, 12, and 20% divergence from the published strain IID 1275 L1 (L1a), respectively. The most unusual L1 enzyme (L1e) displayed markedly different kinetic properties, with respect to hydrolysis of nitrocefin and imipenem, compared to those of L1a (250- and 100-fold lower kcat/Km ratios respectively). L1c and L1d, in contrast, displayed levels of hydrolysis very similar to that of L1a. Several nonconservative amino acid differences with respect to L1a, L1b, L1c, and L1d were observed in the substrate binding-catalytic regions of L1e, and this could explain the kinetic differences. Three novel L2 genes (L2b, L2c, and L2d) were sequenced from the same isolates, and their sequences diverge from the published sequence of strain IID 1275 L2 (L2a) by 4, 9, and 25%, respectively. Differences in L1 and L2 gene sequences were not accompanied by similar divergences in 16S rRNA gene sequences, for which differences of <1% were found. It is therefore apparent that the L1 and L2 genes have evolved relatively quickly, perhaps because of their presence on a plasmid. PMID:11158734

  15. Microscopic analysis of 10,11Be elastic scattering on protons and 12C and breakup processes of 11Be within the 10Be+n cluster model

    NASA Astrophysics Data System (ADS)

    Spasova, K.; Lukyanov, V. K.; Kadrev, D. N.; Antonov, A. N.; Zemlyanaya, E. V.; Lukyanov, K. V.; Gaidarov, M. K.

    2016-06-01

    The elastic scattering cross-sections of 10,11Be on protons and 12C at energy E < 100 MeV/nucleon using microscopically calculated optical potentials (OP) are presented. The real OP is obtained by a folding procedure with effective NN interactions, while the imaginary OP is estimated within the high energy approximation (HEA). The spin-orbit part of the OP is also included. The characteristics of the breakup processes of 11Be on different nuclear targets are also considered. The cross-sections of diffractive breakup and stripping reactions of 11Be on 9Be, 93Nb, 181Ta and 238U at energy E = 63 MeV/nucleon and the longitudinal momentum distributions of 10Be fragments produced in the breakup of 11Be on these nuclei are presented. The results are in a good agreement with the available experimental data, in particular the obtained widths of about 50 MeV/c are closed to the empirical ones.

  16. Quantification of carbamazepine and its 10,11-epoxide metabolite in rat plasma by UPLC-UV and application to pharmacokinetic study.

    PubMed

    Beig, Avital; Dahan, Arik

    2014-07-01

    A rapid, selective and sensitive UPLC-UV method was developed and validated for the quantitative analysis of carbamazepine and its epoxide metabolite in rat plasma. A relatively small volume of plasma sample (200 μL) is required for the described analytical method. The method includes simple protein precipitation, liquid-liquid extraction, evaporation, and reconstitution steps. Samples were separated on a Waters Acquity UPLC BEH C18 column (1.7 µm, 2.1 × 100 mm) with a gradient mobile phase consisted of 60:40 going to 40:60 (v/v) water-acetonitrile at a flow rate of 0.5 mL/min. The total run time was as low as 6 min, representing a significant improvement in comparison to existing methods. Excellent linearity (r(2)  > 0.999) was achieved over a wide concentration range. Close to complete recovery, short analysis time, high stability, accuracy, precision and reproducibility, and low limit of quantitation were demonstrated. Finally, we successfully applied this analytical method to a pre-clinical oral pharmacokinetic study, revealing the plasma profiles of both carbamazepine and carbamazepine-10,11-epoxide following oral administration of carbamazepine to rats. The advantages demonstrated in this work make this analytical method both time- and cost-efficient approach for drug and metabolite monitoring in the pre-clinical/clinical laboratory. PMID:24327551

  17. A PLS-based extractive spectrophotometric method for simultaneous determination of carbamazepine and carbamazepine-10,11-epoxide in plasma and comparison with HPLC

    NASA Astrophysics Data System (ADS)

    Hemmateenejad, Bahram; Rezaei, Zahra; Khabnadideh, Soghra; Saffari, Maryam

    2007-11-01

    Carbamazepine (CBZ) undergoes enzyme biotransformation through epoxidation with the formation of its metabolite, carbamazepine-10,11-epoxide (CBZE). A simple chemometrics-assisted spectrophotometric method has been proposed for simultaneous determination of CBZ and CBZE in plasma. A liquid extraction procedure was operated to separate the analytes from plasma, and the UV absorbance spectra of the resultant solutions were subjected to partial least squares (PLS) regression. The optimum number of PLS latent variables was selected according to the PRESS values of leave-one-out cross-validation. A HPLC method was also employed for comparison. The respective mean recoveries for analysis of CBZ and CBZE in synthetic mixtures were 102.57 (±0.25)% and 103.00 (±0.09)% for PLS and 99.40 (±0.15)% and 102.20 (±0.02)%. The concentrations of CBZ and CBZE were also determined in five patients using the PLS and HPLC methods. The results showed that the data obtained by PLS were comparable with those obtained by HPLC method.

  18. Comorbidity of 9/11-related PTSD and depression in the World Trade Center Health Registry 10-11 years postdisaster.

    PubMed

    Caramanica, Kimberly; Brackbill, Robert M; Liao, Tim; Stellman, Steven D

    2014-12-01

    Many studies report elevated prevalence of posttraumatic stress disorder (PTSD) and depression among persons exposed to the September 11, 2001 (9/11) disaster compared to those unexposed; few have evaluated long-term PTSD with comorbid depression. We examined prevalence and risk factors for probable PTSD, probable depression, and both conditions 10-11 years post-9/11 among 29,486 World Trade Center Health Registry enrollees who completed surveys at Wave 1 (2003-2004), Wave 2 (2006-2007), and Wave 3 (2011-2012). Enrollees reporting physician diagnosed pre-9/11 PTSD or depression were excluded. PTSD was defined as scoring ≥ 44 on the PTSD Checklist and depression as scoring ≥ 10 on the 8-item Patient Health Questionnaire. We examined 4 groups: comorbid PTSD and depression, PTSD only, depression only, and neither. Among enrollees, 15.2% reported symptoms indicative of PTSD at Wave 3, 14.9% of depression, and 10.1% of both. Comorbid PTSD and depression was associated with high 9/11 exposures, low social integration, health-related unemployment, and experiencing ≥ 1 traumatic life event post-9/11. Comorbid persons experienced poorer outcomes on all PTSD-related impairment measures, life satisfaction, overall health, and unmet mental health care need compared to those with only a single condition. These findings highlight the importance of ongoing screening and treatment for both conditions, particularly among those at risk for mental health comorbidity. PMID:25470556

  19. Automated protein motif generation in the structure-based protein function prediction tool ProMOL.

    PubMed

    Osipovitch, Mikhail; Lambrecht, Mitchell; Baker, Cameron; Madha, Shariq; Mills, Jeffrey L; Craig, Paul A; Bernstein, Herbert J

    2015-12-01

    ProMOL, a plugin for the PyMOL molecular graphics system, is a structure-based protein function prediction tool. ProMOL includes a set of routines for building motif templates that are used for screening query structures for enzyme active sites. Previously, each motif template was generated manually and required supervision in the optimization of parameters for sensitivity and selectivity. We developed an algorithm and workflow for the automation of motif building and testing routines in ProMOL. The algorithm uses a set of empirically derived parameters for optimization and requires little user intervention. The automated motif generation algorithm was first tested in a performance comparison with a set of manually generated motifs based on identical active sites from the same 112 PDB entries. The two sets of motifs were equally effective in identifying alignments with homologs and in rejecting alignments with unrelated structures. A second set of 296 active site motifs were generated automatically, based on Catalytic Site Atlas entries with literature citations, as an expansion of the library of existing manually generated motif templates. The new motif templates exhibited comparable performance to the existing ones in terms of hit rates against native structures, homologs with the same EC and Pfam designations, and randomly selected unrelated structures with a different EC designation at the first EC digit, as well as in terms of RMSD values obtained from local structural alignments of motifs and query structures. This research is supported by NIH grant GM078077. PMID:26573864

  20. An extensively modified version of MolScript that includes greatly enhanced coloring capabilities.

    PubMed

    Esnouf, R M

    1997-04-01

    Owing to its flexibility, MolScript has become one of the most widely used programs for generating publication-quality molecular graphics. Integration with the Raster3D package, to allow the production of photorealistic rendered images, has increased its popularity still further. However, this intensive use has shown the need for enhancement of some areas of the program, especially for controlling the coloring of atoms, bonds, and molecules. This work describes a heavily modified version of MolScript that has added syntax for describing complicated coloring schemes and also has new graphics commands. Enhancements include drawing split-bond ball-and-stick models, smoothly varying the color of molecules (color ramping), abrupt color changes within secondary structural units, and the creation of dashed bonds. Making use of these added features is simple because all MolScript syntax is still supported and one typically needs only to add a few control commands. The final section of this article suggests some uses for this modified MolScript and provides illustrative examples. PMID:9385560

  1. Aberrant structures of Parkinson's disease-associated ubiquitin C-terminal hydrolase L1 predicted by molecular dynamics

    NASA Astrophysics Data System (ADS)

    Koseki, Yuji; Kinjo, Tomohiro; Kuroki, Masato; Aoki, Shunsuke

    2012-05-01

    Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) is a neuron-specific deubiquitinating enzyme. Single amino acid changes (S18Y and I93M) within UCH-L1 are associated with decreased and increased risk of Parkinson's disease (PD), respectively. However, the molecular mechanism of pathogenesis in UCH-L1-associated PD remains to be elucidated. In this study, we performed molecular dynamics simulations of UCH-L1 variants. The simulation results show that I93M UCH-L1 is less stable than S18Y UCH-L1. In particular, the H7 and H8 α-helices in I93M UCH-L1 are partially denatured. Information regarding the aberrant UCH-L1 structures provides new insight into UCH-L1-associated PD.

  2. Dithranol abolishes UCH-L1 immunoreactivity in the nerve fibers of the rat orofacial skin.

    PubMed

    Orojan, Ivan; Szigeti, Csaba; Varszegi, Szilvia; Dobo, Endre; Gulya, Karoly

    2006-11-22

    Dithranol has been used to treat psoriasis for decades. Although its beneficial effect may involve the induction of cutaneous inflammation, and inflammation often leads to damages in nerve fibers, these alterations are not well documented. Therefore, we investigated the effects of dithranol on the immunohistochemical characteristics of the cutaneous nerve fibers in the rat skin. Epidermal nerve fiber staining was achieved with ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) immunohistochemistry in the orofacial skin of control rats, rats treated with (a) dithranol for 5 days, (b) corticosteroid for 5 days following dithranol treatment for 5 days, and (c) corticosteroid for 5 days. The results revealed a complete loss of UCH-L1 immunoreactivity in the dithranol-treated animals. Topical application of corticosteroid onto the inflamed skin for 5 days reversed this effect: the UCH-L1 immunoreactivity was almost completely restored. Steroid treatment for 5 days did not change the appearance of the UCH-L1-immunoreactive nerve fibers. These findings were supported by Western blot analyses. We conclude that dithranol, incidentally similarly to psoriasis, causes inflammation and abolishes UCH-L1 immunoreactivity in the rat orofacial skin in a corticosteroid-reversible manner. This phenomenon may be due to the ability of dithranol to cause oxidative damage to the UCH-L1 protein, and to the antioxidant activity of the corticosteroids countering this effect. PMID:17011532

  3. Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes

    PubMed Central

    Tubio, Jose M. C.; Martincorena, Inigo; Cooke, Susanna L.; Tojo, Marta; Gundem, Gunes; Pipinikas, Christodoulos P.; Zamora, Jorge; Raine, Keiran; Menzies, Andrew; Roman-Garcia, Pablo; Fullam, Anthony; Gerstung, Moritz; Shlien, Adam; Tarpey, Patrick S.; Papaemmanuil, Elli; Knappskog, Stian; Van Loo, Peter; Ramakrishna, Manasa; Davies, Helen R.; Marshall, John; Wedge, David C.; Teague, Jon W.; Butler, Adam P.; Nik-Zainal, Serena; Alexandrov, Ludmil; Behjati, Sam; Yates, Lucy R.; Bolli, Niccolo; Mudie, Laura; Hardy, Claire; Martin, Sancha; McLaren, Stuart; O'Meara, Sarah; Anderson, Elizabeth; Maddison, Mark; Gamble, Stephen; Foster, Christopher; Warren, Anne Y.; Whitaker, Hayley; Brewer, Daniel; Eeles, Rosalind; Cooper, Colin; Neal, David; Lynch, Andy G.; Visakorpi, Tapio; Isaacs, William B.; Veer, Laura van't; Caldas, Carlos; Desmedt, Christine; Sotiriou, Christos; Aparicio, Sam; Foekens, John A.; Eyfjörd, Jórunn Erla; Lakhani, Sunil R.; Thomas, Gilles; Myklebost, Ola; Span, Paul N.; Børresen-Dale, Anne-Lise; Richardson, Andrea L.; Van de Vijver, Marc; Vincent-Salomon, Anne; Van den Eynden, Gert G.; Flanagan, Adrienne M.; Futreal, P. Andrew; Janes, Sam M.; Bova, G. Steven; Stratton, Michael R.; McDermott, Ultan; Campbell, Peter J.

    2015-01-01

    Long interspersed nuclear element–1 (L1) retrotransposons are mobile repetitive elements that are abundant in the human genome. L1 elements propagate through RNA intermediates. In the germ line, neighboring, nonrepetitive sequences are occasionally mobilized by the L1 machinery, a process called 3′ transduction. Because 3′ transductions are potentially mutagenic, we explored the extent to which they occur somatically during tumorigenesis. Studying cancer genomes from 244 patients, we found that tumors from 53% of the patients had somatic retrotranspositions, of which 24% were 3′ transductions. Fingerprinting of donor L1s revealed that a handful of source L1 elements in a tumor can spawn from tens to hundreds of 3′ transductions, which can themselves seed further retrotranspositions. The activity of individual L1 elements fluctuated during tumor evolution and correlated with L1 promoter hypomethylation. The 3′ transductions disseminated genes, exons, and regulatory elements to new locations, most often to heterochromatic regions of the genome. PMID:25082706

  4. PD-L1 expression is associated with advanced non-small cell lung cancer

    PubMed Central

    Chen, Zhiquan; Mei, Jiandong; Liu, Lunxu; Wang, Guochen; Li, Zuosheng; Hou, Jingpu; Zhang, Qiuyang; You, Zongbing; Zhang, Liu

    2016-01-01

    Lung cancer is the most common cause of cancer-associated mortalities worldwide. Novel immunotherapies have been developed to improve the clinical outcomes of non-small cell lung cancer (NSCLC). Antibodies against programmed cell death protein 1 (PD-1) and programmed cell death protein 1 ligand 1 (PD-L1) have been tested in clinical trials, and anti-PD-1 antibody has been approved for the treatment of NSCLC. The aim of the present study was to assess expression of PD-1, PD-L1 and programmed cell death protein 1 ligand 2 (PD-L2) in 48 patients with NSCLC, using immunohistochemical staining. The results found that 35.4% (17/48) of patients were positive for PD-1 expression, 64.6% (31/48) were positive for PD-L1 expression and 45.8% (22/48) were positive for PD-L2 expression. Neither PD-1 nor PD-L2 expression was associated with gender, histology, differentiation status, tumor stage or lymph node metastasis. PD-L1 expression was not associated with gender, histology, differentiation status or lymph node metastasis; however, PD-L1 expression was significantly increased in stage III NSCLC (85.7% PD-L1+) compared with stage I/II NSCLC (55.9% PD-L1+) (P=0.049). PMID:27446371

  5. The role of L1 stalk:tRNA interaction in the ribosome elongation cycle

    PubMed Central

    Trabuco, Leonardo G.; Schreiner, Eduard; Eargle, John; Cornish, Peter; Ha, Taekjip; Luthey-Schulten, Zaida; Schulten, Klaus

    2010-01-01

    The ribosomal L1 stalk is a mobile structure implicated in directing tRNA movement during translocation through the ribosome. This article investigates three aspects of L1 stalk:tRNA interaction. First, by combining through the molecular dynamics flexible fitting method data from cryo-electron microscopy, X-ray crystallography, and molecular dynamics simulations, atomic models of different tRNAs occupying the hybrid P/E state interacting with the L1 stalk are obtained. These models confirm the assignment of FRET states from previous single-molecule investigations of L1 stalk dynamics. Second, the models reconcile how initiator tRNAfMet interacts less strongly with the L1 stalk than elongator tRNAPhe, as seen in previous single-molecule experiments. Third, results from a simulation of the entire ribosome in which the L1 stalk is moved from a half-closed to its open conformation are found to support the hypothesis that L1 stalk opening is involved in tRNA release from the ribosome. PMID:20691699

  6. PD-L1 Deficiency within Islets Reduces Allograft Survival in Mice

    PubMed Central

    Ma, Dongxia; Duan, Wu; Li, Yakun; Wang, Zhimin; Li, Shanglin; Gong, Nianqiao; Chen, Gang; Chen, Zhishui; Wan, Chidan; Yang, Jun

    2016-01-01

    Background Islet transplantation may potentially cure type 1 diabetes mellitus (T1DM). However, immune rejection, especially that induced by the alloreactive T-cell response, remains a restraining factor for the long-term survival of grafted islets. Programmed death ligand-1 (PD-L1) is a negative costimulatory molecule. PD-L1 deficiency within the donor heart accelerates allograft rejection. Here, we investigate whether PD-L1 deficiency in donor islets reduces allograft survival time. Methods Glucose Stimulation Assays were performed to evaluate whether PD-L1 deficiency has detrimental effects on islet function. Islets isolated from PDL1-deficient mice or wild- type (WT) mice (C57BL/6j) were implanted beneath the renal capsule of streptozotocin (STZ)-induced diabetic BALB/c mice. Blood glucose levels and graft survival time after transplantation were monitored. Moreover, we analyzed the residual islets, infiltrating immune cells and alloreactive cells from the recipients. Results PD-L1 deficiency within islets does not affect islet function. However, islet PD-L1 deficiency increased allograft rejection and was associated with enhanced inflammatory cell infiltration and recipient T-cell alloreactivity. Conclusions This is the first report to demonstrate that PD-L1 deficiency accelerated islet allograft rejection and regulated recipient alloimmune responses. PMID:26990974

  7. The potential role of CAMSAP1L1 in symptomatic epilepsy.

    PubMed

    Zhang, Shuai; Kwan, Patrick; Baum, Larry

    2013-11-27

    In a recent genome-wide association study (GWAS) of symptomatic epilepsy in the Chinese population, the most significant single nucleotide polymorphism (SNP) allele was rs2292096 [G] (P=1.0×10(-8), odds ratio [OR]=0.63), in the CAMSAP1L1 gene (also known as CAMSAP2). Here, we report that rs2292096 genotypes tended to associate with expression of CAMSAP1L1 RNA in the temporal lobe (p=0.054) and hippocampus (p=0.20) of epilepsy surgery patients, with expression tending to increase with the G allele. CAMSAP1L1 and β-tubulin double immunofluorescence exhibited partial overlap. CAMSAP1L1 siRNA transfection of human SH-SY5Y neuroblastoma cells treated with or without retinoic acid reduced the CAMSAP1L1 protein level nearly 60% and stimulated neurite outgrowth, as measured by total length, number of processes and number of branches. Therefore, the rs2292096 G allele of CAMSAP1L1, which was associated with reduced risk of symptomatic epilepsy, tended to associate with increased expression of CAMSAP1L1, which represses neurite outgrowth. Greater neurite growth in response to brain insults might increase formation of ectopic neural circuits and thus the risk of epileptogenesis. PMID:24148305

  8. Wnt/β-Catenin Signaling Mediated-UCH-L1 Expression in Podocytes of Diabetic Nephropathy.

    PubMed

    Zhang, Hongxia; Luo, Weili; Sun, Yonghong; Qiao, Yanchun; Zhang, Liying; Zhao, Zhilian; Lv, Shijun

    2016-01-01

    Increasing studies identified podocyte injury as a key early risk factor resulting in diabetic nephropathy (DN). The ubiquitin carboxy-terminal hydrolase 1 (UCH-L1) participates in podocyte differentiation and injury, which is elevated in the podocytes of a variety of nephritis. Whether UCH-L1 expression is positively related to podocyte injury of DN remains unclear. In this study, elevated expression of UCH-L1 and its intrinsic mechanism in high glucose (HG)-stimulated murine podocytes were investigated using western blot and real-time quantitative PCR. Kidney biopsies of DN patients and health individuals were stained by immunofluorescence (IF) method. The morphological and functional changes of podocytes were tested by F-actin staining and cell migration assay. Results demonstrated that HG induced upregulation of UCH-L1 and activation of the Wnt/β-catenin signaling pathway in podocytes. However, blocking of the Wnt pathway by dickkopf related protein 1 (DKK1) eliminated the above changes. Furthermore, IF staining confirmed that, compared with healthy individuals, the expression of UCH-L1 and β-catenin were obviously increased in kidney biopsy of DN patients. Overexpression of UCH-L1 remodeled its actin cytoskeleton, increased its cell migration and impacted its important proteins. All the findings manifested that Wnt/β-catenin/UCH-L1 may be a new potential therapy method in the treatment of DN in future. PMID:27571062

  9. Novel Functions for the Endocytic Regulatory Proteins MICAL-L1 AND EHD1 in Mitosis

    PubMed Central

    Reinecke, James B.; Katafiasz, Dawn; Naslavsky, Naava; Caplan, Steve

    2014-01-01

    During interphase, recycling endosomes mediate the transport of internalized cargo back to the plasma membrane. However, in mitotic cells, recycling endosomes are essential for the completion of cytokinesis, the last phase of mitosis that promotes the physical separation the two daughter cells. Despite recent advances, our understanding of the molecular determinants that regulate recycling endosome dynamics during cytokinesis remains incomplete. We have previously demonstrated that Molecule Interacting with CasL Like-1 (MICAL-L1) and C-terminal Eps15 Homology Domain protein 1 (EHD1) coordinately regulate receptor transport from tubular recycling endosomes during interphase. However, their potential roles in controlling cytokinesis had not been addressed. In this study, we show that MICAL-L1 and EHD1 regulate mitosis. Depletion of either protein resulted in increased numbers of bi-nucleated cells. We provide evidence that bi-nucleation in MICAL-L1- and EHD1-depleted cells is a consequence of impaired recycling endosome transport during late cytokinesis. However, depletion of MICAL-L1, but not EHD1, resulted in aberrant chromosome alignment and lagging chromosomes, suggesting an EHD1-independent function for MICAL-L1 earlier in mitosis. Moreover, we provide evidence that MICAL-L1 and EHD1 differentially influence microtubule dynamics during early and late mitosis. Collectively, our new data suggest several unanticipated roles for MICAL-L1 and EHD1 during the cell cycle. PMID:25287187

  10. Engineering the vaccinia virus L1 protein for increased neutralizing antibody response after DNA immunization

    PubMed Central

    Shinoda, Kaori; Wyatt, Linda S; Irvine, Kari R; Moss, Bernard

    2009-01-01

    Background The licensed smallpox vaccine, comprised of infectious vaccinia virus, has associated adverse effects, particularly for immunocompromised individuals. Therefore, safer DNA and protein vaccines are being investigated. The L1 protein, a component of the mature virion membrane that is conserved in all sequenced poxviruses, is required for vaccinia virus entry into host cells and is a target for neutralizing antibody. When expressed by vaccinia virus, the unglycosylated, myristoylated L1 protein attaches to the viral membrane via a C-terminal transmembrane anchor without traversing the secretory pathway. The purpose of the present study was to investigate modifications of the gene expressing the L1 protein that would increase immunogenicity in mice when delivered by a gene gun. Results The L1 gene was codon modified for optimal expression in mammalian cells and potential N-glycosylation sites removed. Addition of a signal sequence to the N-terminus of L1 increased cell surface expression as shown by confocal microscopy and flow cytometry of transfected cells. Removal of the transmembrane domain led to secretion of L1 into the medium. Induction of binding and neutralizing antibodies in mice was enhanced by gene gun delivery of L1 containing the signal sequence with or without the transmembrane domain. Each L1 construct partially protected mice against weight loss caused by intranasal administration of vaccinia virus. Conclusion Modifications of the vaccinia virus L1 gene including codon optimization and addition of a signal sequence with or without deletion of the transmembrane domain can enhance the neutralizing antibody response of a DNA vaccine. PMID:19257896

  11. Identification and Characterization of MEDI4736, an Antagonistic Anti-PD-L1 Monoclonal Antibody.

    PubMed

    Stewart, Ross; Morrow, Michelle; Hammond, Scott A; Mulgrew, Kathy; Marcus, Danielle; Poon, Edmund; Watkins, Amanda; Mullins, Stefanie; Chodorge, Matthieu; Andrews, John; Bannister, David; Dick, Emily; Crawford, Nicola; Parmentier, Julie; Alimzhanov, Marat; Babcook, John S; Foltz, Ian N; Buchanan, Andrew; Bedian, Vahe; Wilkinson, Robert W; McCourt, Matthew

    2015-09-01

    Programmed cell-death 1 ligand 1 (PD-L1) is a member of the B7/CD28 family of proteins that control T-cell activation. Many tumors can upregulate expression of PD-L1, inhibiting antitumor T-cell responses and avoiding immune surveillance and elimination. We have identified and characterized MEDI4736, a human IgG1 monoclonal antibody that binds with high affinity and specificity to PD-L1 and is uniquely engineered to prevent antibody-dependent cell-mediated cytotoxicity. In vitro assays demonstrate that MEDI4736 is a potent antagonist of PD-L1 function, blocking interaction with PD-1 and CD80 to overcome inhibition of primary human T-cell activation. In vivo MEDI4736 significantly inhibits the growth of human tumors in a novel xenograft model containing coimplanted human T cells. This activity is entirely dependent on the presence of transplanted T cells, supporting the immunological mechanism of action for MEDI4736. To further determine the utility of PD-L1 blockade, an anti-mouse PD-L1 antibody was investigated in immunocompetent mice. Here, anti-mouse PD-L1 significantly improved survival of mice implanted with CT26 colorectal cancer cells. The antitumor activity of anti-PD-L1 was enhanced by combination with oxaliplatin, which resulted in increased release of HMGB1 within CT26 tumors. Taken together, our results demonstrate that inhibition of PD-L1 function can have potent antitumor activity when used as monotherapy or in combination in preclinical models, and suggest it may be a promising therapeutic approach for the treatment of cancer. MEDI4736 is currently in several clinical trials both alone and in combination with other agents, including anti-CTLA-4, anti-PD-1, and inhibitors of IDO, MEK, BRAF, and EGFR. PMID:25943534

  12. Clinical significance of programmed death ligand-1 (PD-L1) in colorectal serrated adenocarcinoma

    PubMed Central

    Zhu, Hailong; Qin, Huali; Huang, Ziling; Li, Shuai; Zhu, Xuyou; He, Jian; Yang, Jing; Yu, Xiaoting; Yi, Xianghua

    2015-01-01

    Preliminary research results with antibody of the negative costimulatory molecule programmed cell death ligand-1 (PD-L1) suggested its expression on tumor cells associated with various tumor grade and postoperative prognosis. However, to date, there is no information of PD-L1 expression in colorectal serrated adenocarcinoma (SAC) and its clinical relevance. Therefore, the purpose of this study is to investigate the clinical significance of PD-L1 expression in a large cohort of patients with SAC. Here, we first retrospectively identified all SAC collected at our institution between August 2008 and May 2013. The expression levels of PD-L1 were examined by immunohistochemistry in 120 patients with SAC. We further evaluated the correlation between expression data and clinical parameters, including patient age, sex, tumor size, location, grade, primary tumor classification (pT), lymph node metastasis (pN), distant metastases (pM), and vascular invasion. Strong PD-L1 expression was detected in 25% of SAC. Higher expression of PD-L1 was significantly associated with pN (P=0.003) and pM (P=0.014). Survival analysis showed that patients with higher expression of PD-L1 had a poorer prognosis (P=0.045). However, multivariate regression analysis did not support PD-L1 as an independent prognostic factor (P=0.430). Our data suggest that PD-L1 may represent a new biomarker of metastasis and prognosis for patients with SAC, but as a target in the treatment of SAC is less certain. PMID:26464688

  13. Active form Notch4 promotes the proliferation and differentiation of 3T3-L1 preadipocytes

    SciTech Connect

    Lai, Peng-Yeh; Tsai, Chong-Bin; Department of Ophthalmology, Chiayi Christian Hospital, Chiayi 600, Taiwan, ROC ; Tseng, Min-Jen

    2013-01-18

    Highlights: ► Notch4IC modulates the ERK pathway and cell cycle to promote 3T3-L1 proliferation. ► Notch4IC facilitates 3T3-L1 differentiation by up-regulating proadipogenic genes. ► Notch4IC promotes proliferation during the early stage of 3T3-L1 adipogenesis. ► Notch4IC enhances differentiation during subsequent stages of 3T3-L1 adipogenesis. -- Abstract: Adipose tissue is composed of adipocytes, which differentiate from precursor cells in a process called adipogenesis. Many signal molecules are involved in the transcriptional control of adipogenesis, including the Notch pathway. Previous adipogenic studies of Notch have focused on Notch1 and HES1; however, the role of other Notch receptors in adipogenesis remains unclear. Q-RT-PCR analyses showed that the augmentation of Notch4 expression during the differentiation of 3T3-L1 preadipocytes was comparable to that of Notch1. To elucidate the role of Notch4 in adipogenesis, the human active form Notch4 (N4IC) was transiently transfected into 3T3-L1 cells. The expression of HES1, Hey1, C/EBPδ and PPARγ was up-regulated, and the expression of Pref-1, an adipogenic inhibitor, was down-regulated. To further characterize the effect of N4IC in adipogenesis, stable cells expressing human N4IC were established. The expression of N4IC promoted proliferation and enhanced differentiation of 3T3-L1 cells compared with those of control cells. These data suggest that N4IC promoted proliferation through modulating the ERK pathway and the cell cycle during the early stage of 3T3-L1 adipogenesis and facilitated differentiation through up-regulating adipogenic genes such as C/EBPα, PPARγ, aP2, LPL and HSL during the middle and late stages of 3T3-L1 adipogenesis.

