Science.gov

Sample records for 10-9 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. 33 CFR 6.10-9 - Appeals.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Appeals. 6.10-9 Section 6.10-9... and Waterfront Facilities § 6.10-9 Appeals. Persons who are refused employment or who are refused the... right of appeal, and the Commandant shall appoint Boards for acting on such appeals. Each such...

  3. 33 CFR 6.10-9 - Appeals.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 33 Navigation and Navigable Waters 1 2012-07-01 2012-07-01 false Appeals. 6.10-9 Section 6.10-9... and Waterfront Facilities § 6.10-9 Appeals. Persons who are refused employment or who are refused the... right of appeal, and the Commandant shall appoint Boards for acting on such appeals. Each such...

  4. 33 CFR 6.10-9 - Appeals.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 33 Navigation and Navigable Waters 1 2014-07-01 2014-07-01 false Appeals. 6.10-9 Section 6.10-9... and Waterfront Facilities § 6.10-9 Appeals. Persons who are refused employment or who are refused the... right of appeal, and the Commandant shall appoint Boards for acting on such appeals. Each such...

  5. 40 CFR 10.9 - Penalties.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... of Environment ENVIRONMENTAL PROTECTION AGENCY GENERAL ADMINISTRATIVE CLAIMS UNDER FEDERAL TORT CLAIMS ACT Procedures § 10.9 Penalties. A person who files a false claim or makes a false or fraudulent statement in a claim against the United States may be liable to a fine of not more than $10,000 or...

  6. 40 CFR 10.9 - Penalties.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... of Environment ENVIRONMENTAL PROTECTION AGENCY GENERAL ADMINISTRATIVE CLAIMS UNDER FEDERAL TORT CLAIMS ACT Procedures § 10.9 Penalties. A person who files a false claim or makes a false or fraudulent statement in a claim against the United States may be liable to a fine of not more than $10,000 or...

  7. 40 CFR 10.9 - Penalties.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... of Environment ENVIRONMENTAL PROTECTION AGENCY GENERAL ADMINISTRATIVE CLAIMS UNDER FEDERAL TORT CLAIMS ACT Procedures § 10.9 Penalties. A person who files a false claim or makes a false or fraudulent statement in a claim against the United States may be liable to a fine of not more than $10,000 or...

  8. 17 CFR 10.9 - Separation of functions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 1 2010-04-01 2010-04-01 false Separation of functions. 10.9 Section 10.9 Commodity and Securities Exchanges COMMODITY FUTURES TRADING COMMISSION RULES OF PRACTICE General Provisions § 10.9 Separation of functions. (a) An Administrative Law Judge will not be...

  9. 17 CFR 10.9 - Separation of functions.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 17 Commodity and Securities Exchanges 1 2014-04-01 2014-04-01 false Separation of functions. 10.9 Section 10.9 Commodity and Securities Exchanges COMMODITY FUTURES TRADING COMMISSION RULES OF PRACTICE General Provisions § 10.9 Separation of functions. (a) An Administrative Law Judge will not be...

  10. 17 CFR 10.9 - Separation of functions.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 17 Commodity and Securities Exchanges 1 2013-04-01 2013-04-01 false Separation of functions. 10.9 Section 10.9 Commodity and Securities Exchanges COMMODITY FUTURES TRADING COMMISSION RULES OF PRACTICE General Provisions § 10.9 Separation of functions. (a) An Administrative Law Judge will not be...

  11. 17 CFR 10.9 - Separation of functions.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 17 Commodity and Securities Exchanges 1 2012-04-01 2012-04-01 false Separation of functions. 10.9 Section 10.9 Commodity and Securities Exchanges COMMODITY FUTURES TRADING COMMISSION RULES OF PRACTICE General Provisions § 10.9 Separation of functions. (a) An Administrative Law Judge will not be...

  12. 17 CFR 10.9 - Separation of functions.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 1 2011-04-01 2011-04-01 false Separation of functions. 10.9 Section 10.9 Commodity and Securities Exchanges COMMODITY FUTURES TRADING COMMISSION RULES OF PRACTICE General Provisions § 10.9 Separation of functions. (a) An Administrative Law Judge will not be...

  13. 46 CFR 113.10-9 - Power supply.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 4 2010-10-01 2010-10-01 false Power supply. 113.10-9 Section 113.10-9 Shipping COAST... SYSTEMS AND EQUIPMENT Fire and Smoke Detecting and Alarm Systems § 113.10-9 Power