  14. Bilingual Lexical Access during L1 Sentence Reading: The Effects of L2 Knowledge, Semantic Constraint, and L1-L2 Intermixing

    ERIC Educational Resources Information Center

    Titone, Debra; Libben, Maya; Mercier, Julie; Whitford, Veronica; Pivneva, Irina

    2011-01-01

    Libben and Titone (2009) recently observed that cognate facilitation and interlingual homograph interference were attenuated by increased semantic constraint during bilingual second language (L2) reading, using eye movement measures. We now investigate whether cross-language activation also occurs during first language (L1) reading as a function…

  15. L1 and L2 Word Recognotion in Finnish. Examining L1 Effects on L2 Processing of Morphological Complexity and Morphophonological Transparency

    ERIC Educational Resources Information Center

    Vainio, Seppo; Anneli, Pajunen; Hyona, Jukka

    2014-01-01

    This study investigated the effect of the first language (L1) on the visual word recognition of inflected nouns in second language (L2) Finnish by native Russian and Chinese speakers. Case inflection is common in Russian and in Finnish but nonexistent in Chinese. Several models have been posited to describe L2 morphological processing. The unified…

  16. Development of Phonological Awareness in English-Mandarin Bilinguals: A Comparison of English-L1 and Mandarin-L1 Kindergarten Children

    ERIC Educational Resources Information Center

    Yeong, Stephanie H. M.; Rickard Liow, Susan J.

    2012-01-01

    Phoneme awareness is critical for literacy acquisition in English, but relatively little is known about the early development of phonological awareness in ESL (English as a second language) bilinguals when their two languages have different phonological structures. Using parallel tasks in English and Mandarin, we tracked the development of L1

  17. Molecular Heterogeneity of the L-1 Metallo-β-Lactamase Family from Stenotrophomonas maltophilia

    PubMed Central

    Sanschagrin, François; Dufresne, Julien; Levesque, Roger C.

    1998-01-01

    We have determined the nucleotide sequence of the blaS gene encoding the carbapenem-hydrolyzing L-1 β-lactamase from Stenotrophomonas maltophilia GN12873. Analysis of the DNA and deduced amino acid sequences identified a product of 290 amino acids. Comparisons of the L-1 amino acid sequence with those of other zinc β-lactamases showed 88.6% identity with the L-1 enzyme from S. maltophilia IID1275 and less than 20% identity with other class B metalloenzymes. PMID:9593158

  18. L1/ℓ1-Gain analysis and synthesis of Markovian jump positive systems with time delay.

    PubMed

    Zhang, Junfeng; Zhao, Xudong; Zhu, Fubo; Han, Zhengzhi

    2016-07-01

    This paper is concerned with stability analysis and control synthesis of Markovian jump positive systems with time delay. The notions of stochastic stability with L1- and ℓ1-gain performances are introduced for continuous- and discrete-time contexts, respectively. Using a stochastic copositive Lyapunov function, sufficient conditions for the stability with L1/ℓ1-gain performance of the systems are established. Furthermore, mode-dependent controllers are designed to achieve the stabilization with L1/ℓ1-gain of the resulting closed-loop systems. All proposed conditions are formulated in terms of linear programming. Numerical examples are provided to verify the effectiveness of the findings of theory. PMID:27062020

  19. PD-L1 and Tumor Infiltrating Lymphocytes as Prognostic Markers in Resected NSCLC

    PubMed Central

    Ameratunga, Malaka; Asadi, Khashayar; Lin, Xihui; Walkiewicz, Marzena; Murone, Carmel; Knight, Simon; Mitchell, Paul; Boutros, Paul; John, Thomas

    2016-01-01

    Introduction Immune checkpoint inhibition has shifted treatment paradigms in non-small cell lung cancer (NSCLC). Conflicting results have been reported regarding the immune infiltrate and programmed death-ligand 1 (PD-L1) as a prognostic marker. We correlated the immune infiltrate and PD-L1 expression with clinicopathologic characteristics in a cohort of resected NSCLC. Methods A tissue microarray was constructed using triplicate cores from consecutive resected NSCLC. Immunohistochemistry was performed for CD8, FOXP3 and PD-L1. Strong PD-L1 expression was predefined as greater than 50% tumor cell positivity. Matched nodal samples were assessed for concordance of PD-L1 expression. Results Of 522 patients, 346 were node-negative (N0), 72 N1 and 109 N2; 265 were adenocarcinomas (AC), 182 squamous cell cancers (SCC) and 75 other. Strong PD-L1 expression was found in 24% cases. In the overall cohort, PD-L1 expression was not associated with survival. In patients with N2 disease, strong PD-L1 expression was associated with significantly improved disease-free (DFS) and overall survival (OS) in multivariate analysis (HR 0.49, 95%CI 0.36–0.94, p = 0.031; HR 0.46, 95%CI 0.26–0.80, p = 0.006). In this resected cohort only 5% harboured EGFR mutations, whereas 19% harboured KRAS and 23% other. KRAS mutated tumors were more likely to highly express PD-L1 compared to EGFR (22% vs 3%). A stromal CD8 infiltrate was associated with significantly improved DFS in SCC (HR 0.70, 95%CI 0.50–0.97, p = 0.034), but not AC, whereas FOXP3 was not prognostic. Matched nodal specimens (N = 53) were highly concordant for PD-L1 expression (89%). Conclusion PD-L1 expression was not prognostic in the overall cohort. PD-L1 expression in primary tumor and matched nodal specimens were highly concordant. The observed survival benefit in N2 disease requires confirmation. PMID:27104612

  20. Global existence in L 1 for the modified nonlinear Enskog equation in ℝ3

    NASA Astrophysics Data System (ADS)

    Polewczak, Jacek

    1989-07-01

    A global existence theorem with large initial data in L 1 is given for the modified Enskog equation in ℝ3. The method, which is based on the existence of a Liapunov functional (analog of the H-Boltzmann theorem), utilizes a weak compactness argument in L 1 in a similar way to the DiPerna-Lions proof for the Boltzmann equation. The existence theorem is obtained under certain condition on the behavior of the geometric factor Y. The condition on Y amounts to the fact that the L 1 norm of the collision term grows linearly when the local density tends to infinity.

  1. Video background tracking and foreground extraction via L1-subspace updates

    NASA Astrophysics Data System (ADS)

    Pierantozzi, Michele; Liu, Ying; Pados, Dimitris A.; Colonnese, Stefania

    2016-05-01

    We consider the problem of online foreground extraction from compressed-sensed (CS) surveillance videos. A technically novel approach is suggested and developed by which the background scene is captured by an L1- norm subspace sequence directly in the CS domain. In contrast to conventional L2-norm subspaces, L1-norm subspaces are seen to offer significant robustness to outliers, disturbances, and rank selection. Subtraction of the L1-subspace tracked background leads then to effective foreground/moving objects extraction. Experimental studies included in this paper illustrate and support the theoretical developments.

  2. AFAP-1L1-mediated actin filaments crosslinks hinder Trypanosoma cruzi cell invasion and intracellular multiplication.

    PubMed

    de Araújo, Karine Canuto Loureiro; Teixeira, Thaise Lara; Machado, Fabrício Castro; da Silva, Aline Alves; Quintal, Amanda Pifano Neto; da Silva, Claudio Vieira

    2016-10-01

    Host actin cytoskeleton polymerization has been shown to play an important role during Trypanosoma cruzi internalization into mammalian cell. The structure and dynamics of the actin cytoskeleton in cells are regulated by a vast number of actin-binding proteins. Here we aimed to verify the impact of AFAP-1L1, during invasion and multiplication of T. cruzi. Knocking-down AFAP-1L1 increased parasite cell invasion and intracellular multiplication. Thus, we have shown that the integrity of the machinery formed by AFAP-1L1 in actin cytoskeleton polymerization is important to hinder parasite infection. PMID:27349187

  3. L 1 group consensus of multi-agent systems with stochastic inputs under directed interaction topology

    NASA Astrophysics Data System (ADS)

    Shang, Yilun

    2013-01-01

    We address L 1 group consensus problems of networked multi-agent systems with fixed directed information exchange in this article. A discrete-time protocol is designed to solve the L 1 group consensus problems via general stochastic inputs. Under some mild assumptions, we derive sufficient conditions to guarantee the L 1 group consensus based on algebraic graph theory and ergodicity theory for finite Markov chains. Moreover, the boundedness of the expected infinite sum of the inputs ensures the boundedness of the expected trajectory. Numerical simulations instantiating the inputs as varied independent and identically distributed random processes as well as autoregressive processes are presented to demonstrate the effectiveness of our theoretical results.

  4. Preliminary report on the July 10-11, 2015 eruption at Volcán de Colima: Pyroclastic density currents with exceptional runouts and volume

    NASA Astrophysics Data System (ADS)

    Capra, L.; Macías, J. L.; Cortés, A.; Dávila, N.; Saucedo, R.; Osorio-Ocampo, S.; Arce, J. L.; Gavilanes-Ruiz, J. C.; Corona-Chávez, P.; García-Sánchez, L.; Sosa-Ceballos, G.; Vázquez, R.

    2016-01-01

    On July 10-11, 2015 an eruption occurred at Colima volcano produced 10.5 km long pyroclastic density currents (PDCs) along the Montegrande, and 6.5 km long along the San Antonio ravines. The summit dome was destroyed and a new crater excavated and breached to the south. This new breach connects to a narrow channel that descends along Colima's southern flank and was used by a subsequent lava flow. The Montegrande PDCs represent the longest and hottest flow of this type recorded during the past 30 years but are still smaller in comparison to the 15-km long PDCs produced during the 1913 Plinian eruption. Data obtained from field reconnaissance, lahar monitoring stations, and satellite imagery suggest that at least six PDCs occurred. The two largest PDCs (H/L 0.2) were able to surmount topographic barriers or bends. Based on field reconnaissance and digital elevation models extracted from SPOT satellite imageries we estimate a minimum volume for the valley-pond and distal fan deposits of 4.5 × 106 m3. After one week, the deposits were still hot with burning trees on the surface and millimeter-sized holes from which fumes were emanating. The juvenile components of the deposits consist of gray dense blocks and vesicular dark-gray blocks and bombs with bread-crust textures and cooling joints. The mineral association of these rocks consists of plagioclase + clinopyroxene + orthopyroxene + FeTi-oxides ± olivine and resorbed hornblende in a dark glassy matrix that corresponds to an andesitic composition.

  5. SCN1A and SCN1B gene polymorphisms and their association with plasma concentrations of carbamazepine and carbamazepine 10, 11 epoxide in Iranian epileptic patients

    PubMed Central

    Namazi, Soha; Azarpira, Negar; Javidnia, Katayoon; Emami, Mehrdad; Rahjoo, Rahimeh; Berahmand, Razieh; Borhani-Haghighi, Afshin

    2015-01-01

    Objective (s): From a genetic point of view, epilepsy is a polygenic multifactorial syndrome. The SCN1A and B genes belong to a family of genes that provide instructions for making sodium channels. Understanding the relevance of SCN1A and SCN1B gene polymorphisms to plasma concentration of carbamazepine (CBZ) and ’its active metabolite carbamazepine 10, 11 epoxide (CBZE), may shed more light on inter-individual variations in response to CBZ. Materials and Methods: In this cross-sectional study, genotype distribution and allele frequency of six non-synonymous exonic single nucleotide polymorphisms (SNPs) of the SCN1A and B genes were selected and determined using PCR-RFLP in 70 epileptic patients treated with CBZ for at least 6 months. The patients had no hepatic or renal diseases and received no medications known to have a major interaction with CBZ. Serum concentrations of CBZ and CBZE were measured using High-Performance Liquid Chromatography (HPLC). Results: The AA, AG and GG alleles of SCN1A were found in 23, 37 and 10 patients, respectively. There were no statistically significant differences in the mean (± standard deviation) of plasma concentrations of CBZ (P=0.8) and CBZE (P=0.1) among these 3 groups. Likewise, there was no statistically significant relationship between SCN1A polymorphisms and CBZ concentration/dose ratio (P=0.7). A significant association was found between CBZ plasma level and CBZ concentration/dose with CBZ daily dose. All patients had the same genotype of SCN1B gene(CC). and no statistical analysis was performed. Conclusion: No significant association between SCN1A gene polymorphisms and plasma levels of CBZ and CBZE were found[u1]. PMID:26877851

  6. Autophagy gene Atg16l1 prevents lethal T cell alloreactivity mediated by dendritic cells

    PubMed Central

    Hubbard-Lucey, Vanessa M.; Shono, Yusuke; Maurer, Katie; West, Mallory L.; Singer, Natalie V.; Ziegler, Carly G. K.; Lezcano, Cecilia; Motta, Ana Carolina Fragoso; Schmid, Karin; Levi, Samuel M.; Murphy, George F.; Liu, Chen; Winkler, Jeffrey D.; Amaravadi, Ravi K.; Rogler, Gerhard; Dickinson, Anne M.; Holler, Ernst; van den Brink, Marcel RM; Cadwell, Ken

    2014-01-01

    SUMMARY Atg16L1 mediates the cellular degradative process of autophagy and is considered a critical regulator of inflammation based on its genetic association with inflammatory bowel disease. Here we find that Atg16L1 deficiency leads to an exacerbated graft-versus-host disease (GVHD) in a mouse model of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Atg16L1-deficient allo-HSCT recipients with GVHD displayed increased T cell proliferation due to increased dendritic cell (DC) numbers and co-stimulatory molecule expression. Reduced autophagy within DCs was associated with lysosomal abnormalities and decreased amounts of A20, a negative regulator of DC activation. These results broaden the function of Atg16L1 and the autophagy pathway to include a role in limiting a DC-mediated response during inflammatory disease, such as GVHD. PMID:25308334

  7. 10. DETAILED INTERIOR VIEW OF WEB AT U1L1, SHOWING VERTICAL, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    10. DETAILED INTERIOR VIEW OF WEB AT U1L1, SHOWING VERTICAL, ARCH RIB WELDED/BOLTED GUSSET PLATE AND GUARDRAIL, LOOKING SOUTH - Cottonville Bridge, County Road D-61 at Farmer's Creek, Maquoketa, Jackson County, IA

  8. 1. SOUTH FRONT OF TURBINE BUILDING BUILDING L1 (LEFT) AND ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    1. SOUTH FRONT OF TURBINE BUILDING BUILDING L1 (LEFT) AND OF L.P. BOILER ROOM BUILDING L2 (RIGHT) - Portland General Electric Company, Turbine Building, 1841 Southeast Water Street, Portland, Multnomah County, OR

  9. Autophagy gene Atg16L1 prevents lethal T cell alloreactivity mediated by dendritic cells.

    PubMed

    Hubbard-Lucey, Vanessa M; Shono, Yusuke; Maurer, Katie; West, Mallory L; Singer, Natalie V; Ziegler, Carly G K; Lezcano, Cecilia; Motta, Ana Carolina Fragoso; Schmid, Karin; Levi, Samuel M; Murphy, George F; Liu, Chen; Winkler, Jeffrey D; Amaravadi, Ravi K; Rogler, Gerhard; Dickinson, Anne M; Holler, Ernst; van den Brink, Marcel R M; Cadwell, Ken

    2014-10-16

    Atg16L1 mediates the cellular degradative process of autophagy and is considered a critical regulator of inflammation based on its genetic association with inflammatory bowel disease. Here we find that Atg16L1 deficiency leads to an exacerbated graft-versus-host disease (GVHD) in a mouse model of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Atg16L1-deficient allo-HSCT recipients with GVHD displayed increased T cell proliferation due to increased dendritic cell (DC) numbers and costimulatory molecule expression. Reduced autophagy within DCs was associated with lysosomal abnormalities and decreased amounts of A20, a negative regulator of DC activation. These results broaden the function of Atg16L1 and the autophagy pathway to include a role in limiting a DC-mediated response during inflammatory disease, such as GVHD. PMID:25308334

  10. Batch gradient method with smoothing L1/2 regularization for training of feedforward neural networks.

    PubMed

    Wu, Wei; Fan, Qinwei; Zurada, Jacek M; Wang, Jian; Yang, Dakun; Liu, Yan

    2014-02-01

    The aim of this paper is to develop a novel method to prune feedforward neural networks by introducing an L1/2 regularization term into the error function. This procedure forces weights to become smaller during the training and can eventually removed after the training. The usual L1/2 regularization term involves absolute values and is not differentiable at the origin, which typically causes oscillation of the gradient of the error function during the training. A key point of this paper is to modify the usual L1/2 regularization term by smoothing it at the origin. This approach offers the following three advantages: First, it removes the oscillation of the gradient value. Secondly, it gives better pruning, namely the final weights to be removed are smaller than those produced through the usual L1/2 regularization. Thirdly, it makes it possible to prove the convergence of the training. Supporting numerical examples are also provided. PMID:24291693

  11. L10 structure formation in slow-cooled Fe-Au nanoclusters

    SciTech Connect

    Mukherjee, P; Zhang, Ying; Kramer, Matthew J; Lewis, L H; Shield, J E

    2012-05-23

    An ordered L10 structure has been formed in near-stoichiometric Fe-Au alloy nanoparticles. The L10 structure with a = 0.367 nm and c = 0.360 nm was observed in nanoclusters with diameters below 10 nm after slow cooling from 600 °C. The stable L10 structure formed from a parent fcc solid solution phase observed in the as-formed clusters. The fcc phase has a lattice parameter of 0.417 nm, significantly expanded compared to both Au and γ-Fe. The saturation magnetization and coercivity of both fcc and L10 structures were much lower than expected considering Fe dilution effects suggesting competing ferromagnetic and anti-ferromagnetic ordering.

  12. Scalable Production of HPV16 L1 Protein and VLPs from Tobacco Leaves

    PubMed Central

    Zahin, Maryam; Joh, Joongho; Khanal, Sujita; Husk, Adam; Mason, Hugh; Warzecha, Heribert; Ghim, Shin-je; Miller, Donald M.; Matoba, Nobuyuki; Jenson, Alfred Bennett

    2016-01-01

    Cervical cancer is the most common malignancy among women particularly in developing countries, with human papillomavirus (HPV) 16 causing 50% of invasive cervical cancers. A plant-based HPV vaccine is an alternative to the currently available virus-like particle (VLP) vaccines, and would be much less expensive. We optimized methods to express HPV16 L1 protein and purify VLPs from tobacco (Nicotiana benthamiana) leaves transfected with the magnICON deconstructed viral vector expression system. L1 proteins were extracted from agro-infiltrated leaves using a series of pH and salt mediated buffers. Expression levels of L1 proteins and VLPs were verified by immunoblot and ELISA, which confirmed the presence of sequential and conformational epitopes, respectively. Among three constructs tested (16L1d22, TPL1d22, and TPL1F), TPL1F, containing a full-length L1 and chloroplast transit peptide, was best. Extraction of HPV16 L1 from leaf tissue was most efficient (> 2.5% of total soluble protein) with a low-salt phosphate buffer. VLPs were purified using both cesium chloride (CsCl) density gradient and size exclusion chromatography. Electron microscopy studies confirmed the presence of assembled forms of HPV16 L1 VLPs. Collectively; our results indicated that chloroplast-targeted transient expression in tobacco plants is promising for the production of a cheap, efficacious HPV16 L1 VLP vaccine. Studies are underway to develop plant VLPs for the production of a cervical cancer vaccine. PMID:27518899

  13. To grow or not to grow: nutritional control of development during Caenorhabditis elegans L1 arrest.

    PubMed

    Baugh, L Ryan

    2013-07-01

    It is widely appreciated that larvae of the nematode Caenorhabditis elegans arrest development by forming dauer larvae in response to multiple unfavorable environmental conditions. C. elegans larvae can also reversibly arrest development earlier, during the first larval stage (L1), in response to starvation. "L1 arrest" (also known as "L1 diapause") occurs without morphological modification but is accompanied by increased stress resistance. Caloric restriction and periodic fasting can extend adult lifespan, and developmental models are critical to understanding how the animal is buffered from fluctuations in nutrient availability, impacting lifespan. L1 arrest provides an opportunity to study nutritional control of development. Given its relevance to aging, diabetes, obesity and cancer, interest in L1 arrest is increasing, and signaling pathways and gene regulatory mechanisms controlling arrest and recovery have been characterized. Insulin-like signaling is a critical regulator, and it is modified by and acts through microRNAs. DAF-18/PTEN, AMP-activated kinase and fatty acid biosynthesis are also involved. The nervous system, epidermis, and intestine contribute systemically to regulation of arrest, but cell-autonomous signaling likely contributes to regulation in the germline. A relatively small number of genes affecting starvation survival during L1 arrest are known, and many of them also affect adult lifespan, reflecting a common genetic basis ripe for exploration. mRNA expression is well characterized during arrest, recovery, and normal L1 development, providing a metazoan model for nutritional control of gene expression. In particular, post-recruitment regulation of RNA polymerase II is under nutritional control, potentially contributing to a rapid and coordinated response to feeding. The phenomenology of L1 arrest will be reviewed, as well as regulation of developmental arrest and starvation survival by various signaling pathways and gene regulatory

  14. L2 Reading in Multilingual Eritrea: The Influences of L1 Reading and English Proficiency

    ERIC Educational Resources Information Center

    Asfaha, Yonas Mesfun; Beckman, Danielle; Kurvers, Jeanne; Kroon, Sjaak

    2009-01-01

    A major question in L2 reading research is whether L2 reading is a language or a reading problem. Existing research, mainly carried out in Western contexts, demonstrates that L2 reading is influenced by L1 reading and L2 proficiency. This study applied the L2 reading theory in a non-Western context (Eritrea, East Africa) with L1 reading acquired…

  15. [Prediction of B cell epitopes of human papillomavirus type 16 L1 protein].

    PubMed

    Wang, Aiping; Jiang, Min; Li, Ning; Zhang, Gaiping; Qi, Yanhua; Liu, Yankai; Xi, Yu; Zhou, Jingming

    2016-04-01

    Objective To predict the B cell epitopes of human papillomavirus type 16 (HPV-16) L1 protein. Methods After fetching the sequence of HPV-16 L1 from the protein data bank of NCBI, we used Protean software of DNAStar package to analyze the secondary structures, flexibility, hydrophilicity, surface accessibility and antigenicity of the protein. Then average antigen index (AI) of dominant regions was calculated using Wu Yuzhang's method. The potential B cell epitopes of HPV-16 L1 were predicted based on a comprehensive consideration of the above parameters. Finally, the homologies of the epitopes were analyzed with BLAST online. Results The B cell epitopes of HPV-16 L1 might exist at amino acids NO. 51-58, 87-97, 214-220, 290-296, 335-341, 351-366, 408-418, 430-442 and 475-496. Analysis of homologies indicated that the dominant B cell epitopes of the HPV-16 L1 protein might present at amino acids NO. 51-58, 335-341, 351-366, 408-418, 430-442 and 475-496. The sequences, such as 51(PIKKPNNN)58, 351(SETTYKNTNFKEYLRH)366, 408(PPPGGTLEDTY)418 and 430(KHTPPAPKEDPLK)442, were unique to HPV-16 L1, while amino acids 475(KAKPKFTLGKRKATPTTSSTST)496 were identical to amino acids in HPV-16 E1, and the amino acids 335(DTTRSTN)341 were identical to amino acids in other types of HPV L1. Conclusion The B cell epitopes of HPV-16 L1 were predicted using multiple schemes. The results will provide a foundation for the further study and development of broadly protective HPV-16 vaccines. PMID:27053606

  16. Immune infiltration and PD-L1 expression in the tumor microenvironment are prognostic in osteosarcoma.

    PubMed

    Koirala, Pratistha; Roth, Michael E; Gill, Jonathan; Piperdi, Sajida; Chinai, Jordan M; Geller, David S; Hoang, Bang H; Park, Amy; Fremed, Michael A; Zang, Xingxing; Gorlick, Richard

    2016-01-01

    Osteosarcoma patient survival has remained stagnant for 30 years. Novel therapeutic approaches are needed to improve outcomes. We examined the expression of Programmed Death Ligand 1 (PD-L1) and defined the tumor immune microenvironment to assess the prognostic utility in osteosarcoma. PD-L1 expression in osteosarcoma was examined in two patient cohorts using immunohistochemistry (IHC) (n = 48, n = 59) and expression was validated using quantitative real time PCR (n = 21) and western blotting (n = 9). IHC was used to determine the presence of tumor infiltrating lymphocytes and antigen-presenting cells (APCs) in the tumor. Expression of PD-L1 was correlated with immune cell infiltration and event-free-survival (EFS). The 25% of primary osteosarcoma tumors that express PD-L1 were more likely to contain cells that express PD-1 than PD-L1 negative tumors (91.7% vs 47.2%, p = 0.002). Expression of PD-L1 was significantly associated with the presence of T cells, dendritic cells, and natural killer cells. Although all immune cell types examined were present in osteosarcoma samples, only infiltration by dendritic cells (28.3% vs. 83.9%, p = 0.001) and macrophages (45.5% vs. 84.4%, p = 0.031) were associated with worse five-year-EFS. PD-L1 expression was significantly associated with poorer five-year-EFS (25.0%. vs. 69.4%, p = 0.014). Further studies in osteosarcoma are needed to determine if targeting the PD-L1:PD-1 axis improves survival. PMID:27456063

  17. Immune infiltration and PD-L1 expression in the tumor microenvironment are prognostic in osteosarcoma

    PubMed Central

    Koirala, Pratistha; Roth, Michael E.; Gill, Jonathan; Piperdi, Sajida; Chinai, Jordan M.; Geller, David S.; Hoang, Bang H.; Park, Amy; Fremed, Michael A.; Zang, Xingxing; Gorlick, Richard

    2016-01-01

    Osteosarcoma patient survival has remained stagnant for 30 years. Novel therapeutic approaches are needed to improve outcomes. We examined the expression of Programmed Death Ligand 1 (PD-L1) and defined the tumor immune microenvironment to assess the prognostic utility in osteosarcoma. PD-L1 expression in osteosarcoma was examined in two patient cohorts using immunohistochemistry (IHC) (n = 48, n = 59) and expression was validated using quantitative real time PCR (n = 21) and western blotting (n = 9). IHC was used to determine the presence of tumor infiltrating lymphocytes and antigen-presenting cells (APCs) in the tumor. Expression of PD-L1 was correlated with immune cell infiltration and event-free-survival (EFS). The 25% of primary osteosarcoma tumors that express PD-L1 were more likely to contain cells that express PD-1 than PD-L1 negative tumors (91.7% vs 47.2%, p = 0.002). Expression of PD-L1 was significantly associated with the presence of T cells, dendritic cells, and natural killer cells. Although all immune cell types examined were present in osteosarcoma samples, only infiltration by dendritic cells (28.3% vs. 83.9%, p = 0.001) and macrophages (45.5% vs. 84.4%, p = 0.031) were associated with worse five-year-EFS. PD-L1 expression was significantly associated with poorer five-year-EFS (25.0%. vs. 69.4%, p = 0.014). Further studies in osteosarcoma are needed to determine if targeting the PD-L1:PD-1 axis improves survival. PMID:27456063

  18. Scalable Production of HPV16 L1 Protein and VLPs from Tobacco Leaves.

    PubMed

    Zahin, Maryam; Joh, Joongho; Khanal, Sujita; Husk, Adam; Mason, Hugh; Warzecha, Heribert; Ghim, Shin-Je; Miller, Donald M; Matoba, Nobuyuki; Jenson, Alfred Bennett

    2016-01-01

    Cervical cancer is the most common malignancy among women particularly in developing countries, with human papillomavirus (HPV) 16 causing 50% of invasive cervical cancers. A plant-based HPV vaccine is an alternative to the currently available virus-like particle (VLP) vaccines, and would be much less expensive. We optimized methods to express HPV16 L1 protein and purify VLPs from tobacco (Nicotiana benthamiana) leaves transfected with the magnICON deconstructed viral vector expression system. L1 proteins were extracted from agro-infiltrated leaves using a series of pH and salt mediated buffers. Expression levels of L1 proteins and VLPs were verified by immunoblot and ELISA, which confirmed the presence of sequential and conformational epitopes, respectively. Among three constructs tested (16L1d22, TPL1d22, and TPL1F), TPL1F, containing a full-length L1 and chloroplast transit peptide, was best. Extraction of HPV16 L1 from leaf tissue was most efficient (> 2.5% of total soluble protein) with a low-salt phosphate buffer. VLPs were purified using both cesium chloride (CsCl) density gradient and size exclusion chromatography. Electron microscopy studies confirmed the presence of assembled forms of HPV16 L1 VLPs. Collectively; our results indicated that chloroplast-targeted transient expression in tobacco plants is promising for the production of a cheap, efficacious HPV16 L1 VLP vaccine. Studies are underway to develop plant VLPs for the production of a cervical cancer vaccine. PMID:27518899

  19. A systematic framework for evaluating standard cell middle-of-line (MOL) robustness for multiple patterning

    NASA Astrophysics Data System (ADS)

    Xu, Xiaoqing; Cline, Brian; Yeric, Greg; Yu, Bei; Pan, David Z.

    2015-03-01

    Multiple patterning (triple and quadruple patterning) is being considered for use on the Middle-Of-Line (MOL) layers at the 10nm technology node and beyond.1 For robust standard cell design, designers need to improve the inter-cell compatibility for all combinations of cells and cell placements. Multiple patterning colorability checks break the locality of traditional rule checking and N-wise checks are strongly needed to verify the multiple patterning colorability for layout interaction across cell boundaries. In this work, a systematic framework is proposed to evaluate the library-level robustness over multiple patterning from two perpectives, including illegal cell combinations and full chip interactions. With efficient N-wise checks, the vertical and horizontal boundary checks are explored to predict illegal cell combinations. For full chip interactions, random benchmarks are generated by cell shifting and tested to evaluate the placement-level efforts needed to reduce the quadruple patterning to triple patterning for the MOL layer.

  20. Ligand-based virtual screening interface between PyMOL and LiSiCA.

    PubMed

    Dilip, Athira; Lešnik, Samo; Štular, Tanja; Janežič, Dušanka; Konc, Janez

    2016-01-01

    Ligand-based virtual screening of large small-molecule databases is an important step in the early stages of drug development. It is based on the similarity principle and is used to reduce the chemical space of large databases to a manageable size where chosen ligands can be experimentally tested. Ligand-based virtual screening can also be used to identify bioactive molecules with different basic scaffolds compared to already known bioactive molecules, thus having the potential to increase the structural variability of compounds. Here, we present an interface between the popular molecular graphics system PyMOL and the ligand-based virtual screening software LiSiCA available at http://insilab.org/lisica-plugin and demonstrate how this interface can be used in the early stages of drug discovery process.Graphical AbstractLigand-based virtual screening interface between PyMOL and LiSiCA. PMID:27606012

  1. Homozygous YME1L1 mutation causes mitochondriopathy with optic atrophy and mitochondrial network fragmentation

    PubMed Central

    Hartmann, Bianca; Wai, Timothy; Hu, Hao; MacVicar, Thomas; Musante, Luciana; Fischer-Zirnsak, Björn; Stenzel, Werner; Gräf, Ralph; van den Heuvel, Lambert; Ropers, Hans-Hilger; Wienker, Thomas F; Hübner, Christoph; Langer, Thomas; Kaindl, Angela M

    2016-01-01

    Mitochondriopathies often present clinically as multisystemic disorders of primarily high-energy consuming organs. Assembly, turnover, and surveillance of mitochondrial proteins are essential for mitochondrial function and a key task of AAA family members of metalloproteases. We identified a homozygous mutation in the nuclear encoded mitochondrial escape 1-like 1 gene YME1L1, member of the AAA protease family, as a cause of a novel mitochondriopathy in a consanguineous pedigree of Saudi Arabian descent. The homozygous missense mutation, located in a highly conserved region in the mitochondrial pre-sequence, inhibits cleavage of YME1L1 by the mitochondrial processing peptidase, which culminates in the rapid degradation of YME1L1 precursor protein. Impaired YME1L1 function causes a proliferation defect and mitochondrial network fragmentation due to abnormal processing of OPA1. Our results identify mutations in YME1L1 as a cause of a mitochondriopathy with optic nerve atrophy highlighting the importance of YME1L1 for mitochondrial functionality in humans. DOI: http://dx.doi.org/10.7554/eLife.16078.001 PMID:27495975

  2. Myelin Basic Protein Cleaves Cell Adhesion Molecule L1 and Improves Regeneration After Injury.

    PubMed

    Lutz, David; Kataria, Hardeep; Kleene, Ralf; Loers, Gabriele; Chaudhary, Harshita; Guseva, Daria; Wu, Bin; Jakovcevski, Igor; Schachner, Melitta

    2016-07-01

    Myelin basic protein (MBP) is a serine protease that cleaves neural cell adhesion molecule L1 and generates a transmembrane L1 fragment which facilitates L1-dependent functions in vitro, such as neurite outgrowth, neuronal cell migration and survival, myelination by Schwann cells as well as Schwann cell proliferation, migration, and process formation. Ablation and blocking of MBP or disruption of its proteolytic activity by mutation of a proteolytically active serine residue abolish L1-dependent cellular responses. In utero injection of adeno-associated virus encoding proteolytically active MBP into MBP-deficient shiverer mice normalizes differentiation, myelination, and synaptogenesis in the developing postnatal spinal cord, in contrast to proteolytically inactive MBP. Application of active MBP to the injured wild-type spinal cord and femoral nerve augments levels of a transmembrane L1 fragment, promotes remyelination, and improves functional recovery after injury. Application of MBP antibody impairs recovery. Virus-mediated expression of active MBP in the lesion site after spinal cord injury results in improved functional recovery, whereas injection of virus encoding proteolytically inactive MBP fails to do so. The present study provides evidence for a novel L1-mediated function of MBP in the developing spinal cord and in the injured adult mammalian nervous system that leads to enhanced recovery after acute trauma. PMID:26081148

  3. Systemic Immunization with Papillomavirus L1 Protein Completely Prevents the Development of Viral Mucosal Papillomas

    NASA Astrophysics Data System (ADS)

    Suzich, Joann A.; Ghim, Shin-Je; Palmer-Hill, Frances J.; White, Wendy I.; Tamura, James K.; Bell, Judith A.; Newsome, Joseph A.; Bennett Jenson, A.; Schlegel, Richard

    1995-12-01

    Infection of mucosal epithelium by papillomaviruses is responsible for the induction of genital and oral warts and plays a critical role in the development of human cervical and oropharyngeal cancer. We have employed a canine model to develop a systemic vaccine that completely protects against experimentally induced oral mucosal papillomas. The major capsid protein, L1, of canine oral papillomavirus (COPV) was expressed in Sf9 insect cells in native conformation. L1 protein, which self-assembled into virus-like particles, was purified on CsCl gradients and injected intradermally into the foot pad of beagles. Vaccinated animals developed circulating antibodies against COPV and became completely resistant to experimental challenge with COPV. Successful immunization was strictly dependent upon native L1 protein conformation and L1 type. Partial protection was achieved with as little as 0.125 ng of L1 protein, and adjuvants appeared useful for prolonging the host immune response. Serum immunoglobulins passively transferred from COPV L1-immunized beagles to naive beagles conferred protection from experimental infection with COPV. Our results indicate the feasibility of developing a human vaccine to prevent mucosal papillomas, which can progress to malignancy.

  4. Frequent expression of PD-L1 on circulating breast cancer cells.

    PubMed

    Mazel, Martine; Jacot, William; Pantel, Klaus; Bartkowiak, Kai; Topart, Delphine; Cayrefourcq, Laure; Rossille, Delphine; Maudelonde, Thierry; Fest, Thierry; Alix-Panabières, Catherine

    2015-11-01

    Immune checkpoint regulators such as PD-L1 have become exciting new therapeutic targets leading to long lasting remissions in patients with advanced malignancies. However, in view of the remarkable costs and the toxicity profiles of these therapies, predictive biomarkers able to discriminate responders from non-responders are urgently needed. In the present paper, we provide evidence that PD-L1 is frequently expressed on metastatic cells circulating in the blood of hormone receptor-positive, HER2-negative breast cancer patients. We performed western blot, flow cytometry and immunocytochemical analyses to demonstrate the specificity of the PDL1 antibody used in our study and established immunoscores for PDL1 expression on single tumor cells. We then selected sixteen patients with circulating tumor cells (CTCs) using the CellSearch(®) system and found PD-L1((+)) CTCs in 11 patients (68.8%). The fraction of PD-L1((+)) CTCs varied from 0.2 to 100% in individual patients. This is the first report demonstrating the expression of PD-L1 on CTCs. The established CTC/PD-L1 assay can be used for liquid biopsy in future clinical trials for stratification and monitoring of cancer patients undergoing immune checkpoint blockade. PMID:26093818

  5. The clathrin adaptor Numb regulates intestinal cholesterol absorption through dynamic interaction with NPC1L1.

    PubMed

    Li, Pei-Shan; Fu, Zhen-Yan; Zhang, Ying-Yu; Zhang, Jin-Hui; Xu, Chen-Qi; Ma, Yi-Tong; Li, Bo-Liang; Song, Bao-Liang

    2014-01-01

    Hypercholesterolemia, typically due to excessive cholesterol uptake, is a major risk factor for cardiovascular disease, which is responsible for ∼50% of all deaths in developed societies. Although it has been shown that intestinal cholesterol absorption is mediated by vesicular endocytosis of the Niemann-Pick C1-like 1 (NPC1L1) protein, the mechanism of sterol-stimulated NPC1L1 internalization is still mysterious. Here, we identified an endocytic peptide signal, YVNXXF (where X stands for any amino acid), in the cytoplasmic C-terminal tail of NPC1L1. Cholesterol binding on the N-terminal domain of NPC1L1 released the YVNXXF-containing region of NPC1L1 from association with the plasma membrane and enabled Numb binding. We also found that Numb, a clathrin adaptor, specifically recognized this motif and recruited clathrin for internalization. Disrupting the NPC1L1-Numb interaction decreased cholesterol uptake. Ablation of Numb in mouse intestine significantly reduced dietary cholesterol absorption and plasma cholesterol level. Together, these data show that Numb is a pivotal protein for intestinal cholesterol absorption and may provide a therapeutic target for hypercholesterolemia. PMID:24336247

  6. Systemic immunization with papillomavirus L1 protein completely prevents the development of viral mucosal papillomas.

    PubMed Central

    Suzich, J A; Ghim, S J; Palmer-Hill, F J; White, W I; Tamura, J K; Bell, J A; Newsome, J A; Jenson, A B; Schlegel, R

    1995-01-01

    Infection of mucosal epithelium by papillomaviruses is responsible for the induction of genital and oral warts and plays a critical role in the development of human cervical and oropharyngeal cancer. We have employed a canine model to develop a systemic vaccine that completely protects against experimentally induced oral mucosal papillomas. The major capsid protein, L1, of canine oral papillomavirus (COPV) was expressed in Sf9 insect cells in native conformation. L1 protein, which self-assembled into virus-like particles, was purified on CsCl gradients and injected intradermally into the foot pad of beagles. Vaccinated animals developed circulating antibodies against COPV and became completely resistant to experimental challenge with COPV. Successful immunization was strictly dependent upon native L1 protein conformation and L1 type. Partial protection was achieved with as little as 0.125 ng of L1 protein, and adjuvants appeared useful for prolonging the host immune response. Serum immunoglobulins passively transferred from COPV L1-immunized beagles to naive beagles conferred protection from experimental infection with COPV. Our results indicate the feasibility of developing a human vaccine to prevent mucosal papillomas, which can progress to malignancy. Images Fig. 1 PMID:8524802

  7. Homozygous YME1L1 mutation causes mitochondriopathy with optic atrophy and mitochondrial network fragmentation.

    PubMed

    Hartmann, Bianca; Wai, Timothy; Hu, Hao; MacVicar, Thomas; Musante, Luciana; Fischer-Zirnsak, Björn; Stenzel, Werner; Gräf, Ralph; van den Heuvel, Lambert; Ropers, Hans-Hilger; Wienker, Thomas F; Hübner, Christoph; Langer, Thomas; Kaindl, Angela M

    2016-01-01

    Mitochondriopathies often present clinically as multisystemic disorders of primarily high-energy consuming organs. Assembly, turnover, and surveillance of mitochondrial proteins are essential for mitochondrial function and a key task of AAA family members of metalloproteases. We identified a homozygous mutation in the nuclear encoded mitochondrial escape 1-like 1 gene YME1L1, member of the AAA protease family, as a cause of a novel mitochondriopathy in a consanguineous pedigree of Saudi Arabian descent. The homozygous missense mutation, located in a highly conserved region in the mitochondrial pre-sequence, inhibits cleavage of YME1L1 by the mitochondrial processing peptidase, which culminates in the rapid degradation of YME1L1 precursor protein. Impaired YME1L1 function causes a proliferation defect and mitochondrial network fragmentation due to abnormal processing of OPA1. Our results identify mutations in YME1L1 as a cause of a mitochondriopathy with optic nerve atrophy highlighting the importance of YME1L1 for mitochondrial functionality in humans. PMID:27495975

  8. Doxorubicin blocks proliferation of cancer cells through proteolytic activation of CREB3L1

    PubMed Central

    Denard, Bray; Lee, Ching; Ye, Jin

    2012-01-01

    Doxorubicin is used extensively for chemotherapy of diverse types of cancer, yet the mechanism through which it inhibits proliferation of cancer cells remains unclear. Here we report that doxorubicin stimulates de novo synthesis of ceramide, which in turn activates CREB3L1, a transcription factor synthesized as a membrane-bound precursor. Doxorubicin stimulates proteolytic cleavage of CREB3L1 by Site-1 Protease and Site-2 Protease, allowing the NH2-terminal domain of CREB3L1 to enter the nucleus where it activates transcription of genes encoding inhibitors of the cell cycle, including p21. Knockdown of CREB3L1 mRNA in human hepatoma Huh7 cells and immortalized human fibroblast SV589 cells conferred increased resistance to doxorubicin, whereas overexpression of CREB3L1 in human breast cancer MCF-7 cells markedly enhanced the sensitivity of these cells to doxorubicin. These results suggest that measurement of CREB3L1 expression may be a useful biomarker in identifying cancer cells sensitive to doxorubicin. DOI: http://dx.doi.org/10.7554/eLife.00090.001 PMID:23256041

  9. Characterization of an RNA Aptamer Against HPV-16 L1 Virus-Like Particles

    PubMed Central

    Leija-Montoya, Ana Gabriela; Benítez-Hess, María Luisa; Toscano-Garibay, Julia Dolores

    2014-01-01

    The human papillomavirus (HPV) capsid is mainly composed of the L1 protein that can self-assemble into virus-like particles (VLPs) that are structurally and immunologically similar to the infectious virions. We report here the characterization of RNA aptamers that recognize baculovirus-produced HPV-16 L1 VLPs. Interaction and slot-blot binding assays showed that all isolated aptamers efficiently bound HPV-16 VLPs, although the Sc5-c3 aptamer showed the highest specificity and affinity (Kd=0.05 pM). Sc5-c3 secondary structure consisted of a hairpin with a symmetric bubble and an unstructured 3′end. Biochemical and genetic analyses showed that the Sc5-c3 main loop is directly involved on VLPs binding. In particular, binding specificity appeared mediated by five non-consecutive nucleotide positions. Experiments using bacterial-produced HPV-16 L1 resulted in low Sc5-c3 binding, suggesting that recognition of HPV-16 L1 VLPs relies on quaternary structure features not present in bacteria-produced L1 protein. Sc5-c3 produced specific and stable binding to HPV-16 L1 VLPs even in biofluid protein mixes and thus it may provide a potential diagnostic tool for active HPV infection. PMID:25111024

  10. Characterization of an RNA aptamer against HPV-16 L1 virus-like particles.

    PubMed

    Leija-Montoya, Ana Gabriela; Benítez-Hess, María Luisa; Toscano-Garibay, Julia Dolores; Alvarez-Salas, Luis Marat

    2014-10-01

    The human papillomavirus (HPV) capsid is mainly composed of the L1 protein that can self-assemble into virus-like particles (VLPs) that are structurally and immunologically similar to the infectious virions. We report here the characterization of RNA aptamers that recognize baculovirus-produced HPV-16 L1 VLPs. Interaction and slot-blot binding assays showed that all isolated aptamers efficiently bound HPV-16 VLPs, although the Sc5-c3 aptamer showed the highest specificity and affinity (Kd=0.05 pM). Sc5-c3 secondary structure consisted of a hairpin with a symmetric bubble and an unstructured 3'end. Biochemical and genetic analyses showed that the Sc5-c3 main loop is directly involved on VLPs binding. In particular, binding specificity appeared mediated by five non-consecutive nucleotide positions. Experiments using bacterial-produced HPV-16 L1 resulted in low Sc5-c3 binding, suggesting that recognition of HPV-16 L1 VLPs relies on quaternary structure features not present in bacteria-produced L1 protein. Sc5-c3 produced specific and stable binding to HPV-16 L1 VLPs even in biofluid protein mixes and thus it may provide a potential diagnostic tool for active HPV infection. PMID:25111024

  11. PD-1/PD-L1 blockade in cancer treatment: perspectives and issues.

    PubMed

    Hamanishi, Junzo; Mandai, Masaki; Matsumura, Noriomi; Abiko, Kaoru; Baba, Tsukasa; Konishi, Ikuo

    2016-06-01

    Recent studies showed that tumor cells 'edit' host immunity in several ways to evade immune defenses in the tumor microenvironment. This phenomenon is called "cancer immune escape." One of the most important components in this system is an immunosuppressive co-signal (immune checkpoint) mediated by the PD-1 receptor and its ligand, PD-L1. PD-1 is mainly expressed on activated T cells, whereas PD-L1 is expressed on several types of tumor cells. Preclinical studies have shown that inhibition of the interaction between PD-1 and PD-L1 enhances the T-cell response and mediates antitumor activity. Several clinical trials of PD-1/PD-L1 signal-blockade agents have exhibited dramatic antitumor efficacy in patients with certain types of solid or hematological malignancies. In this review, we highlight recent clinical trials using anti-PD-1 or anti-PD-L1 antibodies against several types of malignancies, including a trial conducted in our department, and describe the clinical perspectives and issues regarding the PD-1/PD-L1 blockade in cancer treatment. PMID:26899259

  12. PD-L1 (B7-H1) expression and the immune tumor microenvironment in primary and metastatic breast carcinomas.

    PubMed

    Cimino-Mathews, Ashley; Thompson, Elizabeth; Taube, Janis M; Ye, Xiaobu; Lu, Yao; Meeker, Alan; Xu, Haiying; Sharma, Rajni; Lecksell, Kristen; Cornish, Toby C; Cuka, Nathan; Argani, Pedram; Emens, Leisha A

    2016-01-01

    Programmed death ligand 1 (PD-L1) expression by tumor-infiltrating lymphocytes (TILs) and tumor cells in breast cancer has been reported, but the relationships between PD-L1 expression by TIL, carcinoma cells, and other immunologic features of the breast tumor microenvironment remain unclear. We therefore evaluated the interrelationships between tumor cell surface and TIL PD-L1 expression, lymphocyte subpopulations, and patterns of immune cell infiltration in cohorts of treatment-naive, primary breast cancers (PBCs) (n = 45) and matched PBC and metastatic breast cancers (MBC) (n = 26). Seventy-eight percent of untreated PBCs contained PD-L1(+) TILs, but only 21% had PD-L1(+) carcinoma cells. Carcinoma PD-L1 expression localized to the tumor invasive front and was associated with high tumor grade (P = .04). Eighty-nine percent of PD-L1(+) carcinomas contained brisk TIL infiltrates, compared to only 24% of PD-L1(-) carcinomas; this included CD3(+) (P = .02), CD4(+) (P = .04), CD8(+) (P = .002), and FoxP3(+) T cells (P = .02). PD-L1(+) PBCs were more likely to contain PD-L1(+) TIL than PD-L1(-) PBCs (P = .04). Peripheral lymphoid aggregates were present in 100% of PD-L1(+) compared to 41% of PD-L1(-) PBC (P < .001). No patient with PD-L1(+) PBC developed distant recurrence, compared to 15% of patients with PD-L1(-) PBC. For the matched PBC and MBC cohort, 2 patients (8%) had PD-L1(+) tumors, with 1 case concordant and 1 case discordant for carcinoma PD-L1 expression in the PBC and MBC. Our data support PD-L1 expression by tumor cells as a biomarker of active breast tumor immunity and programmed death 1 blockade as a therapeutic strategy for breast cancer. PMID:26527522

  13. SigMol: repertoire of quorum sensing signaling molecules in prokaryotes.

    PubMed

    Rajput, Akanksha; Kaur, Karambir; Kumar, Manoj

    2016-01-01

    Quorum sensing is a widespread phenomenon in prokaryotes that helps them to communicate among themselves and with eukaryotes. It is driven through quorum sensing signaling molecules (QSSMs) in a density dependent manner that assists in numerous biological functions like biofilm formation, virulence factors secretion, swarming motility, bioluminescence, etc. Despite immense implications, dedicated resources of QSSMs are lacking. Therefore, we have developed SigMol (http://bioinfo.imtech.res.in/manojk/sigmol), a specialized repository of these molecules in prokaryotes. SigMol harbors information on QSSMs pertaining to different quorum sensing signaling systems namely acylated homoserine lactones (AHLs), diketopiperazines (DKPs), 4-hydroxy-2-alkylquinolines (HAQs), diffusible signal factors (DSFs), autoinducer-2 (AI-2) and others. Database contains 1382: entries of 182: unique signaling molecules from 215: organisms. It encompasses biological as well as chemical aspects of signaling molecules. Biological information includes genes, preliminary bioassays, identification assays and applications, while chemical detail comprises of IUPAC name, SMILES and structure. We have provided user-friendly browsing and searching facilities for easy data retrieval and comparison. We have gleaned information of diverse QSSMs reported in literature at a single platform 'SigMol'. This comprehensive resource will assist the scientific community in understanding intraspecies, interspecies or interkingdom networking and further help to unfold different facets of quorum sensing and related therapeutics. PMID:26490957

  14. Temperature induced modulation of lipid oxidation and lipid accumulation in palmitate-mediated 3T3-L1 adipocytes and 3T3-L1 adipocytes.

    PubMed

    Lin, Xiaofen; Li, Yi; Leung, Polly Hangmei; Li, Jiashen; Hu, Junyan; Liu, Xuan; Li, Zhi

    2016-05-01

    Human skin temperature can vary widely depending on anatomical location and ambient temperature. It is also known that local changes in skin and subcutaneous temperature can affect fat metabolism. This study aimed to explore the potential effects of surrounding thermal environment on fat by investigating cell viability, lipid oxidation, and lipid accumulation in 3T3-L1 adipocytes and palmitate-treated adipocytes after 4h incubation. No significant differences of viability in 3T3-L1 adipocytes were detected under different temperature conditions. Despite no significant increase being observed under warm temperature (39°C) conditions, a similarly significant suppression of intracellular reactive oxygen species (ROS) and lipid peroxidation were found in 3T3-L1 adipocytes and palmitate-treated adipocytes under 4h exposure to cooler temperatures of 31-33°C (P<0.01). ROS, chemically reactive molecules containing oxygen, are currently understood to be a major contributor to oxidantive stress in obesity. Additionally, cooler temperatures (31-33°C) could improve the size of lipid droplets in 3T3-L1 adipocytes (P<0.01), but no significant effect was generated by temperature change on lipid droplets in palmitate-treated adipocytes. In the palmitate-induced adiposity model, although excessive ROS and lipid peroxidation has been attenuated by temperature decrease (P<0.01), it still does not positively modulate lipid droplet size (P>0.05) and remedy the palmitate damage induced cell death (P<0.01). These findings provide preliminary support for potential interventions based on temperature manipulation for cell metabolism of adipocytes. PMID:27157327

  15. Efficient minimum error bounded particle resampling L1 tracker with occlusion detection.

    PubMed

    Mei, Xue; Ling, Haibin; Wu, Yi; Blasch, Erik P; Bai, Li

    2013-07-01

    Recently, sparse representation has been applied to visual tracking to find the target with the minimum reconstruction error from a target template subspace. Though effective, these L1 trackers require high computational costs due to numerous calculations for l1 minimization. In addition, the inherent occlusion insensitivity of the l1 minimization has not been fully characterized. In this paper, we propose an efficient L1 tracker, named bounded particle resampling (BPR)-L1 tracker, with a minimum error bound and occlusion detection. First, the minimum error bound is calculated from a linear least squares equation and serves as a guide for particle resampling in a particle filter (PF) framework. Most of the insignificant samples are removed before solving the computationally expensive l1 minimization in a two-step testing. The first step, named τ testing, compares the sample observation likelihood to an ordered set of thresholds to remove insignificant samples without loss of resampling precision. The second step, named max testing, identifies the largest sample probability relative to the target to further remove insignificant samples without altering the tracking result of the current frame. Though sacrificing minimal precision during resampling, max testing achieves significant speed up on top of τ testing. The BPR-L1 technique can also be beneficial to other trackers that have minimum error bounds in a PF framework, especially for trackers based on sparse representations. After the error-bound calculation, BPR-L1 performs occlusion detection by investigating the trivial coefficients in the l1 minimization. These coefficients, by design, contain rich information about image corruptions, including occlusion. Detected occlusions are then used to enhance the template updating. For evaluation, we conduct experiments on three video applications: biometrics (head movement, hand holding object, singers on stage), pedestrians (urban travel, hallway monitoring), and

  16. Origin of the human L1 elements: proposed progenitor genes deduced from a consensus DNA sequence.

    PubMed

    Scott, A F; Schmeckpeper, B J; Abdelrazik, M; Comey, C T; O'Hara, B; Rossiter, J P; Cooley, T; Heath, P; Smith, K D; Margolet, L

    1987-10-01

    A consensus sequence for the human long interspersed repeated DNA element, L1Hs (LINE or KpnI sequence), is presented. The sequence contains two open reading frames (ORFs) which are homologous to ORFs in corresponding regions of L1 elements in other species. The L1Hs ORFs are separated by a small evolutionarily nonconserved region. The 5' end of the consensus contains frequent terminators in all three reading frames and has a relatively high GC content with numerous stretches of weak homology with AluI repeats. The 5' ORF extends for a minimum of 723 bp (241 codons). The 3' ORF is 3843 bp (1281 codons) and predicts a protein of 149 kD which has regions of weak homology to the polymerase domain of various reverse transcriptases. The 3' end of the consensus has a 208-bp nonconserved region followed by an adenine-rich end. The organization of the L1Hs consensus sequence resembles the structure of eukaryotic mRNAs except for the noncoding region between ORFs. However, due to base substitutions or truncation most elements appear incapable of producing mRNA that can be translated. Our observation that individual elements cluster into subfamilies on the basis of the presence or absence of blocks of sequence, or by the linkage of alternative bases at multiple positions, suggests that most L1 sequences were derived from a small number of structural genes. An estimate of the mammalian L1 substitution rate was derived and used to predict the age of individual human elements. From this it follows that the majority of human L1 sequences have been generated within the last 30 million years. The human elements studied here differ from each other, yet overall the L1Hs sequences demonstrate a pattern of species-specificity when compared to the L1 families of other mammals. Possible mechanisms that may account for the origin and evolution of the L1 family are discussed. These include pseudogene formation (retroposition), transposition, gene conversion, and RNA recombination. PMID

  17. "I'm on it 24/7 at the moment": A qualitative examination of multi-screen viewing behaviours among UK 10-11 year olds

    PubMed Central

    2011-01-01

    Background Screen-viewing has been associated with increased body mass, increased risk of metabolic syndrome and lower psychological well-being among children and adolescents. There is a shortage of information about the nature of contemporary screen-viewing amongst children especially given the rapid advances in screen-viewing equipment technology and their widespread availability. Anecdotal evidence suggests that large numbers of children embrace the multi-functionality of current devices to engage in multiple forms of screen-viewing at the same time. In this paper we used qualitative methods to assess the nature and extent of multiple forms of screen-viewing in UK children. Methods Focus groups were conducted with 10-11 year old children (n = 63) who were recruited from five primary schools in Bristol, UK. Topics included the types of screen-viewing in which the participants engaged; whether the participants ever engaged in more than one form of screen-viewing at any time and if so the nature of this multiple viewing; reasons for engaging in multi-screen-viewing; the room within the house where multi-screen-viewing took place and the reasons for selecting that room. All focus groups were transcribed verbatim, anonymised and thematically analysed. Results Multi-screen viewing was a common behaviour. Although multi-screen viewing often involved watching TV, TV viewing was often the background behaviour with attention focussed towards a laptop, handheld device or smart-phone. There were three main reasons for engaging in multi-screen viewing: 1) tempering impatience that was associated with a programme loading; 2) multi-screen facilitated filtering out unwanted content such as advertisements; and 3) multi-screen viewing was perceived to be enjoyable. Multi-screen viewing occurred either in the child's bedroom or in the main living area of the home. There was considerable variability in the level and timing of viewing and this appeared to be a function of whether

  18. HPV16L1-attenuated Shigella recombinant vaccine induced strong vaginal and systemic immune responses in guinea pig model

    PubMed Central

    Yan, Xiaofei; Wang, Depu; Liang, Fengli; Fu, Ling; Guo, Cheng

    2014-01-01

    Though human papillomavirus (HPV) vaccines based on L1 virus-like particles (VLPs) have excellent protective effect against HPV-induced cervical cancer, they are too expensive to be afforded by the developing countries, where most cases of cervical cancer occur. A live bacterial-based vaccine could be an inexpensive alternative. The aim of this study was to evaluate the potential value of live attenuated Shigella. flexneri 2a sc602 strain-based HPV16L1 as a high-efficiency, low-cost HPV16L1 mucosal vaccine. Recombinant sc602/L1 vaccine induced high L1-specific systemic and mucosal immune responses as well as cell-mediated Th1 and Th2 immune responses in guinea pig model. Sc602/L1 vaccine induced higher L1-specific IgG and IgA antibodies as well as HPV16-neutralizing antibodies in genital region in sc602/L1 mucosal immunized animals than in L1 intramuscular immunized animals. Though both are via mucosal delivery, immunized sc602/L1 vaccine by rectum route induced higher L1-specific IgA and IgG titers in genital region than by conjunctiva route. In addition, sc602/L1 also strongly increased L1-specific IFN-γ and IL-4 expression, implying its effect on cell-mediated immune response. HPV16L1 was expressed in sc602 bacteria and their biologic characteristics were detected by immunoblot, electron microscope and HeLa cell invasion assay. Guinea pigs were immunized with sc602L1 through conjunctiva (i.c.) or rectum (i.r.). Mucosal and systemic immune responses were detected by ELISA, ELISPOT and Neutralization activity assays. Strong mucosal and systemic immune responses were induced by sc602/L1 vaccine. This study provides evidence that sc602/L1 vaccine may have protective effect on HPV infection. PMID:25483698

  19. PD-1, PD-L1 and PD-L2 expression in mouse prostate cancer

    PubMed Central

    Yang, Shijie; Zhang, Qiuyang; Liu, Sen; Wang, Alun R; You, Zongbing

    2016-01-01

    Programmed cell death protein 1 (PD-1) and its ligands PD-L1 and PD-L2 play critical roles in maintaining an immunosuppressive tumor microenvironment. The purpose of the present study was to assess expression of PD-1, PD-L1, and PD-L2 in mouse prostate tumors. A total of 33 mouse prostate tumors derived from Pten-null mice were examined using immunohistochemical staining for PD-1, PD-L1, and PD-L2. The animals were either with interleukin-17 receptor c (Il-17rc) wild-type or knockout genotype, or fed with regular diet or high-fat diet to 30 weeks of age. We found that Il-17rc wild-type mouse prostate tumors had significantly higher levels of PD-1, PD-L1, and PD-L2 than Il-17rc knockout mouse prostate tumors. High-fat diet-induced obese mice had significantly higher levels of PD-1, PD-L1, and PD-L2 in their prostate tumors than lean mice fed with regular diet. Increased expression of PD-1, PD-L1, and PD-L2 was associated with increased number of invasive prostate tumors formed in the Il-17rc wild-type and obese mice compared to the Il-17rc knockout and lean mice, respectively. Our findings suggest that expression of PD-1, PD-L1, and PD-L2 may enhance development of mouse prostate cancer through creating an immunosuppressive tumor microenvironment. PMID:27069956

  20. ATG16L1 T300A Polymorphism is Correlated with Gastric Cancer Susceptibility.

    PubMed

    Burada, Florin; Ciurea, Marius Eugen; Nicoli, Raluca; Streata, Ioana; Vilcea, Ionica Dan; Rogoveanu, Ion; Ioana, Mihai

    2016-04-01

    Gastric cancer is a major leading cause of cancer-related death in both sexes in Europe. The role of autophagy process in carcinogenesis remains unclear and there is increasing evidence that Helicobacter pylori is a key player in modulating autophagy in gastric carcinogenesis. The aim of this study was to assess the potential association of ATG16L1 T300A polymorphism with susceptibility of gastric cancer, and further to analyze the expression profile of ATG16L1 gene in paired tumoral and peritumoral gastric tissue. A total of 108 patients diagnosed with gastric cancer and 242 healthy controls were enrolled. ATG16L1 T300A polymorphism was detected using TaqMan genotyping assay containing primers and specific probes for A and G allele, respectively. ATG16L1 mRNA level was evaluated in 34 paired tumoral and peritumoral tissues using qRT-PCR. We found a significant association for both carriers of AG (OR 0.52, 95 % CI: 0.30-0.91, p = 0.02) and GG genotype (OR 0.53, 95 % CI: 0.28-0.98, p = 0.043), these were at a lower risk for gastric cancer when compared with the wild-type AA genotype. The strongest association was observed in a dominant model, the carriers of G allele were protected against gastric cancer (OR 0.52, 95 % CI: 0.13-0.88, p = 0.013). In a stratified analyse, the association was limited to non-cardia type and intestinal type. ATG16L1 gene expression was detected in both tumor and peritumoral tissues, with the mRNA-ATG16L1 levels significantly higher in tumor sample. Our results suggest that ATG16L1 T300A polymorphism may be associated with gastric carcinogenesis. PMID:26547861

  1. OmpL1 Is an Extracellular Matrix- and Plasminogen-Interacting Protein of Leptospira spp.

    PubMed Central

    Fernandes, Luis G. V.; Vieira, Monica L.; Kirchgatter, Karin; Alves, Ivy J.; de Morais, Zenaide M.; Vasconcellos, Silvio A.; Romero, Eliete C.

    2012-01-01

    Leptospirosis is a zoonosis with multisystem involvement caused by pathogenic strains of the genus Leptospira. OmpL1 is an outer membrane protein of Leptospira spp. that is expressed during infection. In this work, we investigated novel features of this protein. We describe that OmpL1 is a novel leptospiral extracellular matrix (ECM)-binding protein and a plasminogen (PLG) receptor. The recombinant protein was expressed in Escherichia coli BL21(DE3) Star/pLysS as inclusion bodies, refolded, and purified by metal-chelating chromatography. The protein presented a typical β-strand secondary structure, as evaluated by circular dichroism spectroscopy. The recombinant protein reacted with antibodies in serum samples from convalescent leptospirosis patients with a high specificity compared to serum samples from individuals with unrelated diseases. These data strengthen the usefulness of OmpL1 as a diagnostic marker of leptospirosis. The characterization of the immunogenicity of recombinant OmpL1 in inoculated BALB/c mice showed that the protein has the capacity to elicit humoral and cellular immune responses, as denoted by high antibody titers and the proliferation of lymphocytes. We demonstrate that OmpL1 has the ability to mediate attachment to laminin and plasma fibronectin, with KD (equilibrium dissociation constant) values of 2,099.93 ± 871.03 nM and 1,239.23 ± 506.85 nM, respectively. OmpL1 is also a PLG receptor, with a KD of 368.63 ± 121.23 nM, capable of generating enzymatically active plasmin. This is the first report that shows and characterizes OmpL1 as an ECM-interacting and a PLG-binding protein of Leptospira spp. that may play a role in bacterial pathogenesis when expressed during infection. PMID:22802342

  2. Targeting the vaccinia virus L1 protein to the cell surface enhances production of neutralizing antibodies.

    PubMed

    Golden, Joseph W; Josleyn, Matthew D; Hooper, Jay W

    2008-06-25

    The current live-orthopoxvirus vaccine is associated with minor to serious adverse affects, and is contraindicated for use in a significant portion of the population. As an alternative vaccine, we have previously shown that a DNA subunit vaccine (4pox) based on four orthopoxvirus immunogens (L1R, B5R, A27L and A33R) can produce protective immunity against lethal orthopoxvirus challenges in mice and nonhuman primates. Because antibodies are critical for protection against secondary orthopoxvirus infections, we are now interested in strategies that will enhance the humoral immune response against vaccine targets. Here, we tested the immunogenicity of an L1R construct to which a tissue plasminogen activator signal sequence was placed in frame with the full-length L1R gene. The tPA-L1R construct produced a more robust neutralizing antibody response in vaccinated mice when the DNA vaccine was administered by gene-gun as a prime/single boost. When the tPA-L1R construct was substituted for the unmodified L1R gene in the 4pox vaccine, given as a prime and single boost, animals were better protected from lethal challenge with vaccinia virus (VACV). These findings indicate that adding a tPA-leader sequence can enhance the immunogenicity of the L1R gene when given as a DNA vaccine. Furthermore, our results demonstrate that a DNA-based vaccine is capable of establishing protection from lethal orthopoxvirus challenges when administered as a prime and single boost without requiring adjuvant. PMID:18485547

  3. PD-L1 expression is associated with massive lymphocyte infiltration and histology in gastric cancer.

    PubMed

    Li, Zhongwu; Lai, Yumei; Sun, Li; Zhang, Xiaotian; Liu, Ruping; Feng, Guoshuang; Zhou, Lixin; Jia, Lin; Huang, Xiaozheng; Kang, Qiang; Lin, Dongmei; Gao, Jing; Shen, Lin

    2016-09-01

    The mechanism of carcinogenesis of gastric cancer (GC) is still unclear now. This study aimed to explore the correlations among PD-L1, Epstein-Barr virus (EBV) infection, lymphocyte infiltration, HER2 expression, HER2 gene status, histology, and other clinicopathological factors in GC. A total of 44 GC patients with massive lymphocyte infiltration (GC-MLI) and 93 GC patients without massive lymphocyte infiltration were involved in this study. Immunohistochemical analysis was used to test the expression levels of PD-L1 and HER2. Fluorescence in situ hybridization was used on HER2-positive cases with a score of 2+ to test the HER2 gene status. EBV-encoded RNA was used to test for EBV infection. In univariate analysis, PD-L1 expression was significantly associated with GC-MLI (P<.001), lower age (P=.019), EBV infection (P<.001), lower HER2 expression (P=.011), and diffuse/mixed type of histology (P=.022). EBV-encoded RNA-positive cases were significantly associated with GC-MLI (P<.001), lower age (P=.016), diffuse/mixed type of histology (P=.011), and lower HER2 expression (P=.032). In the multivariate logistic regression model, GC-MLI and the diffuse/mixed type histology were identified as 2 independent factors that affected PD-L1 expression (P<.001). Furthermore, PD-L1-positive cases have worse overall survival than do PD-L1-negative cases (P=.011). These results suggest that massive lymphocyte infiltration and the diffuse/mixed type histology of GC should be taken into consideration to select the appropriate patients for PD-L1 inhibitory treatment in the future. PMID:27260946

  4. Epitope characterization of an anti-PD-L1 antibody using orthogonal approaches.

    PubMed

    Hao, Gang; Wesolowski, John S; Jiang, Xuliang; Lauder, Scott; Sood, Vanita D

    2015-04-01

    The binding of programmed death ligand 1 protein (PD-L1) to its receptor programmed death protein 1 (PD-1) mediates immunoevasion in cancer and chronic viral infections, presenting an important target for therapeutic intervention. Several monoclonal antibodies targeting the PD-L1/PD-1 signaling axis are undergoing clinical trials; however, the epitopes of these antibodies have not been described. We have combined orthogonal approaches to localize and characterize the epitope of a monoclonal antibody directed against PD-L1 at good resolution and with high confidence. Limited proteolysis and mass spectrometry were applied to reveal that the epitope resides in the first immunoglobulin domain of PD-L1. Hydrogen-deuterium exchange mass spectrometry (HDX-MS) was used to identify a conformational epitope comprised of discontinuous strands that fold to form a beta sheet in the native structure. This beta sheet presents an epitope surface that significantly overlaps with the PD-1 binding interface, consistent with a desired PD-1 competitive mechanism of action for the antibody. Surface plasmon resonance screening of mutant PD-L1 variants confirmed that the region identified by HDX-MS is critical for the antibody interaction and further defined specific residues contributing to the binding energy. Taken together, the results are consistent with the observed inhibitory activity of the antibody on PD-L1-mediated immune evasion. This is the first report of an epitope for any antibody targeting PD-L1 and demonstrates the power of combining orthogonal epitope mapping techniques. PMID:25664688

  5. Production and characterization of a monoclonal antibody against recombinant cathepsin L1 of Fasciola gigantica.

    PubMed

    Anuracpreeda, Panat; Srirakam, Thippawan; Pandonlan, Sudarat; Changklungmoa, Narin; Chotwiwatthanakun, Charoonroj; Tinikul, Yotsawan; Poljaroen, Jaruwan; Meemon, Krai; Sobhon, Prasert

    2014-08-01

    Monoclonal antibodies (MoAbs) against a recombinant cathepsin L1 of Fasciola gigantica (rFgCatL1) were produced in vitro by fusion of BALB/c mice spleen cells immunized with rFgCatL1 and mouse myeloma cells. Reactivity and specificity of these MoAbs were evaluated by indirect ELISA and immunoblotting techniques. Seven MoAb clones were selected from the stable hybridoma clones, namely 1E10, 1F5, 3D11, 4B10, 4D3, 4E3 and 5E7. Clones 1E10, 1F5 and 3D11 were IgM, whereas clones 4B10, 4D3, 4E3 and 5E7 were IgG1. All MoAbs had kappa light chain isotypes. All MoAbs reacted with rCatL1 at molecular weight (MW) 30kDa and with the native CatL1 at MW 27kDa in whole body (WB) extracts of metacercariae (Met), newly excysted juveniles (NEJ), 1, 3, 5-week-old juveniles (Ju), adult WB and adult excretory-secretory (ES) fractions, but not with adult tegumental antigens (TA). All of these MoAbs showed no cross-reactions with antigens of other parasites commonly found in ruminants and human, including Paramphistomum cervi, Eurytrema pancreaticum, Gigantocotyle explanatum, Schistosoma spindale, Schistosoma mansoni, Moniezia benedeni, Avitellina centripunctata, Trichuris sp., Haemonchus placei and Setaria labiato-papillosa. Localization of CatL1 in each developmental stages of F. gigantica by immunoperoxidase technique, using these MoAbs as probes, indicated that CatL1 was present at high concentration in the caecal epithelium and caecal lumen of metacercariae, NEJ, 1, 3, 5-week-old juveniles and adult fluke. This finding indicated that CatL1 is a copiously expressed parasite protein that is released into the ES, thus CatL1 and its MoAb could be a good candidate for immunodiagnosis of fasciolosis in ruminant and human. PMID:24736227

  6. The effect of myostatin on proliferation and lipid accumulation in 3T3-L1 preadipocytes.

    PubMed

    Zhu, Hui Juan; Pan, Hui; Zhang, Xu Zhe; Li, Nai Shi; Wang, Lin Jie; Yang, Hong Bo; Gong, Feng Ying

    2015-06-01

    Myostatin is a critical negative regulator of skeletal muscle development, and has been reported to be involved in the progression of obesity and diabetes. In the present study, we explored the effects of myostatin on the proliferation and differentiation of 3T3-L1 preadipocytes by using 3-[4,5-dimethylthiazol-2-yl] 2,5-diphenyl tetrazolium bromide spectrophotometry, intracellular triglyceride (TG) assays, and real-time quantitative RT-PCR methods. The results indicated that recombinant myostatin significantly promoted the proliferation of 3T3-L1 preadipocytes and the expression of proliferation-related genes, including Cyclin B2, Cyclin D1, Cyclin E1, Pcna, and c-Myc, and IGF1 levels in the medium of 3T3-L1 were notably upregulated by 35.2, 30.5, 20.5, 33.4, 51.2, and 179% respectively (all P<0.01) in myostatin-treated 3T3-L1 cells. Meanwhile, the intracellular lipid content of myostatin-treated cells was notably reduced as compared with the non-treated cells. Additionally, the mRNA levels of Pparγ, Cebpα, Gpdh, Dgat, Acs1, Atgl, and Hsl were significantly downregulated by 22-76% in fully differentiated myostatin-treated adipocytes. Finally, myostatin regulated the mRNA levels and secretion of adipokines, including Adiponectin, Resistin, Visfatin, and plasminogen activator inhibitor-1 (PAI-1) in 3T3-L1 adipocytes (all P<0.001). Above all, myostatin promoted 3T3-L1 proliferation by increasing the expression of cell-proliferation-related genes and by stimulating IGF1 secretion. Myostatin inhibited 3T3-L1 adipocyte differentiation by suppressing Pparγ and Cebpα expression, which consequently deceased lipid accumulation in 3T3-L1 cells by inhibiting the expression of critical lipogenic enzymes and by promoting the expression of lipolytic enzymes. Finally, myostatin modulated the expression and secretion of adipokines in fully differentiated 3T3-L1 adipocytes. PMID:25878062

  7. Expression and characterization of HPV-16 L1 capsid protein in Pichia pastoris

    PubMed Central

    Bazan, Silvia Boschi; de Alencar Muniz Chaves, Agtha; Aires, Karina Araújo; Cianciarullo, Aurora Marques; Garcea, Robert L.; Ho, Paulo Lee

    2013-01-01

    Human papillomaviruses (HPVs) are responsible for the most common human sexually transmitted viral infections. Infection with high-risk HPVs, particularly HPV16, is associated with the development of cervical cancer. The papillomavirus L1 major capsid protein, the basis of the currently marketed vaccines, self-assembles into virus-like particles (VLPs). Here, we describe the expression, purification and characterization of recombinant HPV16 L1 produced by a methylotrophic yeast. A codon-optimized HPV16 L1 gene was cloned into a non-integrative expression vector under the regulation of a methanol-inducible promoter and used to transform competent Pichia pastoris cells. Purification of L1 protein from yeast extracts was performed using heparin–sepharose chromatography, followed by a disassembly/reassembly step. VLPs could be assembled from the purified L1 protein, as demonstrated by electron microscopy. The display of conformational epitopes on the VLPs surface was confirmed by hemagglutination and hemagglutination inhibition assays and by immuno-electron microscopy. This study has implications for the development of an alternative platform for the production of a papillomavirus vaccine that could be provided by public health programs, especially in resource-poor areas, where there is a great demand for low-cost vaccines. PMID:19756360

  8. L1 literacy affects L2 pronunciation intake and text vocalization

    NASA Astrophysics Data System (ADS)

    Walton, Martin

    2005-04-01

    For both deaf and hearing learners, L1 acquisition calls on auditive, gestural and visual modes in progressive processes over longer stages imposed in strictly anatomical and social order from the earliest pre-lexical phase [Jusczyk (1993), Kuhl & Meltzoff (1996)] to ultimate literacy. By contrast, L2 learning will call on accelerating procedures but with restricted input, arbitrated by L1 literacy as can be traced in the English of French-speaking learners, whether observed in spontaneous speech or in text vocalization modes. An inventory of their predictable omissions, intrusions and substitutions at suprasegmental and syllabic levels, many of which they can actually hear while unable to vocalize in real-time, suggests that a photogenic segmentation of continuous speech into alphabetical units has eclipsed the indispensable earlier phonogenic module, filtering L2 intake and output. This competing mode analysis hypothesizes a critical effect on L2 pronunciation of L1 graphemic procedures acquired usually before puberty, informing data for any Critical Period Hypothesis or amounts of L1 activation influencing L2 accent [Flege (1997, 1998)] or any psychoacoustic French deafness with regard to English stress-timing [Dupoux (1997)]. A metaphonic model [Howell & Dean (1991)] adapted for French learners may remedially distance L1 from L2 vocalization procedures.

  9. TLR3 triggering regulates PD-L1 (CD274) expression in human neuroblastoma cells.

    PubMed

    Boes, Marianne; Meyer-Wentrup, Friederike

    2015-05-28

    Neuroblastoma is the most common extracranial solid tumor in children, causing 12% of all pediatric cancer mortality. Neuroblastoma specific T-cells have been detected in patients, but usually fail to attack and eradicate the tumors. Tumor immune evasion may thus play an important role in neuroblastoma pathogenicity. Recent research in adult cancer patients shows that targeting T-cell check-point molecules PD-1/PD-L1 (or CD279/CD274) may bolster immune reactivity against solid tumors. Also, infections can be associated with spontaneous neuroblastoma regression. In our current study, we therefore investigated if antibody targeting of PD-L1 and triggering of selective pathogen-receptor Toll-like receptors (TLRs) potentiates immunogenicity of neuroblastoma cells. We find this to be the case. TLR3 triggering induced strong upregulation of both MHC class I and PD-L1 on neuroblastoma cells. At the same time TGF-β levels decreased and IL-8 secretion was induced. The combined neuroblastoma cell treatment using PD-L1 blockade and TLR3 triggering using virus analog poly(I:C) moreover induced CD4(+) and CD8(+) T-cell activation. Thus, we propose combined treatment using PD-L1 blockade with synthetic TLR ligands as an avenue toward new immunotherapy against human neuroblastoma. PMID:25697485

  10. VDR/vitamin D receptor regulates autophagic activity through ATG16L1.

    PubMed

    Sun, Jun

    2016-06-01

    The Paneth cell is a unique intestinal epithelial cell that can sense the gut microbiome and secrete anti-microbial peptides, thereby playing critical roles in the maintenance of homeostasis at the intestinal-microbial interface. These roles in regulating innate immunity and intestinal microbial ecology are dependent on a functional autophagy pathway through ATG16L1. ATG16L1 is a regulator for autophagy and a risk gene for inflammatory bowel disease (IBD). We demonstrated that a low VDR/vitamin D receptor level in the intestine is associated with abnormal Paneth cells, impaired autophagy function, and imbalanced bacterial profile (dysbiosis), accompanied by a reduction of ATG16L1. We determined that VDR transcriptionally regulates ATG16L1 as a VDR target gene. Administration of the bacterial product butyrate increases intestinal VDR expression and suppresses inflammation in a colitis model. Thus, our study indicates that VDR may be a determinant of IBD risk through its actions on ATG16L1. These insights can be leveraged to define therapeutic targets for restoring Paneth cells and autophagy through VDR in chronic inflammation. It may also have applicability for infectious diseases and autoimmune diseases associated with skin or lung, where the host is in contact with bacteria. PMID:26218741

  11. [Mode of action of plantaricin L-1, an antilisteria bacteriocin produced by Lactobacillus plantarum].

    PubMed

    Zhou, Wei; Liu, Guo-rong; Li, Ping-lan; Dai, Yun-qing; Zhou, Kang

    2007-04-01

    Plantaricin L-1, an anti-Listeria bacteriocin, was produced by Lactobacillus plantarum and successfully purified by SP-Sepharose FF cation exchange chromatography. The mechanism on energized cells of Listeria monocytogenes was studied with purified plantaricin L-1. After adding plantaricin L-1 to Listeria monocytogenes at 64 AU/mL, leakage of intercellular K+ ions, inorganic phosphate, lactic dehydrogenase, UV-absorbing materials and the intracellular ATP was observed, and the action resulted in the dissipation of the membrane potential (delta psi) and pH gradient (delta psi), two components of the proton motive force (PMF). All the data suggested that the primary site of action of plantaricin L-1 was the cytoplasmic membrane of sensitive cells. By forming the nonselective pores which leak ions and small organic compounds plantaricin L-1 induced the cells death, this action was similar to membrane corruption caused by peptide effect. Penetrability increased due to the enlarged pore and dysfuction of membrane transporters, which ensured efficient killing of target bacteria. PMID:17552231

  12. Epac, not PKA catalytic subunit, is required for 3T3-L1 preadipocyte differentiation.

    PubMed

    Ji, Zhenyu; Mei, Fang C; Cheng, Xiaodong

    2010-01-01

    Cyclic AMP plays a critical role in adipocyte differentiation and maturation. However, it is not clear which of the two intracellular cAMP receptors, exchange protein directly activated by cAMP/cAMP-regulated guanine nucleotide exchange factor or protein kinase A/cAMP-dependent protein kinase, is essential for cAMP-mediated adipocyte differentiation. In this study, we utilized a well-defined adipose differentiation model system, the murine preadipocyte line 3T3-L1, to address this issue. We showed that knocking down Epac expression in 3T3-L1 cells using lentiviral based small hairpin RNAs down-regulated peroxisome proliferator-activated receptor gamma expression and dramatically inhibited adipogenic conversion of 3T3-L1 cells while inhibiting PKA catalytic subunit activity by two mechanistically distinct inhibitors, heat stable protein kinase inhibitor and H89, had no effect on 3T3-L1 adipocyte differentiation. Moreover, cAMP analog selectively activating Epac was not able to stimulate adipogenic conversion. Our study demonstrated that while PKA catalytic activity is dispensable, activation of Epac is necessary but not sufficient for adipogenic conversion of 3T3-L1 cells. PMID:20036887

  13. MYC regulates the antitumor immune response through CD47 and PD-L1.

    PubMed

    Casey, Stephanie C; Tong, Ling; Li, Yulin; Do, Rachel; Walz, Susanne; Fitzgerald, Kelly N; Gouw, Arvin M; Baylot, Virginie; Gütgemann, Ines; Eilers, Martin; Felsher, Dean W

    2016-04-01

    The MYC oncogene codes for a transcription factor that is overexpressed in many human cancers. Here we show that MYC regulates the expression of two immune checkpoint proteins on the tumor cell surface: the innate immune regulator CD47 (cluster of differentiation 47) and the adaptive immune checkpoint PD-L1 (programmed death-ligand 1). Suppression of MYC in mouse tumors and human tumor cells caused a reduction in the levels of CD47 and PD-L1 messenger RNA and protein. MYC was found to bind directly to the promoters of the Cd47 and Pd-l1 genes. MYC inactivation in mouse tumors down-regulated CD47 and PD-L1 expression and enhanced the antitumor immune response. In contrast, when MYC was inactivated in tumors with enforced expression of CD47 or PD-L1, the immune response was suppressed, and tumors continued to grow. Thus, MYC appears to initiate and maintain tumorigenesis, in part, through the modulation of immune regulatory molecules. PMID:26966191

  14. VizieR Online Data Catalog: ExoMol line list for KCl (Barton+, 2014)

    NASA Astrophysics Data System (ADS)

    Barton, E. J.; Chui, C.; Golpayegani, S.; Yurchenko, S. N.; Tennyson, J.; Frohman, D. J.; Bernath, P. F.

    2014-03-01

    The files comprising this line list are in the standard ExoMol format, and are named sXXkYYcl.dat and tXXkYYcl.dat, where XX and YY are the mass numbers of the potassium and chlorine isotopes, respectively. The isotopologues covered are: (39K)(35Cl), (39K)(37Cl), (41K)(35Cl) and (41K)(37Cl). The partition functions from 1-3000K in 1K intervals for these isotopologues of KCl are also provided in files named pXXkYYcl.dat and consist of two columns (T/K followed by Q). (12 data files).

  15. Moléculas orgánicas obtenidas en simulaciones experimentales del medio interestelar.

    NASA Astrophysics Data System (ADS)

    Muñoz-Caro, Guillermo Manuel

    Las nubes moleculares son regiones de formación de estrellas, con temperaturas cinéticas entre 10-50 K y densidades de 103-106 átomos cm-3. Su materia está formada por gas y polvo interestelar. Estas partículas de polvo están cubiertas por una fina capa de hielo, de unos 0.01 μm, que contiene H2O y a menudo CO, CO2, CH3OH y NH3. El hielo es presumiblemente irradiado por fotones ultravioleta y rayos cósmicos en las zonas poco profundas de las nubes moleculares y las regiones circunestelares. En un sistema de vacío, P ˜ 10-7 mbar, simulamos la deposición de hielo a partir de 10 K y la irradiación ultravioleta por medio de una lámpara de descarga de hidrógeno activada con microondas. La evolución del hielo se observa por medio de un espectrómetro infrarrojo. De este modo es posible determinar la composición del hielo observado en el medio interestelar y predecir la presencia de moléculas aún no detectadas en el espacio, que han sido producto del procesamiento del hielo en nuestros experimentos. También es posible calentar el sistema hasta temperatura ambiente para sublimar el hielo depositado. Cuando el hielo ha sido previamente irradiado, se observa un residuo compuesto por moléculas orgánicas complejas, algunas prebióticas, como varios ácidos carboxílicos, aminas, amidas, ésteres y en menor proporción moléculas heterocíclicas y aminoácidos. Algunas de estas moléculas podrían detectarse en estado gaseoso por medio de observaciones milimétricas y de radio. También podrían estar presentes en el polvo cometario, cuyo análisis químico está planeado por las misiones Stardust y Rosetta. Mientras tanto, nuestro grupo está llevando a cabo el análisis de partículas de polvo interplanetario (IDPs), algunas de las cuales pueden ser de origen cometario. Al igual que ocurre con los productos obtenidos por irradiación del hielo en nuestros experimentos, algunas IDPs son ricas en material orgánico que contiene oxígeno.

  16. Classification moléculaire du cancer du sein au Maroc

    PubMed Central

    Fouad, Abbass; Yousra, Akasbi; Kaoutar, Znati; Omar, El Mesbahi; Afaf, Amarti; Sanae, Bennis

    2012-01-01

    Introduction La classification moléculaire des cancers du sein basée sur l'expression génique puis sur le profil protéique a permis de distinguer cinq groupes moléculaires: luminal A, luminal B, Her2/neu, basal-like et non-classées. L'objectif de cette étude réalisée au CHU Hassan II de Fès est de classer 335 cancers du sein infiltrant en groupes moléculaires, puis de les corréler avec les caractéristiques clinicopathologiques. Méthodes Etude rétrospective étalée sur 45 mois, comportant 335 patientes colligées au CHU pour le diagnostic et le suivi. Les tumeurs sont analysées histologiquement et classées après une étude immunohistochimique en groupes: luminal A, luminal B, Her2+, basal-like et non-classées. Résultats 54.3% des tumeurs sont du groupe luminal A, 16% luminal B, 11.3% Her2+, 11.3% basal-like et 7% non-classées. Le groupe luminal A renferme le plus faible taux de grade III, d'emboles vasculaires ainsi que de métastases; alors que le groupe des non-classées et basal-like représentent un taux élevé de grade III, une faible proportion d'emboles vasculaires et d'envahissement ganglionnaire. Ces facteurs sont significativement élevés dans les groupes luminal B et Her2+ avec un taux de survie globale de 78% et 76% respectivement. Dans le groupe luminal A, la survie globale des patientes est élevée (87%) alors qu'elle n'est que de 49% dans le groupe des triples négatifs (basal-like et non-classés). Conclusion Le groupe luminal B est différent du luminal A et il est de pronostic péjoratif vis à vis du groupe Her2+. Les caractéristiques clinicopathologiques concordent avec le profil moléculaire donc devraient être pris en considération comme facteurs pronostiques. PMID:23396646

  17. Microbes at their best: first Mol Micro Meeting Würzburg.

    PubMed

    Böhm, Alex; Papenfort, Kai; Lopez, Daniel; Vogel, Jörg

    2011-11-01

    Founded on ground-breaking discoveries such as the operon model by Jacob and Monod more than 50 years ago, molecular microbiology is now one of the most vibrant disciplines of the life sciences. The first Mol Micro Meeting Würzburg ('M3W') hosted more than 160 scientists from 14 countries to exchange their latest ideas in this field of research. Divided into the four main sessions Gene Regulation, Pathogenesis, Microbial Cell Biology and Signalling, the conference provided insight into current advances and future goals and challenges. PMID:21999404

  18. PD-L1 expression is associated with epithelial-mesenchymal transition in head and neck squamous cell carcinoma

    PubMed Central

    Keam, Bhumsuk; Kim, Miso; Kim, Tae Min; Kim, Jin-Ho; Jeon, Yoon Kyung; Lee, Ju-Seog; Kwon, Seong Keun; Hah, J. Hun; Kwon, Tack-Kyun; Kim, Dong-Wan; Wu, Hong-Gyun; Sung, Myung-Whun; Heo, Dae Seog

    2016-01-01

    Virus-associated malignancies and sarcomatoid cancers correlate with high PD-L1 expression, however, underlying mechanisms remain controversial. We evaluated the correlation between PD-L1 expression and epithelial-mesenchymal transition (EMT) in head and neck squamous cell carcinomas (HNSCC). Tumor tissues from 50 patients with HNSCC were evaluated for PD-L1 by immunohistochemistry, which showed 32 (64.0%) were PD-L1 positive (PD-L1+). Interestingly, PD-L1 expression was significantly associated with EMT (P = 0.010), as assessed by low E-cadherin and high vimentin expression. The overall survival of PD-L1+ patients with EMT features was significantly worse than those without EMT features (P = 0.007). In an independent validation cohort (N = 91), as well as in HNSCC cases of The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia, high PD-L1 expression was also associated with the high probability of an EMT signature, referred from the GEO dataset, GSE4824. Survival analysis confirmed PD-L1+/EMT+ patients had a poorer prognosis than PD-L1+/EMT- patients in the TCGA cohort. PD-L1 positivity can thus be divided into two categories according to the absence or presence of EMT. PD-L1 expression is also independently associated with EMT features in HNSCC. PMID:26893364

  19. 26 CFR 301.6103(l)-1 - Disclosure of returns and return information for purposes other than tax administration.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... for purposes other than tax administration. 301.6103(l)-1 Section 301.6103(l)-1 Internal Revenue... ADMINISTRATION Information and Returns Returns and Records § 301.6103(l)-1 Disclosure of returns and return... provisions of section 6103(l) of the Internal Revenue Code, the term agent includes a contractor....

  20. 26 CFR 1.414(l)-1 - Mergers and consolidations of plans or transfers of plan assets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... the Pension Benefit Guaranty Corporation (29 CFR Part 2611) shall be applied. (11) Date of merger or... of plan assets. 1.414(l)-1 Section 1.414(l)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT..., Stock Bonus Plans, Etc. § 1.414(l)-1 Mergers and consolidations of plans or transfers of plan assets....

  1. 26 CFR 1.167(l)-1 - Limitations on reasonable allowance in case of property of certain public utilities.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... property of certain public utilities. 1.167(l)-1 Section 1.167(l)-1 Internal Revenue INTERNAL REVENUE... Deductions for Individuals and Corporations § 1.167(l)-1 Limitations on reasonable allowance in case of property of certain public utilities. (a) In general—(1) Scope. Section 167(l) in general...

  2. 26 CFR 1.167(l)-1 - Limitations on reasonable allowance in case of property of certain public utilities.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... property of certain public utilities. 1.167(l)-1 Section 1.167(l)-1 Internal Revenue INTERNAL REVENUE... Deductions for Individuals and Corporations § 1.167(l)-1 Limitations on reasonable allowance in case of property of certain public utilities. (a) In general—(1) Scope. Section 167(l) in general...

  3. 26 CFR 31.3121(l)-1 - Agreements entered into by domestic corporations with respect to foreign subsidiaries.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 15 2014-04-01 2014-04-01 false Agreements entered into by domestic corporations with respect to foreign subsidiaries. 31.3121(l)-1 Section 31.3121(l)-1 Internal Revenue INTERNAL... (Chapter 21, Internal Revenue Code of 1954) General Provisions § 31.3121(l)-1 Agreements entered into...

  4. 26 CFR 31.3121(l)-1 - Agreements entered into by domestic corporations with respect to foreign subsidiaries.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Agreements entered into by domestic corporations with respect to foreign subsidiaries. 31.3121(l)-1 Section 31.3121(l)-1 Internal Revenue INTERNAL... (Chapter 21, Internal Revenue Code of 1954) General Provisions § 31.3121(l)-1 Agreements entered into...

  5. 26 CFR 301.6103(l)-1 - Disclosure of returns and return information for purposes other than tax administration.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... for purposes other than tax administration. 301.6103(l)-1 Section 301.6103(l)-1 Internal Revenue... ADMINISTRATION Information and Returns Returns and Records § 301.6103(l)-1 Disclosure of returns and return... provisions of section 6103(l) of the Internal Revenue Code, the term agent includes a contractor....

  6. 26 CFR 301.6103(l)-1 - Disclosure of returns and return information for purposes other than tax administration.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... for purposes other than tax administration. 301.6103(l)-1 Section 301.6103(l)-1 Internal Revenue... ADMINISTRATION Information and Returns Returns and Records § 301.6103(l)-1 Disclosure of returns and return... provisions of section 6103(l) of the Internal Revenue Code, the term agent includes a contractor....

  7. 26 CFR 36.3121(l)(1)-1 - Agreements entered into by domestic corporations with respect to foreign subsidiaries.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... corporations with respect to foreign subsidiaries. 36.3121(l)(1)-1 Section 36.3121(l)(1)-1 Internal Revenue... TAX AT SOURCE CONTRACT COVERAGE OF EMPLOYEES OF FOREIGN SUBSIDIARIES § 36.3121(l)(1)-1 Agreements... subsidiary. See § 36.3121(l)(8)-1, relating to the definition of foreign subsidiary. Except as provided...

  8. 26 CFR 31.3121(l)-1 - Agreements entered into by domestic corporations with respect to foreign subsidiaries.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 15 2013-04-01 2013-04-01 false Agreements entered into by domestic corporations with respect to foreign subsidiaries. 31.3121(l)-1 Section 31.3121(l)-1 Internal Revenue INTERNAL... (Chapter 21, Internal Revenue Code of 1954) General Provisions § 31.3121(l)-1 Agreements entered into...

  9. 26 CFR 301.6103(l)-1 - Disclosure of returns and return information for purposes other than tax administration.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... for purposes other than tax administration. 301.6103(l)-1 Section 301.6103(l)-1 Internal Revenue... ADMINISTRATION Information and Returns Returns and Records § 301.6103(l)-1 Disclosure of returns and return... provisions of section 6103(l) of the Internal Revenue Code, the term agent includes a contractor....

  10. 26 CFR 1.167(l)-1 - Limitations on reasonable allowance in case of property of certain public utilities.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... property of certain public utilities. 1.167(l)-1 Section 1.167(l)-1 Internal Revenue INTERNAL REVENUE... Deductions for Individuals and Corporations § 1.167(l)-1 Limitations on reasonable allowance in case of property of certain public utilities. (a) In general—(1) Scope. Section 167(l) in general...

  11. 26 CFR 1.414(l)-1 - Mergers and consolidations of plans or transfers of plan assets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... the Pension Benefit Guaranty Corporation (29 CFR Part 2611) shall be applied. (11) Date of merger or... of plan assets. 1.414(l)-1 Section 1.414(l)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT..., Stock Bonus Plans, Etc. § 1.414(l)-1 Mergers and consolidations of plans or transfers of plan assets....

  12. 26 CFR 1.414(l)-1 - Mergers and consolidations of plans or transfers of plan assets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... the Pension Benefit Guaranty Corporation (29 CFR Part 2611) shall be applied. (11) Date of merger or... of plan assets. 1.414(l)-1 Section 1.414(l)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT..., Stock Bonus Plans, Etc. § 1.414(l)-1 Mergers and consolidations of plans or transfers of plan assets....

  13. 26 CFR 31.3121(l)-1 - Agreements entered into by domestic corporations with respect to foreign subsidiaries.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 15 2011-04-01 2011-04-01 false Agreements entered into by domestic corporations with respect to foreign subsidiaries. 31.3121(l)-1 Section 31.3121(l)-1 Internal Revenue INTERNAL... (Chapter 21, Internal Revenue Code of 1954) General Provisions § 31.3121(l)-1 Agreements entered into...

  14. L2 Acquisition of Prosodic Properties of Speech Rhythm: Evidence from L1 Mandarin and German Learners of English

    ERIC Educational Resources Information Center

    Li, Aike; Post, Brechtje

    2014-01-01

    This study examines the development of speech rhythm in second language (L2) learners of typologically different first languages (L1s) at different levels of proficiency. An empirical investigation of durational variation in L2 English productions by L1 Mandarin learners and L1 German learners compared to native control values in English and the…

  15. 26 CFR 1.414(l)-1 - Mergers and consolidations of plans or transfers of plan assets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... Benefit Guaranty Corporation (29 CFR Part 2611) shall be applied. (11) Date of merger or spinoff. The... of plan assets. 1.414(l)-1 Section 1.414(l)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT... Plans, Etc. § 1.414(l)-1 Mergers and consolidations of plans or transfers of plan assets. (a) In...

  16. 26 CFR 1.167(l)-1 - Limitations on reasonable allowance in case of property of certain public utilities.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... property of certain public utilities. 1.167(l)-1 Section 1.167(l)-1 Internal Revenue INTERNAL REVENUE... Deductions for Individuals and Corporations § 1.167(l)-1 Limitations on reasonable allowance in case of property of certain public utilities. (a) In general—(1) Scope. Section 167(l) in general...

  17. 26 CFR 31.3121(l)-1 - Agreements entered into by domestic corporations with respect to foreign subsidiaries.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 15 2012-04-01 2012-04-01 false Agreements entered into by domestic corporations with respect to foreign subsidiaries. 31.3121(l)-1 Section 31.3121(l)-1 Internal Revenue INTERNAL... (Chapter 21, Internal Revenue Code of 1954) General Provisions § 31.3121(l)-1 Agreements entered into...

  18. 26 CFR 36.3121(l)(1)-1 - Agreements entered into by domestic corporations with respect to foreign subsidiaries.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... corporations with respect to foreign subsidiaries. 36.3121(l)(1)-1 Section 36.3121(l)(1)-1 Internal Revenue... TAX AT SOURCE CONTRACT COVERAGE OF EMPLOYEES OF FOREIGN SUBSIDIARIES § 36.3121(l)(1)-1 Agreements... subsidiary. See § 36.3121(l)(8)-1, relating to the definition of foreign subsidiary. Except as provided...

  19. 26 CFR 36.3121(l)(1)-1 - Agreements entered into by domestic corporations with respect to foreign subsidiaries.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... corporations with respect to foreign subsidiaries. 36.3121(l)(1)-1 Section 36.3121(l)(1)-1 Internal Revenue... TAX AT SOURCE CONTRACT COVERAGE OF EMPLOYEES OF FOREIGN SUBSIDIARIES § 36.3121(l)(1)-1 Agreements... subsidiary. See § 36.3121(l)(8)-1, relating to the definition of foreign subsidiary. Except as provided...

  20. 26 CFR 301.6103(l)-1 - Disclosure of returns and return information for purposes other than tax administration.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... for purposes other than tax administration. 301.6103(l)-1 Section 301.6103(l)-1 Internal Revenue... ADMINISTRATION Information and Returns Returns and Records § 301.6103(l)-1 Disclosure of returns and return... provisions of section 6103(l) of the Internal Revenue Code, the term agent includes a contractor....

  1. 26 CFR 1.414(l)-1 - Mergers and consolidations of plans or transfers of plan assets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... the Pension Benefit Guaranty Corporation (29 CFR Part 2611) shall be applied. (11) Date of merger or... of plan assets. 1.414(l)-1 Section 1.414(l)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT..., Stock Bonus Plans, Etc. § 1.414(l)-1 Mergers and consolidations of plans or transfers of plan assets....

  2. 26 CFR 36.3121(l)(1)-1 - Agreements entered into by domestic corporations with respect to foreign subsidiaries.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... corporations with respect to foreign subsidiaries. 36.3121(l)(1)-1 Section 36.3121(l)(1)-1 Internal Revenue... TAX AT SOURCE CONTRACT COVERAGE OF EMPLOYEES OF FOREIGN SUBSIDIARIES § 36.3121(l)(1)-1 Agreements entered into by domestic corporations with respect to foreign subsidiaries. (a) In general. (1)...

  3. Compression behavior of quaternary and higher order solid-solution L1(2) trialuminides

    NASA Technical Reports Server (NTRS)

    Kumar, K. S.; Brown, S. A.

    1992-01-01

    Results from preliminary studies undertaken to evaluate the existence of single-phase L1(2) solid solutions between pairs of ternary L1(2) trialuminides are presented. Two-kilogram ingots of selected quaternary compositions were cast, homogenized and forged into pancakes; compression specimens were machined from the forgings and tested as a function of temperature. The results are compared against existing data for the ternary alloys. The ternary L1(2) trialuminides Al66Ti25Mn9, Al67Ti25Cr8, and Al22Ti8Fe3 were found to exhibit continuous solubility in one another. The quaternary Cr-Mn composition does not indicate any strength advantage over its ternary counterparts. The continuous replacement of Mn with Fe enhances the strength of the quaternary compound over the ternary Al66Ti25 Mn9.

  4. DNA Methylation Suppresses Leptin Gene in 3T3-L1 Adipocytes

    PubMed Central

    Kuroda, Masashi; Tominaga, Ayako; Nakagawa, Kasumi; Nishiguchi, Misa; Sebe, Mayu; Miyatake, Yumiko; Kitamura, Tadahiro; Tsutsumi, Rie; Harada, Nagakatsu; Nakaya, Yutaka; Sakaue, Hiroshi

    2016-01-01

    Leptin is a key regulator of energy intake and expenditure. This peptide hormone is expressed in mouse white adipose tissue, but hardly expressed in 3T3-L1 adipocytes. Using bisulfite sequencing, we found that CpG islands in the leptin promoter are highly methylated in 3T3-L1cells. 5-azacytidine, an inhibitor of DNA methyltransferase, markedly increased leptin expression as pre-adipocytes matured into adipocytes. Remarkably, leptin expression was stimulated by insulin in adipocytes derived from precursor cells exposed to 5-azacytidine, but suppressed by thiazolidinedione and dexamethasone. In contrast, adipocytes derived from untreated precursor cells were unresponsive to both 5-azacytidine and hormonal stimuli, although lipid accumulation was sufficient to boost leptin expression in the absence of demethylation. Taken together, the results suggest that leptin expression in 3T3-L1 cells requires DNA demethylation prior to adipogenesis, transcriptional activation during adipogenesis, and lipid accumulation after adipogenesis. PMID:27494408

  5. Human Cancer Immunotherapy with PD-1/PD-L1 Blockade

    PubMed Central

    Zheng, Peilin; Zhou, Zhiguang

    2015-01-01

    The ligation of programmed cell death-1 (PD-1) to its ligands PD-L1 and PD-L2 counteracts T-cell activation, which is critical in immune tolerance. The persistent high expression of PD-1 and PD-L1 are also observed on tumor-infiltrating lymphocytes and various tumor cells, maintaining the highly suppressive microenvironment in tumor sites and promoting tumor malignancies. The blockade of PD-1 axis with PD-L2 fusion protein or monoclonal antibodies against either PD-1 or PD-L1 has been clinically evaluated in various tumor types. This short review summarizes the progress of PD-1 axis blockade in clinical trials to evaluate its effectiveness in the antitumor immunotherapy. PMID:26448693

  6. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies.

    PubMed

    Naidoo, J; Page, D B; Li, B T; Connell, L C; Schindler, K; Lacouture, M E; Postow, M A; Wolchok, J D

    2015-12-01

    Immune checkpoint antibodies that augment the programmed cell death protein 1 (PD-1)/PD-L1 pathway have demonstrated antitumor activity across multiple malignancies, and gained recent regulatory approval as single-agent therapy for the treatment of metastatic malignant melanoma and nonsmall-cell lung cancer. Knowledge of toxicities associated with PD-1/PD-L1 blockade, as well as effective management algorithms for these toxicities, is pivotal in order to optimize clinical efficacy and safety. In this article, we review selected published and presented clinical studies investigating single-agent anti-PD-1/PD-L1 therapy and trials of combination approaches with other standard anticancer therapies, in multiple tumor types. We summarize the key adverse events reported in these studies and their management algorithms. PMID:26371282

  7. L1/2 regularization based numerical method for effective reconstruction of bioluminescence tomography

    NASA Astrophysics Data System (ADS)

    Chen, Xueli; Yang, Defu; Zhang, Qitan; Liang, Jimin

    2014-05-01

    Even though bioluminescence tomography (BLT) exhibits significant potential and wide applications in macroscopic imaging of small animals in vivo, the inverse reconstruction is still a tough problem that has plagued researchers in a related area. The ill-posedness of inverse reconstruction arises from insufficient measurements and modeling errors, so that the inverse reconstruction cannot be solved directly. In this study, an l1/2 regularization based numerical method was developed for effective reconstruction of BLT. In the method, the inverse reconstruction of BLT was constrained into an l1/2 regularization problem, and then the weighted interior-point algorithm (WIPA) was applied to solve the problem through transforming it into obtaining the solution of a series of l1 regularizers. The feasibility and effectiveness of the proposed method were demonstrated with numerical simulations on a digital mouse. Stability verification experiments further illustrated the robustness of the proposed method for different levels of Gaussian noise.

  8. A Crohn's disease variant in Atg16l1 enhances its degradation by caspase 3

    NASA Astrophysics Data System (ADS)

    Murthy, Aditya; Li, Yun; Peng, Ivan; Reichelt, Mike; Katakam, Anand Kumar; Noubade, Rajkumar; Roose-Girma, Merone; Devoss, Jason; Diehl, Lauri; Graham, Robert R.; van Lookeren Campagne, Menno

    2014-02-01

    Crohn's disease is a debilitating inflammatory bowel disease (IBD) that can involve the entire digestive tract. A single-nucleotide polymorphism (SNP) encoding a missense variant in the autophagy gene ATG16L1 (rs2241880, Thr300Ala) is strongly associated with the incidence of Crohn's disease. Numerous studies have demonstrated the effect of ATG16L1 deletion or deficiency; however, the molecular consequences of the Thr300Ala (T300A) variant remains unknown. Here we show that amino acids 296-299 constitute a caspase cleavage motif in ATG16L1 and that the T300A variant (T316A in mice) significantly increases ATG16L1 sensitization to caspase-3-mediated processing. We observed that death-receptor activation or starvation-induced metabolic stress in human and murine macrophages increased degradation of the T300A or T316A variants of ATG16L1, respectively, resulting in diminished autophagy. Knock-in mice harbouring the T316A variant showed defective clearance of the ileal pathogen Yersinia enterocolitica and an elevated inflammatory cytokine response. In turn, deletion of the caspase-3-encoding gene, Casp3, or elimination of the caspase cleavage site by site-directed mutagenesis rescued starvation-induced autophagy and pathogen clearance, respectively. These findings demonstrate that caspase 3 activation in the presence of a common risk allele leads to accelerated degradation of ATG16L1, placing cellular stress, apoptotic stimuli and impaired autophagy in a unified pathway that predisposes to Crohn's disease.

  9. Structural and biochemical characterization of the cell fate determining nucleotidyltransferase fold protein MAB21L1

    PubMed Central

    de Oliveira Mann, Carina C.; Kiefersauer, Reiner; Witte, Gregor; Hopfner, Karl-Peter

    2016-01-01

    The exceptionally conserved metazoan MAB21 proteins are implicated in cell fate decisions and share considerable sequence homology with the cyclic GMP-AMP synthase. cGAS is the major innate immune sensor for cytosolic DNA and produces the second messenger 2′-5′, 3′-5′ cyclic GMP-AMP. Little is known about the structure and biochemical function of other proteins of the cGAS-MAB21 subfamily, such as MAB21L1, MAB21L2 and MAB21L3. We have determined the crystal structure of human full-length MAB21L1. Our analysis reveals high structural conservation between MAB21L1 and cGAS but also uncovers important differences. Although monomeric in solution, MAB21L1 forms a highly symmetric double-pentameric oligomer in the crystal, raising the possibility that oligomerization could be a feature of MAB21L1. In the crystal, MAB21L1 is in an inactive conformation requiring a conformational change - similar to cGAS - to develop any nucleotidyltransferase activity. Co-crystallization with NTP identified a putative ligand binding site of MAB21 proteins that corresponds to the DNA binding site of cGAS. Finally, we offer a structure-based explanation for the effects of MAB21L2 mutations in patients with eye malformations. The underlying residues participate in fold-stabilizing interaction networks and mutations destabilize the protein. In summary, we provide a first structural framework for MAB21 proteins. PMID:27271801

  10. PD-L1 testing for lung cancer in the UK: recognizing the challenges for implementation.

    PubMed

    Cree, Ian A; Booton, Richard; Cane, Paul; Gosney, John; Ibrahim, Merdol; Kerr, Keith; Lal, Rohit; Lewanski, Conrad; Navani, Neal; Nicholson, Andrew G; Nicolson, Marianne; Summers, Yvonne

    2016-08-01

    A new approach to the management of non-small-cell lung cancer (NSCLC) has recently emerged that works by manipulating the immune checkpoint controlled by programmed death receptor 1 (PD-1) and its ligand programmed death ligand 1 (PD-L1). Several drugs targeting PD-1 (pembrolizumab and nivolumab) or PD-L1 (atezolizumab, durvalumab, and avelumab) have been approved or are in the late stages of development. Inevitably, the introduction of these drugs will put pressure on healthcare systems, and there is a need to stratify patients to identify those who are most likely to benefit from such treatment. There is evidence that responsiveness to PD-1 inhibitors may be predicted by expression of PD-L1 on neoplastic cells. Hence, there is considerable interest in using PD-L1 immunohistochemical staining to guide the use of PD-1-targeted treatments in patients with NSCLC. This article reviews the current knowledge about PD-L1 testing, and identifies current research requirements. Key factors to consider include the source and timing of sample collection, pre-analytical steps (sample tracking, fixation, tissue processing, sectioning, and tissue prioritization), analytical decisions (choice of biomarker assay/kit and automated staining platform, with verification of standardized assays or validation of laboratory-devised techniques, internal and external quality assurance, and audit), and reporting and interpretation of the results. This review addresses the need for integration of PD-L1 immunohistochemistry with other tests as part of locally agreed pathways and protocols. There remain areas of uncertainty, and guidance should be updated regularly as new information becomes available. PMID:27196116

  11. PCR walking from microdissection clone M54 identifies three exons from the human gene for the neural cell adhesion molecule L1 (CAM-L1).

    PubMed Central

    Rosenthal, A; MacKinnon, R N; Jones, D S

    1991-01-01

    Microdissection has proved to be a powerful tool in the construction of libraries from specific chromosome segments (11) which are poorly covered by existing RFLP markers. Microclones also represent starting points for finding genes of interest. However, their length (100 to 200 bp) can make their use as probes problematic and identifying them as coding sequence is difficult. We report here that microclones can be extended in vitro by a modified version of our original PCR walking method (10) which utilises oligo-cassettes and the solid phase biotin/streptavidin separation system. We have extended the microclone M54, derived by dissection from Xq27.2 to proximal Xq28 (12), in both directions for approximately 700 bp. Direct sequencing of these products revealed that M54 was located within an intron of the human gene encoding the neural cell adhesion molecule L1 (CAM-L1) which has been recently mapped to Xq28 (13). The extension of M54 also identified three exons of this gene. This information allowed subsequent amplification of a 2.4 kb cDNA molecule from fetal human brain mRNA which encodes most of human CAM-L1. Sequencing of this cDNA revealed a high degree of sequence conservation with the mouse homologue (14). This is the first description of extension of a human derived microclone by PCR mediated walking within total human genomic DNA. These results show that anonymous DNA sequences may be extended into coding or any sequence. Images PMID:1923824

  12. Magnetic and electronic properties of bulk and clusters of FePt L1(0).

    PubMed

    Barreteau, Cyrille; Spanjaard, Daniel

    2012-10-10

    An efficient tight-binding model including magnetism and spin-orbit interactions is extended to metallic alloys. The tight-binding parameters are determined from a fit to bulk ab initio calculations of each metal and rules are given to obtain the heteroatomic parameters. The spin and orbital magnetic moments as well as the magneto-crystalline anisotropy are derived. We apply this method to bulk FePt L1(0) and the results are compared with success to ab initio results where available. Finally this model is applied to a set of FePt L1(0) clusters and physical trends are derived. PMID:22987868

  13. Association between PD-1/PD-L1 and T regulate cells in early recurrent miscarriage

    PubMed Central

    Li, Guiyu; Lu, Caixia; Gao, Jing; Wang, Xietong; Wu, Huanling; Lee, Chao; Xing, Baoxiang; Zhang, Qi

    2015-01-01

    In this study, we try to testify the relationship between the programmed cell death receptor-1 (PD-1)/programmed cell death ligand 1 (PD-L1) passway and Treg cells in maternal-fetal immune regulation through PD-1 blockade on lymphocytes of normal early pregnancy in vitro and investigation of the PD-1 and PD-L1 changes in early recurrent miscarriage patients. CD4+ CD25+ Treg cells and PD-1 (CD279) positive cell were detected in deciduas in early recurrent miscarriage patients by flow cytometry. And the normal early pregnant women were as controls. Meanwhile the mRNA level of PD-1 and molecular expression of PD-L1 in deciduas of early recurrent miscarriage patients were detected by real time RT-PCR test and Immunohistochemical staining respectively. Also through antibody blocking assay to block PD-1 on lymphocytes of normal early pregnancy in vitro further testify the relationship between PD-1/PD-L1 and Treg cells, the results were analyzed by flow cytometry. CD4+ CD25+ Treg cells decreased both in deciduas in RM (P < 0.05), and for all almost 100% Treg cells (CD4+ CD25+) expressed PD-1, but there was no difference between the PD-1 positive cells in decidual lymphocytes in RM and that in normal pregnancy women (P > 0.05). PD-L1 mRNA in deciduas decreased in RM (P < 0.001), but PD-1 mRNA no difference (P > 0.1). After PD-1 blockade there was no change in CD4+ CD25+ Treg cells percentage, while the CD4+ T cell percentage increased (P < 0.01), as well as the level of IFN-gamma in cells supernatant (P < 0.01). PD-1 blockade has a little influence on the number of Treg cells, and may lead to impaired Treg cells function, the decrease of PD-L1 may closely relates to the occurrence of early recurrent miscarriage and implies that Treg cells may through PD-1/PD-L1 pathway play a role of immunosuppression regulation, and the impairment of Treg cells function in recurrent early abortion cases may be due to PD-L1 decrease in deciduas or trophoblast cells rather than PD-1 change

  14. The clinical spectrum of mutations in L1, a neuronal cell adhesion molecule

    SciTech Connect

    Fransen, E.; Vits, L.; Van Camp, G.; Willems, P.J.

    1996-07-12

    Mutations in the gene encoding the neuronal cell adhesion molecule L1 are responsible for several syndromes with clinical overlap, including X-linked hydrocephalus (XLH, HSAS), MASA (mental retardation, aphasia, shuffling gait, adducted thumbs) syndrome, complicated X-linked spastic paraplegia (SP 1), X-linked mental retardation-clasped thumb (MR-CT) syndrome, and some forms of X-linked agenesis of the corpus callosum (ACC). We review 34 L1 mutations in patients with these phenotypes. 22 refs., 3 figs., 4 tabs.

  15. Variation in CCL3L1 Copy Number in Rhesus Macaques (Macaca mulatta)

    PubMed Central

    Taormina, Patrick L; Trask, Jessica A Satkoski; Smith, David G; Kanthaswamy, Sreetharan

    2012-01-01

    We used real-time quantitative PCR (qPCR) methodology to examine copy number variation (CNV) of the CCL3L1 gene among pure Indian-origin, pure Chinese-origin, and hybrid Indian–Chinese rhesus macaques (Macaca mulatta). CNV among purebred macaques fell within expected ranges, with Indian macaques having lower copy numbers than those of Chinese macaques. Compared with the purebred macaques, Indian–Chinese hybrid rhesus macaques showed much greater variance in copy number and an intermediate average copy number. Copy numbers of CCL3L1 in rhesus macaque trios (sire, dam, and offspring) were consistent with Mendelian inheritance. PMID:22776055

  16. Variation in CCL3L1 copy number in rhesus macaques (Macaca mulatta).

    PubMed

    Taormina, Patrick L; Satkoski Trask, Jessica A; Smith, David G; Kanthaswamy, Sreetharan

    2012-06-01

    We used real-time quantitative PCR (qPCR) methodology to examine copy number variation (CNV) of the CCL3L1 gene among pure Indian-origin, pure Chinese-origin, and hybrid Indian-Chinese rhesus macaques (Macaca mulatta). CNV among purebred macaques fell within expected ranges, with Indian macaques having lower copy numbers than those of Chinese macaques. Compared with the purebred macaques, Indian-Chinese hybrid rhesus macaques showed much greater variance in copy number and an intermediate average copy number. Copy numbers of CCL3L1 in rhesus macaque trios (sire, dam, and offspring) were consistent with Mendelian inheritance. PMID:22776055

  17. Observation and elimination of broken symmetry in L1{sub 0} FePt nanostructures

    SciTech Connect

    Quarterman, P.; Wang, Hao; Qiu, Jiao-Ming; Ma, Bin; Liu, Xiaoqi; Wang, Jian-Ping; Guo, Honghua

    2015-12-07

    An unexplained surface anisotropy effect was observed and confirmed in the magnetization reversal process of both L1{sub 0} phase FePt nanoparticles with octahedral shape and (001) textured L1{sub 0} FePt thin films with island nanostructures. We suggest that the nature of the observed surface effect is caused by broken symmetry on the FePt surface, which results in weakened exchange coupling for surface atoms. Furthermore, we propose, and experimentally demonstrate, a method to repair the broken symmetry by capping the FePt islands with a Pt layer, which could prove invaluable in understanding fundamental limitations of magnetic nanostructures.

  18. Preliminary Design Considerations for Access and Operations in Earth-Moon L1/L2 Orbits

    NASA Technical Reports Server (NTRS)

    Folta, David C.; Pavlak, Thomas A.; Haapala, Amanda F.; Howell, Kathleen C.

    2013-01-01

    Within the context of manned spaceflight activities, Earth-Moon libration point orbits could support lunar surface operations and serve as staging areas for future missions to near-Earth asteroids and Mars. This investigation examines preliminary design considerations including Earth-Moon L1/L2 libration point orbit selection, transfers, and stationkeeping costs associated with maintaining a spacecraft in the vicinity of L1 or L2 for a specified duration. Existing tools in multi-body trajectory design, dynamical systems theory, and orbit maintenance are leveraged in this analysis to explore end-to-end concepts for manned missions to Earth-Moon libration points.

  19. A new value for mol percent guanine + cytosine of DNA for the salmonid fish pathogen Renibacterium salmoninarum.

    PubMed

    Banner, C R; Rohovec, J S; Fryer, J L

    1991-03-15

    The mol% G + C of DNA extracted from seven different isolates of Renibacterium salmoninarum was determined. Organisms studied were from selected geographical areas (U.S.A., Canada, England and France) and were isolated from five different species of salmonid fish. The mol% G + C was determined to be 55.5, higher than the currently reported value of 53. PMID:2044940

  20. The Completion Agenda: A Call to Action. Summary Report from the November 10-11, 2010, Meeting of the American Association of Community Colleges Commissions and Board of Directors

    ERIC Educational Resources Information Center

    McPhail, Christine Johnson

    2011-01-01

    At its annual joint board and commission meeting (Washington, DC, November 10-11, 2010), American Association of Community Colleges (AACC) focused attention on college completion by presenting two panel discussions on the completion agenda, followed by breakout sessions in which participants were assigned to focus groups tasked with providing…

  1. Adult and Higher Education in the Contemporary World: Its Role in Cultural Literacy. Conference Proceedings of the Adult Higher Education Alliance Annual Conference (35th, Orlando, Florida, March 10-11, 2015)

    ERIC Educational Resources Information Center

    Elufiede, Oluwakemi, Ed.; Flynn, Bonnie, Ed.

    2015-01-01

    This document is Conference Proceedings Of The Adult Higher Education Alliance, 35th Annual Conference. The theme of the conference was Adult And Higher Education In The Contemporary World: Its Role In Cultural Literacy. Conference was March 10-11, 2015. The event was hosted by and held at the College Of Education And Human Performance, Morgridge…

  2. Genetic demonstration of intestinal NPC1L1 as a major determinant of hepatic cholesterol and blood atherogenic lipoprotein levels

    PubMed Central

    Xie, Ping; Zhu, Hongling; Jia, Lin; Ma, Yinyan; Tang, Weiqing; Wang, Youlin; Xue, Bingzhong; Shi, Hang; Yu, Liqing

    2014-01-01

    Objective The correlation between intestinal cholesterol absorption values and plasma low-density lipoprotein-cholesterol (LDL-C) levels remains controversial. Niemann-Pick-C1-Like 1 (NPC1L1) is essential for intestinal cholesterol absorption, and is the target of ezetimibe, a cholesterol absorption inhibitor. However, studies with NPC1L1 knockout mice or ezetimibe cannot definitively clarify this correlation because NPC1L1 expression is not restricted to intestine in humans and mice. In this study we sought to genetically address this issue. Methods and results We developed a mouse model that lacks endogenous (NPC1L1) and LDL receptor (LDLR) (DKO), but transgenically expresses human NPC1L1 in gastrointestinal tract only (DKO/L1IntOnly mice). Our novel model eliminated potential effects of non-intestinal NPC1L1 on cholesterol homeostasis. We found that human NPC1L1 was localized at the intestinal brush border membrane of DKO/L1IntOnly mice. Cholesterol feeding induced formation of NPC1L1-positive vesicles beneath this membrane in an ezetimibe-sensitive manner. Compared to DKO mice, DKO/L1IntOnly mice showed significant increases in cholesterol absorption and blood/hepatic/biliary cholesterol. Increased blood cholesterol was restricted to very low-density lipoprotein (VLDL) and LDL fractions, which was associated with increased secretion and plasma levels of apolipoproteins B100 and B48. Additionally, DKO/L1IntOnly mice displayed decreased fecal cholesterol excretion and hepatic/intestinal expression of cholesterologenic genes. Ezetimibe treatment virtually reversed all of the transgene-related phenotypes in DKO/L1IntOnly mice. Conclusion Our findings from DKO/L1IntOnly mice clearly demonstrate that NPC1L1-mediated cholesterol absorption is a major determinant of blood levels of apolipoprotein B-containing atherogenic lipoproteins, at least in mice. PMID:25463095

  3. L1CAM protein expression is associated with poor prognosis in non-small cell lung cancer

    PubMed Central

    2011-01-01

    Background The L1 cell adhesion molecule (L1CAM) is potentially involved in epithelial-mesenchymal transition (EMT). EMT marker expression is of prognostic significance in non-small cell lung cancer (NSCLC). The relevance of L1CAM for NSCLC is unclear. We investigated the protein expression of L1CAM in a cohort of NSCLC patients. L1CAM protein expression was correlated with clinico-pathological parameters including survival and markers of epithelial-mesenchymal transition. Results L1CAM protein expression was found in 25% of squamous cell carcinomas and 24% of adenocarcinomas and correlated with blood vessel invasion and metastasis (p < 0.05). L1CAM was an independent predictor of survival in a multivariate analysis including pT, pN, and pM category, and tumor differentiation grade. L1CAM expression positively correlated with vimentin, beta-catenin, and slug, but inversely with E-cadherin (all p-values < 0.05). E-cadherin expression was higher in the tumor center than in the tumor periphery, whereas L1CAM and vimentin were expressed at the tumor-stroma interface. In L1CAM-negative A549 cells the L1CAM expression was upregulated and matrigel invasion was increased after stimulation with TGF-beta1. In L1CAM-positive SK-LU-1 and SK-LC-LL cells matrigel invasion was decreased after L1CAM siRNA knockdown. Conclusions A subset of NSCLCs with vessel tropism and increased metastasis aberrantly expresses L1CAM. L1CAM is a novel prognostic marker for NSCLCs that is upregulated by EMT induction and appears to be instrumental for enhanced cell invasion. PMID:21985405

  4. KSHV LANA and EBV LMP1 induce the expression of UCH-L1 following viral transformation

    SciTech Connect

    Bentz, Gretchen L.; Bheda-Malge, Anjali; Wang, Ling; Shackelford, Julia; Damania, Blossom; Pagano, Joseph S.

    2014-01-05

    Ubiquitin C-terminal Hydrolase L1 (UCH-L1) has oncogenic properties and is highly expressed during malignancies. We recently documented that Epstein-Barr virus (EBV) infection induces uch-l1 expression. Here we show that Kaposi's Sarcoma-associated herpesvirus (KSHV) infection induced UCH-L1 expression, via cooperation of KSHV Latency-Associated Nuclear Antigen (LANA) and RBP-Jκ and activation of the uch-l1 promoter. UCH-L1 expression was also increased in Primary Effusion Lymphoma (PEL) cells co-infected with KSHV and EBV compared with PEL cells infected only with KSHV, suggesting EBV augments the effect of LANA on uch-l1. EBV latent membrane protein 1 (LMP1) is one of the few EBV products expressed in PEL cells. Results showed that LMP1 was sufficient to induce uch-l1 expression, and co-expression of LMP1 and LANA had an additive effect on uch-l1 expression. These results indicate that viral latency products of both human γ-herpesviruses contribute to uch-l1 expression, which may contribute to the progression of lymphoid malignancies. - Highlights: • Infection of endothelial cells with KSHV induced UCH-L1 expression. • KSHV LANA is sufficient for the induction of uch-l1. • Co-infection with KSHV and EBV (observed in some PELs) results in the additive induction of uch-l1. • EBV LMP1 also induced UCH-L1 expression. • LANA- and LMP1-mediated activation of the uch-l1 promoter is in part through RBP-Jκ.

  5. Data structures for ExoMol: Molecular line lists for exoplanet and other atmospheres

    NASA Astrophysics Data System (ADS)

    Tennyson, Jonathan; Hill, Christian; Yurchenko, Sergei N.

    2013-07-01

    At elevated temperatures the spectra of polyatomic molecules become extremely complicated with millions, or even billions, of transitions potentially playing an important role. The atmospheres of cool stars and "hot Jupiter" extrasolar planets are rich with molecules in the temperature range 1000 to 3000 K and their properties are strongly influenced by the infrared and visible spectra of these molecules. Access to extensive lists of transitions is essential for interpreting even the rather simple spectra that can be obtained from exoplanets. So far there are extensive, reliable lists of spectral lines for a number species including some stable diatomics, water and ammonia. Data are almost completely lacking for many key species such as methane. The ExoMol project aims to construct line lists of molecular transitions suitable for spectroscopic and atmospheric modelling of cool stars and exoplanets. At high temperatures it is necessary to consider huge numbers of lines even for a single species. Examples of line lists are given; data protocols defined and data handling issues which arise from trying to distribute these huge datasets discussed. In particular, a uniform but flexible format is given for the representation of line lists and cross sections resulting from the ExoMol project.

  6. SigMol: repertoire of quorum sensing signaling molecules in prokaryotes

    PubMed Central

    Rajput, Akanksha; Kaur, Karambir; Kumar, Manoj

    2016-01-01

    Quorum sensing is a widespread phenomenon in prokaryotes that helps them to communicate among themselves and with eukaryotes. It is driven through quorum sensing signaling molecules (QSSMs) in a density dependent manner that assists in numerous biological functions like biofilm formation, virulence factors secretion, swarming motility, bioluminescence, etc. Despite immense implications, dedicated resources of QSSMs are lacking. Therefore, we have developed SigMol (http://bioinfo.imtech.res.in/manojk/sigmol), a specialized repository of these molecules in prokaryotes. SigMol harbors information on QSSMs pertaining to different quorum sensing signaling systems namely acylated homoserine lactones (AHLs), diketopiperazines (DKPs), 4-hydroxy-2-alkylquinolines (HAQs), diffusible signal factors (DSFs), autoinducer-2 (AI-2) and others. Database contains 1382 entries of 182 unique signaling molecules from 215 organisms. It encompasses biological as well as chemical aspects of signaling molecules. Biological information includes genes, preliminary bioassays, identification assays and applications, while chemical detail comprises of IUPAC name, SMILES and structure. We have provided user-friendly browsing and searching facilities for easy data retrieval and comparison. We have gleaned information of diverse QSSMs reported in literature at a single platform ‘SigMol’. This comprehensive resource will assist the scientific community in understanding intraspecies, interspecies or interkingdom networking and further help to unfold different facets of quorum sensing and related therapeutics. PMID:26490957

  7. MegaMol--A Prototyping Framework for Particle-Based Visualization.

    PubMed

    Grottel, Sebastian; Krone, Michael; Muller, Christoph; Reina, Guido; Ertl, Thomas

    2015-02-01

    Visualization applications nowadays not only face increasingly larger datasets, but have to solve increasingly complex research questions. They often require more than a single algorithm and consequently a software solution will exceed the possibilities of simple research prototypes. Well-established systems intended for such complex visual analysis purposes have usually been designed for classical, mesh-based graphics approaches. For particle-based data, however, existing visualization frameworks are too generic - e.g. lacking possibilities for consistent low-level GPU optimization for high-performance graphics - and at the same time are too limited - e.g. by enforcing the use of structures suboptimal for some computations. Thus, we developed the system softwareMegaMol for visualization research on particle-based data. On the one hand, flexible data structures and functional module design allow for easy adaption to changing research questions, e.g. studying vapors in thermodynamics, solid material in physics, or complex functional macromolecules like proteins in biochemistry. Therefore, MegaMol is designed as a development framework. On the other hand, common functionality for data handling and advanced rendering implementations are available and beneficial for all applications. We present several case studies of work implemented using our system as well as a comparison to other freely available or open source systems. PMID:26357030

  8. MolProbity’s Ultimate Rotamer-Library Distributions for Model Validation

    PubMed Central

    Hintze, Bradley J.; Lewis, Steven M.; Richardson, Jane S.; Richardson, David C.

    2016-01-01

    Here we describe the updated MolProbity rotamer-library distributions derived from an order-of-magnitude larger and more stringently quality-filtered dataset of about 8000 (vs. 500) protein chains, and we explain the resulting changes and improvements to model validation as seen by users. To include only sidechains with satisfactory justification for their given conformation, we added residue-specific filters for electron-density value and model-to-density fit. The combined new protocol retains a million residues of data, while cleaning up false-positive noise in the multi-χ datapoint distributions. It enables unambiguous characterization of conformational clusters nearly 1000-fold less frequent than the most common ones. We describe examples of local interactions that favor these rare conformations, including the role of authentic covalent bond-angle deviations in enabling presumably strained sidechain conformations. Further, along with favored and outlier, an allowed category (0.3% to 2.0% occurrence in reference data) has been added, analogous to Ramachandran validation categories. The new rotamer distributions are used for current rotamer validation in Mol-Probity and PHENIX, and for rotamer choice in PHENIX model-building and refinement. The multi-dimensional χ distributions and Top8000 reference dataset are freely available on GitHub. These rotamers are termed “ultimate” because data sampling and quality are now fully adequate for this task, and also because we believe the future of conformational validation should integrate sidechain with backbone criteria. PMID:27018641

  9. Increase of cells expressing PD-L1 in bovine leukemia virus infection and enhancement of anti-viral immune responses in vitro via PD-L1 blockade

    PubMed Central

    2011-01-01

    The inhibitory receptor programmed death-1 (PD-1) and its ligand, programmed death-ligand 1 (PD-L1) are involved in immune evasion mechanisms for several pathogens causing chronic infections. Blockade of the PD-1/PD-L1 pathway restores anti-virus immune responses, with concomitant reduction in viral load. In a previous report, we showed that, in bovine leukemia virus (BLV) infection, the expression of bovine PD-1 is closely associated with disease progression. However, the functions of bovine PD-L1 are still unknown. To investigate the role of PD-L1 in BLV infection, we identified the bovine PD-L1 gene, and examined PD-L1 expression in BLV-infected cattle in comparison with uninfected cattle. The deduced amino acid sequence of bovine PD-L1 shows high homology to the human and mouse PD-L1. The proportion of PD-L1 positive cells, especially among B cells, was upregulated in cattle with the late stage of the disease compared to cattle at the aleukemic infection stage or uninfected cattle. The proportion of PD-L1 positive cells correlated positively with prediction markers for the progression of the disease such as leukocyte number, virus load and virus titer whilst on the contrary, it inversely correlated with the degree of interferon-gamma expression. Blockade of the PD-1/PD-L1 pathway in vitro by PD-L1-specific antibody upregulated the production of interleukin-2 and interferon-gamma, and correspondingly, downregulated the BLV provirus load and the proportion of BLV-gp51 expressing cells. These data suggest that PD-L1 induces immunoinhibition in disease progressed cattle during chronic BLV infection. Therefore, PD-L1 would be a potential target for developing immunotherapies against BLV infection. PMID:21943148

  10. Role of L1CAM in the Regulation of the Canonical Wnt Pathway and Class I MAGE Genes.

    PubMed

    Shkurnikov, M Yu; Knyazev, E N; Wicklein, D; Schumacher, U; Samatov, T R; Tonevitskii, A G

    2016-04-01

    Molecule L1CAM is specific for nerve cells and tumors of various localizations. The expression of L1CAM is significantly higher in melanoma in comparison with benign nevi and correlates with the progress of melanoma and transition from radial to vertical growth. Monoclonal antibodies to L1CAM effectively and specifically attenuate melanoma growth, though stimulates the epithelial-mesenchymal transition. shRNA-mediated knock-down of L1CAM showed the involvement of L1CAM in regulation of activity of the canonical Wnt pathway and expression of genes of class I melanoma-associated antigens (MAGE). PMID:27165065

  11. Effect of Ag addition to L1{sub 0} FePt and L1{sub 0} FePd films grown by molecular beam epitaxy

    SciTech Connect

    Tokuoka, Y.; Seto, Y.; Kato, T.; Iwata, S.

    2014-05-07

    L1{sub 0} ordered FePt-Ag (5 nm) and FePd-Ag (5 nm) films were grown on MgO (001) substrate at temperatures of 250–400 °C by using molecular beam epitaxy method, and their crystal and surface structures, perpendicular magnetic anisotropies and Curie temperatures were investigated. In the case of FePt-Ag, Ag addition with the amount of 10–20 at. % was effective to promote L1{sub 0} ordering and granular growth, resulting in the increase of the perpendicular magnetic anisotropy and coercivity of the FePt-Ag films. On the other hand, in the case of FePd-Ag, Ag addition changed the surface morphology from island to continuous film associated with the reductions of its coercivity and perpendicular anisotropy. The variations of lattice constants and Curie temperature with Ag addition were significantly different between FePt-Ag and FePd-Ag. For FePd-Ag, the c and a axes lattice spacings and Curie temperature gradually changed with increasing Ag content, while they unchanged for FePt-Ag. These results suggest the possibility of the formation of FePdAg alloy in FePd-Ag, while Ag segregation in FePt-Ag.

  12. L1cam is crucial for cell locomotion and terminal translocation of the Soma in radial migration during murine corticogenesis.

    PubMed

    Tonosaki, Madoka; Itoh, Kyoko; Umekage, Masafumi; Kishimoto, Tomokazu; Yaoi, Takeshi; Lemmon, Vance P; Fushiki, Shinji

    2014-01-01

    L1cam (L1) is a cell adhesion molecule associated with a spectrum of human neurological diseases, the most well-known being X-linked hydrocephalus. Although we recently demonstrated that L1 plays an important role in neuronal migration during cortical histogenesis, the mechanisms of delayed migration have still not been clarified. In this study, we found that cell locomotion in the intermediate zone and terminal translocation in the primitive cortical zone (PCZ) were affected by L1-knockdown (L1-KD). Time-lapse analyses revealed that L1-KD neurons produced by in utero electroporation of shRNA targeting L1 (L1-shRNAs) molecules showed decreased locomotion velocity in the intermediate zone, compared with control neurons. Furthermore, L1-KD neurons showed longer and more undulated leading processes during translocation through the primitive cortical zone. The curvature index, a quantitative index for curvilinearity, as well as the length of the leading process, were increased, whereas the somal movement was decreased in L1-KD neurons during terminal translocation in the PCZ. These results suggest that L1 has a role in radial migration of cortical neurons. PMID:24489698

  13. L1cam Is Crucial for Cell Locomotion and Terminal Translocation of the Soma in Radial Migration during Murine Corticogenesis

    PubMed Central

    Tonosaki, Madoka; Itoh, Kyoko; Umekage, Masafumi; Kishimoto, Tomokazu; Yaoi, Takeshi; Lemmon, Vance P.; Fushiki, Shinji

    2014-01-01

    L1cam (L1) is a cell adhesion molecule associated with a spectrum of human neurological diseases, the most well-known being X-linked hydrocephalus. Although we recently demonstrated that L1 plays an important role in neuronal migration during cortical histogenesis, the mechanisms of delayed migration have still not been clarified. In this study, we found that cell locomotion in the intermediate zone and terminal translocation in the primitive cortical zone (PCZ) were affected by L1-knockdown (L1-KD). Time-lapse analyses revealed that L1-KD neurons produced by in utero electroporation of shRNA targeting L1 (L1-shRNAs) molecules showed decreased locomotion velocity in the intermediate zone, compared with control neurons. Furthermore, L1-KD neurons showed longer and more undulated leading processes during translocation through the primitive cortical zone. The curvature index, a quantitative index for curvilinearity, as well as the length of the leading process, were increased, whereas the somal movement was decreased in L1-KD neurons during terminal translocation in the PCZ. These results suggest that L1 has a role in radial migration of cortical neurons. PMID:24489698

  14. CTLA-4 and PD-L1 Checkpoint Blockade Enhances Oncolytic Measles Virus Therapy

    PubMed Central

    Engeland, Christine E; Grossardt, Christian; Veinalde, Rūta; Bossow, Sascha; Lutz, Diana; Kaufmann, Johanna K; Shevchenko, Ivan; Umansky, Viktor; Nettelbeck, Dirk M; Weichert, Wilko; Jäger, Dirk; von Kalle, Christof; Ungerechts, Guy

    2014-01-01

    We hypothesized that the combination of oncolytic virotherapy with immune checkpoint modulators would reduce tumor burden by direct cell lysis and stimulate antitumor immunity. In this study, we have generated attenuated Measles virus (MV) vectors encoding antibodies against CTLA-4 and PD-L1 (MV-aCTLA-4 and MV-aPD-L1). We characterized the vectors in terms of growth kinetics, antibody expression, and cytotoxicity in vitro. Immunotherapeutic effects were assessed in a newly established, fully immunocompetent murine model of malignant melanoma, B16-CD20. Analyses of tumor-infiltrating lymphocytes and restimulation experiments indicated a favorable immune profile after MV-mediated checkpoint modulation. Therapeutic benefits in terms of delayed tumor progression and prolonged median overall survival were observed for animals treated with vectors encoding anti-CTLA-4 and anti-PD-L1, respectively. Combining systemic administration of antibodies with MV treatment also improved therapeutic outcome. In vivo oncolytic efficacy against human tumors was studied in melanoma xenografts. MV-aCTLA-4 and MV-aPD-L1 were equally efficient as parental MV in this model, with high rates of complete tumor remission (> 80%). Furthermore, we could demonstrate lysis of tumor cells and transgene expression in primary tissue from melanoma patients. The current results suggest rapid translation of combining immune checkpoint modulation with oncolytic viruses into clinical application. PMID:25156126

  15. The Wnt Target Gene L1 in Colon Cancer Invasion and Metastasis

    PubMed Central

    Haase, Gal; Gavert, Nancy; Brabletz, Thomas; Ben-Ze’ev, Avri

    2016-01-01

    The Wnt-β-catenin signaling pathway is highly conserved during evolution and determines normal tissue homeostasis. Hyperactivation of Wnt-β-catenin signaling is a characteristic feature of colorectal cancer (CRC) development. β-catenin is a major transducer of the Wnt signal from the cytoplasm into the nucleus where it acts as a co-transcriptional activator of β-catenin-TCF target genes. β-catenin is also required for linking cadherin type cell-cell adhesion receptors to the cytoskeleton, and consequently Wnt-β-catenin signaling is an attractive system for investigating the role of adhesion-mediated signaling in both normal intestinal tissue homeostasis and CRC development. In this review, we summarize our studies on one Wnt-β-catenin target gene, L1, a member of the immunoglobulin-like cell adhesion transmembrane receptor family. We describe the mechanisms of L1-mediated signaling in CRC cells, its exclusive localization in invasive areas of CRC tissue, and its ability to increase cell motility and confer metastasis to the liver. We discuss the activation (by L1) of genes via an ezrin-NF-κB pathway and the induction of genes also found in the intestinal stem cell signature. By studying L1 (adhesion)-mediated signaling, we expect to learn about mechanisms regulating both normal intestinal homeostasis and CRC development. PMID:27187476

  16. The Effects of Repetition and L1 Lexicalization on Incidental Vocabulary Acquisition by Iranian EFL Learners

    ERIC Educational Resources Information Center

    Heidari-Shahreza, Mohammad Ali; Tavakoli, Mansoor

    2016-01-01

    Based on a prior study by Chen and Truscott, the present study investigated the possible effects of repetition (repeated exposure) and L1 lexicalization on the incidental acquisition and retention of 10 English target words by 90 Persian-speaking EFL learners at an Iranian university. Seven aspects of vocabulary knowledge were measured, including…

  17. Reprogramming triggers endogenous L1 and Alu retrotransposition in human induced pluripotent stem cells

    PubMed Central

    Klawitter, Sabine; Fuchs, Nina V.; Upton, Kyle R.; Muñoz-Lopez, Martin; Shukla, Ruchi; Wang, Jichang; Garcia-Cañadas, Marta; Lopez-Ruiz, Cesar; Gerhardt, Daniel J.; Sebe, Attila; Grabundzija, Ivana; Merkert, Sylvia; Gerdes, Patricia; Pulgarin, J. Andres; Bock, Anja; Held, Ulrike; Witthuhn, Anett; Haase, Alexandra; Sarkadi, Balázs; Löwer, Johannes; Wolvetang, Ernst J.; Martin, Ulrich; Ivics, Zoltán; Izsvák, Zsuzsanna; Garcia-Perez, Jose L.; Faulkner, Geoffrey J.; Schumann, Gerald G.

    2016-01-01

    Human induced pluripotent stem cells (hiPSCs) are capable of unlimited proliferation and can differentiate in vitro to generate derivatives of the three primary germ layers. Genetic and epigenetic abnormalities have been reported by Wissing and colleagues to occur during hiPSC derivation, including mobilization of engineered LINE-1 (L1) retrotransposons. However, incidence and functional impact of endogenous retrotransposition in hiPSCs are yet to be established. Here we apply retrotransposon capture sequencing to eight hiPSC lines and three human embryonic stem cell (hESC) lines, revealing endogenous L1, Alu and SINE-VNTR-Alu (SVA) mobilization during reprogramming and pluripotent stem cell cultivation. Surprisingly, 4/7 de novo L1 insertions are full length and 6/11 retrotransposition events occurred in protein-coding genes expressed in pluripotent stem cells. We further demonstrate that an intronic L1 insertion in the CADPS2 gene is acquired during hiPSC cultivation and disrupts CADPS2 expression. These experiments elucidate endogenous retrotransposition, and its potential consequences, in hiPSCs and hESCs. PMID:26743714

  18. Enhancing Foreign Language Learning through Listening Strategies Delivered in L1: An Experimental Study

    ERIC Educational Resources Information Center

    Bozorgian, Hossein; Pillay, Hitendra

    2013-01-01

    Listening used in language teaching refers to a complex process that allows us to understand spoken language. The current study, conducted in Iran with an experimental design, investigated the effectiveness of teaching listening strategies delivered in L1 (Persian) and its effect on listening comprehension in L2. Five listening strategies:…

  19. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure).

    PubMed

    Kim, J M; Chen, D S

    2016-08-01

    The emergence of programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1)-targeted therapy has demonstrated the importance of the PD-L1 : PD-1 interaction in inhibiting anticancer T-cell immunity in multiple human cancers, generating durable responses and extended overall survival. However, not all patients treated with PD-L1/PD-1-targeted therapy experience tumor shrinkage, durable responses, or prolonged survival. To extend such benefits to more cancer patients, it is necessary to understand why some patients experience primary or secondary immune escape, in which the immune response is incapable of eradicating all cancer cells. Understanding immune escape from PD-L1/PD-1-targeted therapy will be important to the development of rational immune-combination therapy and predictive diagnostics and to the identification of novel immune targets. Factors that likely relate to immune escape include the lack of strong cancer antigens or epitopes recognized by T cells, minimal activation of cancer-specific T cells, poor infiltration of T cells into tumors, downregulation of the major histocompatibility complex on cancer cells, and immunosuppressive factors and cells in the tumor microenvironment. Precisely identifying and understanding these mechanisms of immune escape in individual cancer patients will allow for personalized cancer immunotherapy, in which monotherapy and combination immunotherapy are chosen based on the presence of specific immune biology. This approach may enable treatment with immunotherapy without inducing immune escape, resulting in a larger proportion of patients obtaining clinical benefit. PMID:27207108

  20. Olanzapine induces SREBP-1-related adipogenesis in 3T3-L1 cells.

    PubMed

    Yang, Li-Hung; Chen, Tzer-Ming; Yu, Sung-Tsai; Chen, Yen-Hui

    2007-09-01

    Olanzapine is a second-generation atypical antipsychotic drug (AAPD). Major side effects of olanzapine are weight gain and development of diabetes mellitus, which are risk factors of cardiovascular diseases. The possible causes of metabolic adverse effects are known as poor satiety and increased food intake due to blockade of receptors such as 5-HT(2C) in CNS. In this study, we examine the effect of olanzapine on peripheral adipogenesis using cultured 3T3-L1 cell model. Olanzapine increased triacylglyceride (TG) accumulation during 3T3-L1 preadipocyte differentiation to mature adipocyte phenotype. TG accumulation was accompanied by overexpression of fatty acid synthase and adiponectin that are the downstream genes of sterol regulatory element binding protein-1 (SREBP-1), one of the key transcription factors in lipid homeostasis. We further consisted that mostly SREBP-1 and at a lesser extent peroxisome proliferator-activated receptor gamma (PPAR-gamma), but not CCAAT/enhancer binding protein-alpha (C/EBP-alpha), were overexpressed and activated in 3T3-L1 adipocytes exposed to olanzapine. Furthermore, we showed that olanzapine enhanced the activity of SRE-1-containing LDLR promoter in transfected 3T3-L1 adipocytes and HepG2 cells. Taken together, olanzapine may cause body weight gain not only through influencing CNS receptors, but also affecting the peripheral adipogenesis regulated by SREBP-1. PMID:17651982

  1. 16. DETAIL, L1 JOINT, FROM BELOW AND SOUTH, SHOWING RIVETED ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    16. DETAIL, L1 JOINT, FROM BELOW AND SOUTH, SHOWING RIVETED CONNECTION, AND CONFIGURATION OF VERTICAL U1-I1, LOWER CHORD AND FLOOR SYSTEM - Glendale Road Bridge, Spanning Deep Creek Lake on Glendale Road, McHenry, Garrett County, MD

  2. Reprogramming triggers endogenous L1 and Alu retrotransposition in human induced pluripotent stem cells.

    PubMed

    Klawitter, Sabine; Fuchs, Nina V; Upton, Kyle R; Muñoz-Lopez, Martin; Shukla, Ruchi; Wang, Jichang; Garcia-Cañadas, Marta; Lopez-Ruiz, Cesar; Gerhardt, Daniel J; Sebe, Attila; Grabundzija, Ivana; Merkert, Sylvia; Gerdes, Patricia; Pulgarin, J Andres; Bock, Anja; Held, Ulrike; Witthuhn, Anett; Haase, Alexandra; Sarkadi, Balázs; Löwer, Johannes; Wolvetang, Ernst J; Martin, Ulrich; Ivics, Zoltán; Izsvák, Zsuzsanna; Garcia-Perez, Jose L; Faulkner, Geoffrey J; Schumann, Gerald G

    2016-01-01

    Human induced pluripotent stem cells (hiPSCs) are capable of unlimited proliferation and can differentiate in vitro to generate derivatives of the three primary germ layers. Genetic and epigenetic abnormalities have been reported by Wissing and colleagues to occur during hiPSC derivation, including mobilization of engineered LINE-1 (L1) retrotransposons. However, incidence and functional impact of endogenous retrotransposition in hiPSCs are yet to be established. Here we apply retrotransposon capture sequencing to eight hiPSC lines and three human embryonic stem cell (hESC) lines, revealing endogenous L1, Alu and SINE-VNTR-Alu (SVA) mobilization during reprogramming and pluripotent stem cell cultivation. Surprisingly, 4/7 de novo L1 insertions are full length and 6/11 retrotransposition events occurred in protein-coding genes expressed in pluripotent stem cells. We further demonstrate that an intronic L1 insertion in the CADPS2 gene is acquired during hiPSC cultivation and disrupts CADPS2 expression. These experiments elucidate endogenous retrotransposition, and its potential consequences, in hiPSCs and hESCs. PMID:26743714

  3. Anti-Obesity Effects of Starter Fermented Kimchi on 3T3-L1 Adipocytes

    PubMed Central

    Lee, Kyung-Hee; Song, Jia-Le; Park, Eui-Seong; Ju, Jaehyun; Kim, Hee-Young; Park, Kun-Young

    2015-01-01

    The anti-obesity effects of starter (Leuconostoc mesenteroides+Lactobacillus plantarum) fermented kimchi on 3T3-L1 adipocyte were studied using naturally fermented kimchi (NK), a functional kimchi (FK, NK supplemented with green tea), and FK supplemented with added starters (FKS). Oil red O staining and cellular levels of triglyceride (TG) and glycerol were used to evaluate the in vitro anti-obesity effects of these kimchis in 3T3-L1 cells. The expressions of adipogenesis/lipogenesis-related genes of peroxisome proliferator-active receptor (PPAR)-γ, CCAAT/enhance-binding protein (C/EBP)-α, and fatty acid synthase (FAS) were determined by RT-PCR. Kimchis, especially FKS, markedly decreased TG levels and increased levels of intracellular glycerol and lipid lipolysis. In addition, FKS also reduced the mRNA levels of PPAR-γ, C/EBP-α, and FAS, which are related to adipogenesis/lipogenesis in 3T3-L1 cells. These results suggest the anti-obesity effects of FKS were to due to enhanced lipolysis and reduced adipogenesis/lipogenesis in 3T3-L1 adipocytes. PMID:26770918

  4. Niemann-Pick C1-Like 1 (NPC1L1) Inhibition and Cardiovascular Diseases.

    PubMed

    Pirillo, A; Catapano, A L; Norata, G D

    2016-01-01

    Circulating levels of cholesterol are derived from either endogenous production or intestinal absorption of dietary and biliary cholesterol. Niemann-Pick C1-Like 1 (NPC1L1) is a transmembrane protein that plays a key role in the intestinal absorption of cholesterol by facilitating its uptake through vesicular endocytosis. NPC1L1 is the molecular target of ezetimibe which binds its extracellular loop and inhibits sterol absorption without affecting the absorption of other molecules. Ezetimibe significantly reduces plasma levels of total and low density lipoprotein cholesterol (LDL-C) as monotherapy or when added to statins, the association with a low dose of statin is of particular interest for patients experiencing statin-related side effects. The recent results of the IMPROVE-IT study, which evaluated the cardiovascular effect of ezetimibe added to simvastatin therapy in subjects who had had an acute coronary syndrome and with LDL-C levels within the recommended range, showed that a further LDL-C lowering reduced the incidence of cardiovascular events. To date, ezetimibe represents the only inhibitor of NPC1L1 available for clinical use, however, novel aminoß- lactam ezetimibe derivatives have been synthesized and their efficacy to inhibit NPC1L1 protein and decrease plasma cholesterol levels is under evaluation. PMID:26923679

  5. Application of L1-norm regularization to epicardial potential reconstruction based on gradient projection

    NASA Astrophysics Data System (ADS)

    Wang, Liansheng; Qin, Jing; Tsin Wong, Tien; Heng, Pheng Ann

    2011-10-01

    The epicardial potential (EP)-targeted inverse problem of electrocardiography (ECG) has been widely investigated as it is demonstrated that EPs reflect underlying myocardial activity. It is a well-known ill-posed problem as small noises in input data may yield a highly unstable solution. Traditionally, L2-norm regularization methods have been proposed to solve this ill-posed problem. But the L2-norm penalty function inherently leads to considerable smoothing of the solution, which reduces the accuracy of distinguishing abnormalities and locating diseased regions. Directly using the L1-norm penalty function, however, may greatly increase computational complexity due to its non-differentiability. We propose an L1-norm regularization method in order to reduce the computational complexity and make rapid convergence possible. Variable splitting is employed to make the L1-norm penalty function differentiable based on the observation that both positive and negative potentials exist on the epicardial surface. Then, the inverse problem of ECG is further formulated as a bound-constrained quadratic problem, which can be efficiently solved by gradient projection in an iterative manner. Extensive experiments conducted on both synthetic data and real data demonstrate that the proposed method can handle both measurement noise and geometry noise and obtain more accurate results than previous L2- and L1-norm regularization methods, especially when the noises are large.

  6. Comparing Hypertext Reading in L1 and L2: The Case of Filipino Adults

    ERIC Educational Resources Information Center

    Gruspe, Michael Angelo M.; Marinas, Christian Joshua L.; Villasin, Marren Nicole F.; Villanueva, Ariel Josephe Therese R.; Vizconde, Camilla J.

    2015-01-01

    This research probed into the reading experiences of adult readers in their first language (L1) and second language (L2). Qualitative in nature, the investigation focused on twelve (12) adult readers , six (6) males and six (6) females, whose first language is Filipino. Data were gathered through interviews and focus-group discussions. Based on…

  7. Assessment of Serum UCH-L1 and GFAP in Acute Stroke Patients

    PubMed Central

    Ren, Changhong; Kobeissy, Firas; Alawieh, Ali; Li, Na; Li, Ning; Zibara, Kazem; Zoltewicz, Susie; Guingab-Cagmat, Joy; Larner, Stephen F.; Ding, Yuchuan; Hayes, Ronald L.; Ji, Xunming; Mondello, Stefania

    2016-01-01

    A rapid and reliable diagnostic test to distinguish ischemic from hemorrhagic stroke in patients presenting with stroke-like symptoms is essential to optimize management and triage for thrombolytic therapy. The present study measured serum concentrations of ubiquitin C-terminal hydrolase (UCH-L1) and glial fibrillary astrocytic protein (GFAP) in acute stroke patients and healthy controls and investigated their relation to stroke severity and patient characteristics. We also assessed the diagnostic performance of these markers for the differentiation of intracerebral hemorrhage (ICH) from ischemic stroke (IS). Both UCH-L1 and GFAP concentrations were significantly greater in ICH patients than in controls (p < 0.0001). However, exclusively GFAP differed in ICH compared with IS (p < 0.0001). GFAP yielded an AUC of 0.86 for differentiating between ICH and IS within 4.5hrs of symptom onset with a sensitivity of 61% and a specificity of 96% using a cut-off of 0.34ng/ml. Higher GFAP levels were associated with stroke severity and history of prior stroke. Our results demonstrate that blood UCH-L1 and GFAP are increased early after stroke and distinct biomarker-specific release profiles are associated with stroke characteristics and type. We also confirmed the potential of GFAP as a tool for early rule-in of ICH, while UCH-L1 was not clinically useful. PMID:27074724

  8. Effect of Gambisan on the Inhibition of Adipogenesis in 3T3-L1 Adipocytes

    PubMed Central

    Kang, Jung Won; Nam, Dongwoo; Kim, Kun Hyung; Huh, Jeong-Eun; Lee, Jae-Dong

    2013-01-01

    This study was conducted to explore the antiadipogenic effect and possible mechanism of Gambisan on 3T3-L1 cells. For quality control, Gambisan was standardized by HPLC and the standard compounds ephedrine, epigallocatechin-3-gallate, and caffeine were screened. Cultured 3T3-L1 cells that had been induced to differentiate were treated with various concentrations of Gambisan or its major component extracts (Ephedra intermedia Schrenk, Atractylodes lancea DC., and Thea sinensis L.) for 72 hours for MTT assay to determine cell viability or 10 days for LDH assay, triglyceride assay, DNA content measurement, Oil red O staining, RT-PCR, and western blot. Gambisan significantly inhibited adipogenesis in 3T3-L1 cells by reducing triglyceride contents and lipid accumulation in a dose-dependent manner without obvious cytotoxicity. Viability and DNA content in 3T3-L1 cells treated with Gambisan were significantly higher than cells treated with the major component extracts at every concentration. The anti-adipogenic effects of Gambisan appeared to be mediated by a significant downregulation of the expression of lipoprotein lipase mRNA and PPARγ, C/EBPα, and SREBP-1 protein apart from the expression of hormone-sensitive lipase. Gambisan could act as a possible therapeutic agent for obesity. However, further studies including in vivo assays and clinical trials are needed to confirm the efficacy, safety and mechanisms of the antiobesity effects of Gambisan. PMID:24069055

  9. MASA syndrome is caused by mutations in the neural cell adhesion gene, L1CAM

    SciTech Connect

    Schwartz, C.E.; Wang, Y.; Schroer, R.J.; Stevenson, R.E.

    1994-09-01

    The MASA syndrome is a recessive X-linked disorder characterized by Mental retardation, Adducted thumbs, Shuffling gait and Aphasia. Recently we found that MASA in one family was likely caused by a point mutation in exon 6 of the L1CAM gene. This gene has also been shown to be involved in X-linked hydrocephalus (HSAS). We have screened 60 patients with either sporadic HSAS or MASA as well as two additional families with MASA. For the screening, we initially utilized 3 cDNA probes for the L1CAM gene. In one of the MASA families, K8310, two affected males were found to have an altered BglII band. The band was present in their carrier mother but not in their normal brothers. This band was detected by the entire cDNA probe as well as the cDNA probe for 3{prime} end of the gene. Analysis of the L1CAM sequence indicated the altered BglII site is distal to the exon 28 but proximal to the punative poly A signal site. It is hypothesized that this point mutation alters the stability of the L1CAM mRNA. This is being tested using cell lines established from the two affected males.

  10. Perceptual Processing of Mandarin Nasals by L1 and L2 Mandarin Speakers

    ERIC Educational Resources Information Center

    Lai, Yi-hsiu

    2012-01-01

    Nasals are cross-linguistically susceptible to change, especially in the syllable final position. Acoustic reports on Mandarin nasal production have recently shown that the syllable-final distinction is frequently dropped. Few studies, however, have addressed the issue of perceptual processing in Mandarin nasals for L1 and L2 speakers of Mandarin…

  11. On helium-like 1s2l-1snl prime transitions in solar flare spectra

    NASA Technical Reports Server (NTRS)

    Kastner, S. O.; Neupert, W. M.; Swartz, M.

    1974-01-01

    Expected wavelengths and intensities are computed for 1s2l-1snl prime transitions in helium-like ions of the abundant elements from oxygen to iron under coronal conditions. Probable observations of some of these lines in the spectra of solar flares are discussed, and attention is called to a possible reversal of singlet and triplet intensities as compared to laboratory observations.

  12. A Dutch Comprehension Test for Identifying Reading Problems in L1 and L2 Students.

    ERIC Educational Resources Information Center

    Hacquebord, Hilde

    1999-01-01

    Evaluates the Dutch Text Comprehension Test, developed to help improve the education of secondary school minority students in the Netherlands. Finds the test proved reliable for both L1 students and L2 students. Suggests, although classification results were not optimal, the test can be used for diagnostic purposes provided a relatively large…

  13. Developmental Trends and L1 Effects in Early L2 Learners' Onset Cluster Production

    ERIC Educational Resources Information Center

    Tessier, Anne-Michelle; Duncan, Tamara Sorenson; Paradis, Johanne

    2013-01-01

    This study focuses on English onset cluster production in spontaneous speech samples of 10 children aged 5;04-6;09 from Chinese and Hindi/Punjabi first language (L1) backgrounds, each with less than a year of exposure to English. The results suggest commonalities between early second language (L2) learners and both monolingual and adult L2…

  14. L1 and L2 Observatories for Earth Science Vision in the Post-2010 Era

    NASA Technical Reports Server (NTRS)

    Wiscombe, Warren; Herman, Jay; Valero, Francisco; Lau, William (Technical Monitor)

    2002-01-01

    NASA's Post-2010 Earth Science Vision is partly built around a new paradigm called the Sensor Web, involving a collaborating set of sensors ranging from deep space, at the L1 and L2 (Lagrange) points, down to the ocean and land surfaces. L1 and L2 observatories, roughly 1.5 million km from Earth towards and away from the Sun, respectively, provide unique vantage points. from L1, the entire sunlit face of the Earth is visible, and from L2, the entire night side. In tandem, they can observe the entire Earth simultaneously, with much less stitching than now needed to patch together the five operational geostationary images. This makes new kinds of science possible, especially science requiring synoptic (simultaneous) observations over the whole globe. Triana, the pioneer of these kinds of observatories, is currently waiting for a launch opportunity. We will describe the novel features of the Triana mission, and of the L1 and L2 vantage points, with examples of the kinds of science that can be done from these points and examples of the way in which Earth observation from such great distances is pushing instrument technology.

  15. Fault Tolerance Analysis of L1 Adaptive Control System for Unmanned Aerial Vehicles

    NASA Astrophysics Data System (ADS)

    Krishnamoorthy, Kiruthika

    Trajectory tracking is a critical element for the better functionality of autonomous vehicles. The main objective of this research study was to implement and analyze L1 adaptive control laws for autonomous flight under normal and upset flight conditions. The West Virginia University (WVU) Unmanned Aerial Vehicle flight simulation environment was used for this purpose. A comparison study between the L1 adaptive controller and a baseline conventional controller, which relies on position, proportional, and integral compensation, has been performed for a reduced size jet aircraft, the WVU YF-22. Special attention was given to the performance of the proposed control laws in the presence of abnormal conditions. The abnormal conditions considered are locked actuators (stabilator, aileron, and rudder) and excessive turbulence. Several levels of abnormal condition severity have been considered. The performance of the control laws was assessed over different-shape commanded trajectories. A set of comprehensive evaluation metrics was defined and used to analyze the performance of autonomous flight control laws in terms of control activity and trajectory tracking errors. The developed L1 adaptive control laws are supported by theoretical stability guarantees. The simulation results show that L1 adaptive output feedback controller achieves better trajectory tracking with lower level of control actuation as compared to the baseline linear controller under nominal and abnormal conditions.

  16. CATS-ISS_L1B_D-M7.2-V2-06

    Atmospheric Science Data Center

    2016-04-27

    CATS-ISS_L1B_D-M7.2-V2-06 The Cloud-Aerosol Transport System (CATS) is a three wavelength, polarization-sensitive lidar that provides ... in the Earth's atmosphere. Project Title:  CATS Discipline:  Clouds Aerosols Version:  ...

  17. CATS-ISS_L1B_N-M7.1-V2-04

    Atmospheric Science Data Center

    2016-04-27

    CATS-ISS_L1B_N-M7.1-V2-04 The Cloud-Aerosol Transport System (CATS) is a three wavelength, polarization-sensitive lidar that provides ... in the Earth's atmosphere. Project Title:  CATS Discipline:  Clouds Aerosols Version:  ...

  18. CATS-ISS_L1B_N-M7.2-V2-05

    Atmospheric Science Data Center

    2016-04-27

    CATS-ISS_L1B_N-M7.2-V2-05 The Cloud-Aerosol Transport System (CATS) is a three wavelength, polarization-sensitive lidar that provides ... in the Earth's atmosphere. Project Title:  CATS Discipline:  Clouds Aerosols Version:  ...

  19. Processing Focus Structure in L1 and L2 French: L2 Proficiency Effects on ERPs

    ERIC Educational Resources Information Center

    Reichle, Robert V.; Birdsong, David

    2014-01-01

    This study examined the event-related potentials (ERPs) elicited by focus processing among first language (L1) speakers and second language (L2) learners of French. Participants read wh-questions containing explicit focus marking, followed by responses instantiating contrastive and informational focus. We hypothesized that L2 proficiency would…

  20. Atypical calcium regulation of the PKD2-L1 polycystin ion channel

    PubMed Central

    DeCaen, Paul G; Liu, Xiaowen; Abiria, Sunday; Clapham, David E

    2016-01-01

    Native PKD2-L1 channel subunits are present in primary cilia and other restricted cellular spaces. Here we investigate the mechanism for the channel's unusual regulation by external calcium, and rationalize this behavior to its specialized function. We report that the human PKD2-L1 selectivity filter is partially selective to calcium ions (Ca2+) moving into the cell, but blocked by high internal Ca2+concentrations, a unique feature of this transient receptor potential (TRP) channel family member. Surprisingly, we find that the C-terminal EF-hands and coiled-coil domains do not contribute to PKD2-L1 Ca2+-induced potentiation and inactivation. We propose a model in which prolonged channel activity results in calcium accumulation, triggering outward-moving Ca2+ ions to block PKD2-L1 in a high-affinity interaction with the innermost acidic residue (D523) of the selectivity filter and subsequent long-term channel inactivation. This response rectifies Ca2+ flow, enabling Ca2+ to enter but not leave small compartments such as the cilium. DOI: http://dx.doi.org/10.7554/eLife.13413.001 PMID:27348301

  1. Fluorescence lifetime imaging of lipids during 3T3-L1 cell differentiation

    NASA Astrophysics Data System (ADS)

    Song, Young Sik; Won, Young Jae; Lee, Sang-Hak; Kim, Dug Young

    2014-03-01

    Obesity is becoming a big health problem in these days. Since increased body weight is due to increased number and size of the triglyceride-storing adipocytes, many researchers are working on differentiation conditions and processes of adipocytes. Adipocytes also work as regulators of whole-body energy homeostasis by secreting several proteins that regulate processes as diverse as haemostasis, blood pressure, immune function, angiogenesis and energy balance. 3T3-L1 cells are widely used cell line for studying adipogenesis because it can differentiate into an adipocyte-like phenotype under appropriate conditions. In this paper, we propose an effective fluorescence lifetime imaging technique which can easily distinguish lipids in membrane and those in lipid droplets. Nile red dyes are attached to lipids in 3T3-L1 cells. Fluorescence lifetime images were taken for 2 week during differentiation procedure of 3T3-L1 cells into adipocytes. We used 488 nm pulsed laser with 5MHz repetition rate and emission wavelength is 520 nm of Nile Red fluorescent dye. Results clearly show that the lifetime of Nile red in lipid droplets are smaller than those in cell membrane. Our results suggest that fluorescence lifetime imaging can be a very powerful tool to monitor lipid droplet formation in adipocytes from 3T3-L1 cells.

  2. L1/L2/L3 Writing Development: Longitudinal Case Study of a Japanese Multicompetent Writer

    ERIC Educational Resources Information Center

    Kobayashi, Hiroe; Rinnert, Carol

    2013-01-01

    This longitudinal case study, supplemented by cross-sectional comparisons among five groups of writers with differing backgrounds, investigates how Natsu, a Japanese multilingual writer, developed her L1, L2 (English), and L3 (Chinese) writing competence over two and a half years. To create a comprehensive picture of this multilingual writer, the…

  3. Spanish as a Second Language when L1 Is Quechua: Endangered Languages and the SLA Researcher

    ERIC Educational Resources Information Center

    Kalt, Susan E.

    2012-01-01

    Spanish is one of the most widely spoken languages in the world. Quechua is the largest indigenous language family to constitute the first language (L1) of second language (L2) Spanish speakers. Despite sheer number of speakers and typologically interesting contrasts, Quechua-Spanish second language acquisition is a nearly untapped research area,…

  4. The Wnt Target Gene L1 in Colon Cancer Invasion and Metastasis.

    PubMed

    Haase, Gal; Gavert, Nancy; Brabletz, Thomas; Ben-Ze'ev, Avri

    2016-01-01

    The Wnt-β-catenin signaling pathway is highly conserved during evolution and determines normal tissue homeostasis. Hyperactivation of Wnt-β-catenin signaling is a characteristic feature of colorectal cancer (CRC) development. β-catenin is a major transducer of the Wnt signal from the cytoplasm into the nucleus where it acts as a co-transcriptional activator of β-catenin-TCF target genes. β-catenin is also required for linking cadherin type cell-cell adhesion receptors to the cytoskeleton, and consequently Wnt-β-catenin signaling is an attractive system for investigating the role of adhesion-mediated signaling in both normal intestinal tissue homeostasis and CRC development. In this review, we summarize our studies on one Wnt-β-catenin target gene, L1, a member of the immunoglobulin-like cell adhesion transmembrane receptor family. We describe the mechanisms of L1-mediated signaling in CRC cells, its exclusive localization in invasive areas of CRC tissue, and its ability to increase cell motility and confer metastasis to the liver. We discuss the activation (by L1) of genes via an ezrin-NF-κB pathway and the induction of genes also found in the intestinal stem cell signature. By studying L1 (adhesion)-mediated signaling, we expect to learn about mechanisms regulating both normal intestinal homeostasis and CRC development. PMID:27187476

  5. Factors Influencing Pronunciation Accuracy: L1 Negative Transfer, Task Variables and Individual Aptitude

    ERIC Educational Resources Information Center

    Liu, Qian

    2011-01-01

    This paper investigates the influence of three factors on pronunciation accuracy of Chinese adult foreign language learners. Ten target sounds including phonemes and syllables are included in the pre-test, an analysis of which shows that the mispronunciation of the randomly chosen target sounds mainly results from L1 negative transfer. It is…

  6. Production and characterization of ZFP36L1 antiserum against recombinant protein from Escherichia coli

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Tristetraprolin (TTP/ZFP36) family proteins are anti-inflammatory. They bind and destabilize some AU-rich element-containing mRNAs such as tumor necrosis factor mRNA. In this study, recombinant ZFP36L1/TIS11B (a TTP homologue) was over-expressed in E. coli, purified, and used for polyclonal antibody...

  7. Induced PD-L1 expression mediates acquired resistance to agonistic anti-CD40 treatment.

    PubMed

    Zippelius, Alfred; Schreiner, Jens; Herzig, Petra; Müller, Philipp

    2015-03-01

    CD40 stimulation on antigen-presenting cells (APC) allows direct activation of CD8(+) cytotoxic T cells, independent of CD4⁺ T-cell help. Agonistic anti-CD40 antibodies have been demonstrated to induce beneficial antitumor T-cell responses in mouse models of cancer and early clinical trials. We report here that anti-CD40 treatment induces programmed death ligand-1 (PD-L1) upregulation on tumor-infiltrating monocytes and macrophages, which was strictly dependent on T cells and IFNγ. PD-L1 expression could be counteracted by coadministration of antibodies blocking the PD-1 (programmed death-1)/PD-L1 axis as shown for T cells from tumor models and human donors. The combined treatment was highly synergistic and induced complete tumor rejection in about 50% of mice bearing MC-38 colon and EMT-6 breast tumors. Mechanistically, this was reflected by a strong increase of IFNγ and granzyme-B production in intratumoral CD8⁺ T cells. Concomitant CTLA-4 blockade further improved rejection of established tumors in mice. This study uncovers a novel mechanism of acquired resistance upon agonistic CD40 stimulation and proposes that the concomitant blockade of the PD-1/PD-L1 axis is a viable therapeutic strategy to optimize clinical outcomes. PMID:25623164

  8. Cone Dystrophy in Patient with Homozygous RP1L1 Mutation

    PubMed Central

    Kikuchi, Sachiko; El Shamieh, Said; Akeo, Keiichiro; Sugawara, Yuko; Yamaki, Kunihiko; Takahashi, Hiroshi

    2015-01-01

    The purpose of this study was to determine whether an autosomal recessive cone dystrophy was caused by a homozygous RP1L1 mutation. A family including one subject affected with cone dystrophy and four unaffected members without evidence of consanguinity underwent detailed ophthalmic evaluations. The ellipsoid and interdigitation zones on the spectral-domain optical coherence tomography images were disorganized in the proband. The proband had a reduced amplitude of cone and flicker full-field electroretinograms (ERGs). Focal macular ERGs and multifocal ERGs were severely reduced in the proband. A homozygous RP1L1 mutation (c.3628T>C, p.S1210P) was identified in the proband. Family members who were heterozygous for the p.S1210P mutation had normal visual acuity and normal results of clinical evaluations. To investigate other putative pathogenic variant(s), a next-generation sequencing (NGS) approach was applied to the proband. NGS identified missense changes in the heterozygous state of the PCDH15, RPGRIP1, and GPR98 genes. None of these variants cosegregated with the phenotype and were predicted to be benign reinforcing the putative pathogenicity of the RP1L1 homozygous mutation. The AO images showed a severe reduction of the cone density in the proband. Our findings indicate that a homozygous p.S1210P exchange in the RP1L1 gene can cause cone dystrophy. PMID:25692141

  9. Cdk5 disruption attenuates tumor PD-L1 expression and promotes antitumor immunity.

    PubMed

    Dorand, R Dixon; Nthale, Joseph; Myers, Jay T; Barkauskas, Deborah S; Avril, Stefanie; Chirieleison, Steven M; Pareek, Tej K; Abbott, Derek W; Stearns, Duncan S; Letterio, John J; Huang, Alex Y; Petrosiute, Agne

    2016-07-22

    Cancers often evade immune surveillance by adopting peripheral tissue- tolerance mechanisms, such as the expression of programmed cell death ligand 1 (PD-L1), the inhibition of which results in potent antitumor immunity. Here, we show that cyclin-dependent kinase 5 (Cdk5), a serine-threonine kinase that is highly active in postmitotic neurons and in many cancers, allows medulloblastoma (MB) to evade immune elimination. Interferon-γ (IFN-γ)-induced PD-L1 up-regulation on MB requires Cdk5, and disruption of Cdk5 expression in a mouse model of MB results in potent CD4(+) T cell-mediated tumor rejection. Loss of Cdk5 results in persistent expression of the PD-L1 transcriptional repressors, the interferon regulatory factors IRF2 and IRF2BP2, which likely leads to reduced PD-L1 expression on tumors. Our finding highlights a central role for Cdk5 in immune checkpoint regulation by tumor cells. PMID:27463676

  10. Relations among L1 Reading, L2 Knowledge, and L2 Reading: Revisiting the Threshold Hypothesis

    ERIC Educational Resources Information Center

    Park, Gi-Pyo

    2013-01-01

    This study attempted to test the threshold hypothesis in second/foreign language (L2) reading by investigating the relations among first language (L1) reading, L2 knowledge, and L2 reading comprehension in a sample of 2666 (1333 males and 1333 females) Korean EFL high school students. Three different methods of data analysis were utilized after…

  11. A Prerequisite to L1 Homophone Effects in L2 Spoken-Word Recognition

    ERIC Educational Resources Information Center

    Nakai, Satsuki; Lindsay, Shane; Ota, Mitsuhiko

    2015-01-01

    When both members of a phonemic contrast in L2 (second language) are perceptually mapped to a single phoneme in one's L1 (first language), L2 words containing a member of that contrast can spuriously activate L2 words in spoken-word recognition. For example, upon hearing cattle, Dutch speakers of English are reported to experience activation…

  12. The Interlanguage Grammar of Information Management in L1 and L2 Developing Writing

    ERIC Educational Resources Information Center

    Kenkel, James; Yates, Robert

    2009-01-01

    In the tradition of work by Shaughnessy (1977) and Bartholomae (1980) applying concepts from second language acquisition research to developing writing, we explore the commonalities of L1 and L2 writers on the specific level of linguistic choices needed to order information within and across sentence boundaries. We propose that many of the kinds…

  13. L1-L2 Convergence in Clausal Packaging in Japanese and English

    ERIC Educational Resources Information Center

    Brown, Amanda; Gullberg, Marianne

    2013-01-01

    This study investigates L1-L2 convergence among bilinguals at an intermediate (CEFR-B2) level of L2 proficiency, focusing on the clausal packaging of Manner and Path of motion. Previous research has shown cross-linguistic differences between English and Japanese in this domain (Allen et al., 2003; Kita & Ozyurek, 2003, though note Brown &…

  14. Concentration of the L_1-norm of trigonometric polynomials and entire functions

    NASA Astrophysics Data System (ADS)

    Malykhin, Yu V.; Ryutin, K. S.

    2014-11-01

    For any sufficiently large n, the minimal measure of a subset of \\lbrack -π,π \\rbrack on which some nonzero trigonometric polynomial of order ≤ n gains half of the L_1-norm is shown to be π/(n+1). A similar result for entire functions of exponential type is established. Bibliography: 13 titles.

  15. ZFP36L1 promotes monocyte/macrophage differentiation by repressing CDK6

    PubMed Central

    Chen, Ming-Tai; Dong, Lei; Zhang, Xin-Hua; Yin, Xiao-Lin; Ning, Hong-Mei; Shen, Chao; Su, Rui; Li, Feng; Song, Li; Ma, Yan-Ni; Wang, Fang; Zhao, Hua-Lu; Yu, Jia; Zhang, Jun-Wu

    2015-01-01

    RNA binding proteins (RBPs)-mediated post-transcriptional control has been implicated in influencing various aspects of RNA metabolism and playing important roles in mammalian development and pathological diseases. However, the functions of specific RBPs and the molecular mechanisms through which they act in monocyte/macrophage differentiation remain to be determined. In this study, through bioinformatics analysis and experimental validation, we identify that ZFP36L1, a member of ZFP36 zinc finger protein family, exhibits significant decrease in acute myeloid leukemia (AML) patients compared with normal controls and remarkable time-course increase during monocyte/macrophage differentiation of PMA-induced THP-1 and HL-60 cells as well as induction culture of CD34+ hematopoietic stem/progenitor cells (HSPCs). Lentivirus-mediated gain and loss of function assays demonstrate that ZFP36L1 acts as a positive regulator to participate in monocyte/macrophage differentiation. Mechanistic investigation further reveals that ZFP36L1 binds to the CDK6 mRNA 3′untranslated region bearing adenine-uridine rich elements and negatively regulates the expression of CDK6 which is subsequently demonstrated to impede the in vitro monocyte/macrophage differentiation of CD34+ HSPCs. Collectively, our work unravels a ZFP36L1-mediated regulatory circuit through repressing CDK6 expression during monocyte/macrophage differentiation, which may also provide a therapeutic target for AML therapy. PMID:26542173

  16. Phonological Awareness in Hebrew (L1) and English (L2) in Normal and Disabled Readers

    ERIC Educational Resources Information Center

    Russak, Susie; Saiegh-Haddad, Elinor

    2011-01-01

    The present study examined cross-linguistic relationships between phonological awareness in L1 (Hebrew) and L2 (English) among normal (N = 30) and reading disabled (N = 30) Hebrew native speaking college students. Further, it tested the effect of two factors: the lexical status of the stimulus word (real word vs. pseudoword) and the linguistic…

  17. Task-Modality and L1 Use in EFL Oral Interaction

    ERIC Educational Resources Information Center

    Azkarai, Agurtzane; del Pilar García Mayo, María

    2015-01-01

    This study examines whether task-modality (speaking vs. speaking+writing) influences first language (L1) use in task-based English as a foreign language (EFL) learner-learner interaction. Research on the topic has shown that different task-modality triggers different learning opportunities with collaborative speaking tasks drawing learners'…

  18. Therapeutic potential of an AcHERV-HPV L1 DNA vaccine.

    PubMed

    Lee, Hee-Jung; Yoon, Jong Kwang; Heo, Yoonki; Cho, Hansam; Cho, Yeondong; Gwon, Yongdae; Kim, Kang Chang; Choi, Jiwon; Lee, Jae Sung; Oh, Yu-Kyoung; Kim, Young Bong

    2015-06-01

    Cervical cancer is strongly associated with chronic human papillomavirus infections, among which HPV16 is the most common. Two commercial HPV vaccines, Gardasil and Cervarix are effective for preventing HPV infection, but cannot be used to treat existing HPV infections. Previously, we developed a human endogenous retrovirus (HERV)-enveloped recombinant baculovirus capable of delivering the L1 genes of HPV types 16, 18, and 58 (AcHERV-HP16/18/58L1, AcHERV-HPV). Intramuscular administration of AcHERVHPV vaccines induced a strong cellular immune response as well as a humoral immune response. In this study, to examine the therapeutic effect of AcHERV-HPV in a mouse model, we established an HPV16 L1 expressing tumor cell line. Compared to Cervarix, immunization with AcHERVHPV greatly enhanced HPV16 L1-specific cytotoxic T lymphocytes (CTL) in C57BL/6 mice. Although vaccination could not remove preexisting tumors, strong CTL activity retarded the growth of inoculated tumor cells. These results indicate that AcHERV-HPV could serve as a potential therapeutic DNA vaccine against concurrent infection with HPV 16, 18, and 58. PMID:26025174

  19. L1 Allophones in L2 Speech Production: The Case of English Learners of Spanish

    ERIC Educational Resources Information Center

    Vokic, Gabriela

    2010-01-01

    Although it is broadly accepted that adult second-language (L2) learners focus attention only on those aspects of sounds needed for phonemic contrast, the role that allophony plays in the process of L2 speech learning is less well understood. It is widely assumed that speakers do not have conscious awareness of and access to first-language (L1)…

  20. Conceptualisations of "Grammar Teaching": L1 English Teachers' Beliefs about Teaching Grammar for Writing

    ERIC Educational Resources Information Center

    Watson, Annabel Mary

    2015-01-01

    This paper reports on an investigation of L1 English teachers' conceptual and evaluative beliefs about teaching grammar, one strand of a larger Economic and Social Research Council (ESRC)-funded investigation into the impact of contextualised grammar teaching [RES-062-23-0775]. Thirty-one teachers in English secondary schools were interviewed…

  1. Experimental Validation of L1 Adaptive Control: Rohrs' Counterexample in Flight

    NASA Technical Reports Server (NTRS)

    Xargay, Enric; Hovakimyan, Naira; Dobrokhodov, Vladimir; Kaminer, Issac; Kitsios, Ioannis; Cao, Chengyu; Gregory, Irene M.; Valavani, Lena

    2010-01-01

    The paper presents new results on the verification and in-flight validation of an L1 adaptive flight control system, and proposes a general methodology for verification and validation of adaptive flight control algorithms. The proposed framework is based on Rohrs counterexample, a benchmark problem presented in the early 80s to show the limitations of adaptive controllers developed at that time. In this paper, the framework is used to evaluate the performance and robustness characteristics of an L1 adaptive control augmentation loop implemented onboard a small unmanned aerial vehicle. Hardware-in-the-loop simulations and flight test results confirm the ability of the L1 adaptive controller to maintain stability and predictable performance of the closed loop adaptive system in the presence of general (artificially injected) unmodeled dynamics. The results demonstrate the advantages of L1 adaptive control as a verifiable robust adaptive control architecture with the potential of reducing flight control design costs and facilitating the transition of adaptive control into advanced flight control systems.

  2. Antiadopogenic effects of rice hull smoke extract in 3T3-L1 cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The present study investigates the inhibitory effects of a rice hull smoke extract (RHSE) against adipogenesis in 3T3-L1 pre-adipocyte cells. At concentrations of 0.1% and 0.5% RHSE, MDI-induced cells were shown to reduce their cellular lipid content by about 72% and 88%, respectively, compared to ...

  3. Atypical calcium regulation of the PKD2-L1 polycystin ion channel.

    PubMed

    DeCaen, Paul G; Liu, Xiaowen; Abiria, Sunday; Clapham, David E

    2016-01-01

    Native PKD2-L1 channel subunits are present in primary cilia and other restricted cellular spaces. Here we investigate the mechanism for the channel's unusual regulation by external calcium, and rationalize this behavior to its specialized function. We report that the human PKD2-L1 selectivity filter is partially selective to calcium ions (Ca(2+)) moving into the cell, but blocked by high internal Ca(2+)concentrations, a unique feature of this transient receptor potential (TRP) channel family member. Surprisingly, we find that the C-terminal EF-hands and coiled-coil domains do not contribute to PKD2-L1 Ca(2+)-induced potentiation and inactivation. We propose a model in which prolonged channel activity results in calcium accumulation, triggering outward-moving Ca(2+) ions to block PKD2-L1 in a high-affinity interaction with the innermost acidic residue (D523) of the selectivity filter and subsequent long-term channel inactivation. This response rectifies Ca(2+) flow, enabling Ca(2+) to enter but not leave small compartments such as the cilium. PMID:27348301

  4. CATS-ISS_L1B_D-M7.2-V2-05

    Atmospheric Science Data Center

    2016-05-03

    CATS-ISS_L1B_D-M7.2-V2-05 The Cloud-Aerosol Transport System (CATS) is a three wavelength, polarization-sensitive lidar that provides ... in the Earth's atmosphere. Project Title:  CATS Discipline:  Clouds Aerosols Version:  ...

  5. SARA regulates neuronal migration during neocortical development through L1 trafficking.

    PubMed

    Mestres, Iván; Chuang, Jen-Zen; Calegari, Federico; Conde, Cecilia; Sung, Ching-Hwa

    2016-09-01

    Emerging evidence suggests that endocytic trafficking of adhesion proteins plays a crucial role in neuronal migration during neocortical development. However, molecular insights into these processes remain elusive. Here, we study the early endosomal protein Smad anchor for receptor activation (SARA) in the developing mouse brain. SARA is enriched at the apical endfeet of radial glia of the neocortex. Although SARA knockdown did not lead to detectable neurogenic phenotypes, SARA-suppressed neurons exhibited impaired orientation and migration across the intermediate zone. Mechanistically, we show that SARA knockdown neurons exhibit increased surface expression of the L1 cell adhesion molecule. Neurons ectopically expressing L1 phenocopy the migration and orientation defects caused by SARA knockdown and display increased contact with neighboring neurites. L1 knockdown effectively rescues SARA suppression-induced phenotypes. SARA knockdown neurons eventually overcome their migration defect and enter later into the cortical plate. Nevertheless, these neurons localize at more superficial cortical layers than their control counterparts. These results suggest that SARA regulates the orientation, multipolar-to-bipolar transition and the positioning of cortical neurons via modulating surface L1 expression. PMID:27471254

  6. Identification of L1 ORF2p sequence important to retrotransposition using Bipartile Alu retrotransposition (BAR)

    PubMed Central

    Christian, Claiborne M.; deHaro, Dawn; Kines, Kristine J.; Sokolowski, Mark; Belancio, Victoria P.

    2016-01-01

    Long Interspersed Element 1 (LINE-1 or L1) is capable of causing genomic instability through the activity of the L1 ORF2 protein (ORF2p). This protein contains endonuclease (EN) and reverse transcriptase (RT) domains that are necessary for the retrotransposition of L1 and the Short Interspersed Element (SINE) Alu. The functional importance of approximately 50% of the ORF2p molecule remains unknown, but some of these sequences could play a role in retrotransposition, or be necessary for the enzymatic activities of the EN and/or RT domains. Conventional approaches using the full-length, contiguous ORF2p make it difficult to study the involvement of these unannotated sequences in the function of L1 ORF2p. Our lab has developed a Bipartile Alu Retrotransposition (BAR) assay that relies on separate truncated ORF2p fragments: an EN-containing and an RT-containing fragment. We validated the utility of this method for studying the ORF2p function in retrotransposition by assessing the effect of expression levels and previously characterized mutations on BAR. Using BAR, we identified two pairs of amino acids important for retrotransposition, an FF and a WD. The WD appears to play a role in cDNA synthesis by the ORF2p molecule, despite being outside the canonical RT domain. PMID:27095191

  7. CATS-ISS_L1B_D-M7.2-V2-07

    Atmospheric Science Data Center

    2016-06-22

    CATS-ISS_L1B_D-M7.2-V2-07 The Cloud-Aerosol Transport System (CATS) is a three wavelength, polarization-sensitive lidar that provides ... in the Earth's atmosphere. Project Title:  CATS Discipline:  Clouds Aerosols Version:  ...

  8. CATS-ISS_L1B_N-M7.2-V2-07

    Atmospheric Science Data Center

    2016-06-22

    CATS-ISS_L1B_N-M7.2-V2-07 The Cloud-Aerosol Transport System (CATS) is a three wavelength, polarization-sensitive lidar that provides ... in the Earth's atmosphere. Project Title:  CATS Discipline:  Clouds Aerosols Version:  ...

  9. Similarities of L1 (Mother Tongue) in Terms of Grammar and Language Structure in Translation

    ERIC Educational Resources Information Center

    Subramaniam, Vijayaletchumy

    2011-01-01

    Malaysian philosophy, purpose and objective of the education system are rooted and based on policies stated in the National Education Policy 1956 and Education Act 1961. Whereas the Education Ordinance 1952 urged all Chinese and Tamil schools to be given an equal opportunity to learn English and Malay language together with their L1 (mother…

  10. The Potential Influence of L1 (Chinese) on L2 (English) Communication

    ERIC Educational Resources Information Center

    Huang, Li-Shih

    2010-01-01

    A major issue in the field of L2 acquisition is the role that language learners' L1 plays in the acquisition of an L2. This article shows some of the salient linguistic features of Chinese that may present communication challenges for Chinese-speaking learners of English as an additional language. Instructors' awareness of such features will…

  11. Identification of L1 ORF2p sequence important to retrotransposition using Bipartile Alu retrotransposition (BAR).

    PubMed

    Christian, Claiborne M; deHaro, Dawn; Kines, Kristine J; Sokolowski, Mark; Belancio, Victoria P

    2016-06-01

    Long Interspersed Element 1 (LINE-1 or L1) is capable of causing genomic instability through the activity of the L1 ORF2 protein (ORF2p). This protein contains endonuclease (EN) and reverse transcriptase (RT) domains that are necessary for the retrotransposition of L1 and the Short Interspersed Element (SINE) Alu. The functional importance of approximately 50% of the ORF2p molecule remains unknown, but some of these sequences could play a role in retrotransposition, or be necessary for the enzymatic activities of the EN and/or RT domains. Conventional approaches using the full-length, contiguous ORF2p make it difficult to study the involvement of these unannotated sequences in the function of L1 ORF2p. Our lab has developed a Bipartile Alu Retrotransposition (BAR) assay that relies on separate truncated ORF2p fragments: an EN-containing and an RT-containing fragment. We validated the utility of this method for studying the ORF2p function in retrotransposition by assessing the effect of expression levels and previously characterized mutations on BAR. Using BAR, we identified two pairs of amino acids important for retrotransposition, an FF and a WD. The WD appears to play a role in cDNA synthesis by the ORF2p molecule, despite being outside the canonical RT domain. PMID:27095191

  12. Monte Carlo simulation of equilibrium L1{sub 0} ordering in FePt nanoparticles

    SciTech Connect

    Chepulskii, R.V.; Velev, J.; Butler, W.H.

    2005-05-15

    First, second, and third nearest-neighbor mixing potentials for FePt alloys were calculated from first principles using the Connolly-Williams approach. Using the mixing potentials obtained in this manner, the dependency of equilibrium L1{sub 0} ordering on temperature was studied for bulk and for a spherical nanoparticle with a 3.5-nm diameter at equiatomic composition by use of Monte Carlo simulation and the analytical ring approximation. The calculated order-disorder temperature for bulk (1495-1514 K) was in relatively good agreement (4% error) with the experimental value (1572 K). For nanoparticles of finite size, the (long-range) order parameter changed continuously from unity to zero with increasing temperature. Rather than a discontinuity indicative of a phase-transition we obtained an inflection point in the order as a function of temperature. This inflection point occurred at a temperature below the bulk phase-transition temperature and which decreased as the particle size decreased. Our calculations predict that 3.5-nm diameter particles in configurational equilibrium at 600 deg. C (a typical annealing temperature for promoting L1{sub 0} ordering) have an L1{sub 0} order parameter of 0.83 (compared to a maximum possible value equal to unity). According to our investigations, the experimental absence of a (relatively) high L1{sub 0} order in 3.5-nm diameter nanoparticles annealed at 600 deg. C or below is primarily a problem of kinetics rather than equilibrium.

  13. Downregulation of L1 perturbs neuronal migration and alters the expression of transcription factors in murine neocortex

    PubMed Central

    Kishimoto, Tomokazu; Itoh, Kyoko; Umekage, Masafumi; Tonosaki, Madoka; Yaoi, Takeshi; Fukui, Kenji; Lemmon, Vance P; Fushiki, Shinji

    2013-01-01

    Abstract L1 is a cell adhesion molecule associated with a spectrum of human neurological diseases, the most well-known being X-linked hydrocephalus. L1 knockout (L1-KO) mice have revealed a variety of functions of L1 that were crucial in brain development in different brain regions. However; the function of L1 in neuronal migration during cortical histogenesis remains to be clarified. We therefore investigated the corticogenesis of mouse embryos in which L1 molecules were knocked down in selected neurons, by employing in utero electroporation with shRNAs targeting L1 (L1 shRNA). Although more than 50% of the cells transfected with no small hairpin RNA (shRNA; monster green fluorescent protein: MGFP only) vector at embryonic day 13 (E13) reached the cortical plate at E16, significantly fewer (27%) cells transfected with L1 shRNA migrated to the same extent. At E17, 22% of cells transfected with the MGFP-only vector were found in the intermediate zone, and significantly more (34%) cells transfected with L1 shRNA remained in the same zone. Furthermore, the directions of the leading process of neurons transfected with L1 shRNA became more dispersed compared with cells with the MGFP-only vector. In addition, two transcription factors expressed in the neurons, Satb2 and Tbr1, were shown to be reduced or aberrantly expressed in neurons transfected with L1 shRNA. These observations suggest that L1 plays an important role in regulating the locomotion and orientation of migrating neurons and the expression of transcription factors during neocortical development that might partially be responsible for the abnormal tract formation seen in L1-KO mice. © 2012 Wiley Periodicals, Inc. PMID:23073969

  14. Downregulation of L1 perturbs neuronal migration and alters the expression of transcription factors in murine neocortex.

    PubMed

    Kishimoto, Tomokazu; Itoh, Kyoko; Umekage, Masafumi; Tonosaki, Madoka; Yaoi, Takeshi; Fukui, Kenji; Lemmon, Vance P; Fushiki, Shinji

    2013-01-01

    L1 is a cell adhesion molecule associated with a spectrum of human neurological diseases, the most well-known being X-linked hydrocephalus. L1 knockout (L1-KO) mice have revealed a variety of functions of L1 that were crucial in brain development in different brain regions. However; the function of L1 in neuronal migration during cortical histogenesis remains to be clarified. We therefore investigated the corticogenesis of mouse embryos in which L1 molecules were knocked down in selected neurons, by employing in utero electroporation with shRNAs targeting L1 (L1 shRNA). Although more than 50% of the cells transfected with no small hairpin RNA (shRNA; monster green fluorescent protein: MGFP only) vector at embryonic day 13 (E13) reached the cortical plate at E16, significantly fewer (27%) cells transfected with L1 shRNA migrated to the same extent. At E17, 22% of cells transfected with the MGFP-only vector were found in the intermediate zone, and significantly more (34%) cells transfected with L1 shRNA remained in the same zone. Furthermore, the directions of the leading process of neurons transfected with L1 shRNA became more dispersed compared with cells with the MGFP-only vector. In addition, two transcription factors expressed in the neurons, Satb2 and Tbr1, were shown to be reduced or aberrantly expressed in neurons transfected with L1 shRNA. These observations suggest that L1 plays an important role in regulating the locomotion and orientation of migrating neurons and the expression of transcription factors during neocortical development that might partially be responsible for the abnormal tract formation seen in L1-KO mice. PMID:23073969

  15. CLOCK promotes 3T3-L1 cell proliferation via Wnt signaling.

    PubMed

    Zhu, Zhu; Hua, Bingxuan; Xu, Lirong; Yuan, Gongsheng; Li, Ermin; Li, Xiaobo; Sun, Ning; Yan, Zuoqin; Lu, Chao; Qian, Ruizhe

    2016-07-01

    Circadian genes control most of the physiological functions including cell cycle. Cell proliferation is a critical factor in the differentiation of progenitor cells. However, the role of Clock gene in the regulation of cell cycle via wingless-type (Wnt) pathway and the relationship between Clock and adipogenesis are unclear. We found that the circadian locomotor output cycles kaput (Clock) regulated the proliferation and the adipogenesis of 3T3-L1 preadipocytes. We found that Clock attenuation inhibited the viability of 3T3-L1 preadipocytes in the cell counting kit 8. The expression of c-Myc and Cyclin D1 decreased dramatically in 3T3-L1 when Clock was silenced with short interfering RNA and was also decreased in fat tissue and adipose tissue-derived stem cells of Clock(Δ19) mice. Clock directly controls the expression of the components of Wnt signal transduction pathway, which was verified by serum shock, chromatin immunoprecipitation, Western blot, and quantitative real-time polymerase chain reaction (qRT-PCR). Furthermore, IWR-1, a Wnt signal pathway inhibitor, inhibited the cell cycle promotion by CLOCK, which was detected by cell viability assay, flow cytometry, and qRT-PCR. Therefore, CLOCK transcription control of Wnt signaling promotes cell cycle progression in 3T3-L1 preadipocytes. Clock inhibited the adipogenesis on day 2 in 3T3-L1 cells via Oil Red O staining and qRT-PCR detection and probably related to cellular differentiation. These data provide evidence that the circadian gene Clock regulates the proliferation of preadipocytes and affects adipogenesis. © 2016 IUBMB Life, 68(7):557-568, 2016. PMID:27194636

  16. Alterations in insulin binding accompanying differentiation of 3T3-L1 preadipocytes.

    PubMed Central

    Reed, B C; Kaufmann, S H; Mackall, J C; Student, A K; Lane, M D

    1977-01-01

    Expression of the adipocyte phenotype by differentiating 3T3-L1 preadipocytes occurs upon exposure of the cells to insulin. Differentiation-linked changes in 125I-labeled insulin binding to 3T3-L1 cells were monitored and compared with those in nondifferentiating 3T3-C2 controls treated similarly. Without chronic insulin treatment, 3T3-L1 cells failed to express the adipocyte phenotype but maintained a level of 25,000-35,000 insulin-binding sites per cell. Treatment of 3T3-L1 cells with insulin resulted in an initial suppression of insulin binding followed by a 12-fold increase that paralleled the appearance of differentiated cells. A maximum of 170,000 insulin-binding sites per cell was attained for a population in which greater than 75% of the cells had differentiated. The increase of insulin receptor level appears to be differentiation-dependent and is not a general response of cells to the culture conditions. 3T3-C2 cells maintained in the presence of insulin for 30 days exhibited the undifferentiated phenotype and suppressed levels of insulin binding (35,000 sites per cell). The binding capacity of 3T3-L1 cells for epidermal growth factor remained unchanged between 25,000 and 40;000 sites per cell and was independent of the state of differentiation. Thus, induction by insulin in receptor-specific changes. Insulin receptors increase in number but epidermal growth factor receptors remain constant. PMID:303773

  17. Induction of pyruvate carboxylase apoenzyme and holoenzyme in 3T3-L1 cells during differentiation

    PubMed Central

    Freytag, Svend O.; Utter, Merton F.

    1980-01-01

    The specific activity of pyruvate carboxylase [pyruvate:carbon-dioxide ligase (ADP-forming); EC 6.4.1.1] in 3T3-L1 cells increases approximately 20-fold when these cells differentiate to an adipocyte-like form [Mackall, J. C. & Lane, M. D. (1977) Biochem. Biophys. Res. Commun. 79, 720-725]. A specific antibody to the purified rat liver enzyme quantitatively precipitated pyruvate carboxylase from 3T3-L1 crude homogenates. Use of this immunological technique permitted us to demonstrate that the increase in pyruvate carboxylase activity is due to an increase in the intracellular concentration of the enzyme. The content of pyruvate carboxylase in differentiated 3T3-L1 cells is sufficiently high (1-2% of total protein) that the increase in this large protein (subunit Mr = 130,000) can be visualized when 3T3-L1 crude extracts are subjected to electrophoresis on sodium dodecyl sulfate/polyacrylamide gels. When 3T3-L1 cells differentiated in the presence of avidin, they contained less than 5% of the pyruvate carboxylase activity of cells that differentiated in the absence of avidin. However, the immunoprecipitable pyruvate carboxylase content of the avidin-treated cells was essentially the same as that of cells that differentiated without avidin. Full activity of the enzyme was rapidly restored in the avidin-treated cells upon the addition of excess biotin. The recovery of activity was closely correlated with the incorporation of [14C]biotin into immunoprecipitable pyruvate carboxylase. The rapidity with which the activity was restored and the insensitivity of the process to inhibitors of protein synthesis strongly suggest that the apoenzyme of pyruvate carboxylase accumulates during differentiation in the presence of avidin. Images PMID:6929488

  18. GTKDynamo: a PyMOL plug-in for QC/MM hybrid potential simulations.

    PubMed

    Bachega, José Fernando R; Timmers, Luís Fernando S M; Assirati, Lucas; Bachega, Leonardo R; Field, Martin J; Wymore, Troy

    2013-09-30

    Hybrid quantum chemical/molecular mechanical (QCMM) potentials are very powerful tools for molecular simulation. They are especially useful for studying processes in condensed phase systems, such as chemical reactions that involve a relatively localized change in electronic structure and where the surrounding environment contributes to these changes but can be represented with more computationally efficient functional forms. Despite their utility, however, these potentials are not always straightforward to apply since the extent of significant electronic structure changes occurring in the condensed phase process may not be intuitively obvious. To facilitate their use, we have developed an open-source graphical plug-in, GTKDynamo that links the PyMOL visualization program and the pDynamo QC/MM simulation library. This article describes the implementation of GTKDynamo and its capabilities and illustrates its application to QC/MM simulations. PMID:24137667

  19. VizieR Online Data Catalog: ExoMol line lists for CS isotopologues (Paulose+, 2015)

    NASA Astrophysics Data System (ADS)

    Paulose, G.; Barton, E. J.; Yurchenko, S. N.; Tennyson, J.

    2015-07-01

    The files comprising this line list are in the standard ExoMol format, and are named XXcYYsst.dat, XXcYYstr.dat, where XX and YY are the mass numbers of the Carbon and Sulphur isotopes, respectively. The isotopologues covered including their nuclear spin degeneracy factors g_ns are: (12C)(32S) g_ns = 1 (12C)(33S) g_ns = 4 (12C)(34S) g_ns = 1 (12C)(36S) g_ns = 1 (13C)(32S) g_ns = 2 (13C)(33S) g_ns = 8 (13C)(34S) g_ns = 2 (13C)(36S) g_ns = 2 The partition functions from 1-3000K in 1K intervals for these isotopologues of CS are also provided in files named XXcYYspf.dat. (24 data files).

  20. Kilogramm und Mol: SI-Basiseinheiten für Masse und Stoffmenge

    NASA Astrophysics Data System (ADS)

    Becker, Peter; Gläser, Michael

    2001-11-01

    Das Kilogramm ist eine SI-Basiseinheit, die bislang nicht hinreichend genau auf Naturkonstanten zurückgeführt werden kann. Gegenwärtig gibt es verschiedene Vorschläge, dieses Problem zu lösen. Ein Vorschlag ist die Neudefinition des Kilogramm auf Basis atomarer Massen. An der Physikalisch-Technischen Bundesanstalt (PTB) wird dazu an zwei verschiedenen Verfahren geforscht. Beim ersten Verfahren werden Goldionen zu einer Referenzmasse akkumuliert, beim zweiten die Avogadro-Konstante an einem Silizium-Einkristall bestimmt. Beide Verfahren könnten eine genau bestimmbare Zahl von Atomen liefern, mit der das Kilogramm neu definiert werden könnte. Dies könnte eine Zahl von 197 Au, von 28 Si oder auch von 12 C-Atomen sein, auf der bereits die SI-Einheit der Stoffmenge des Mol basiert.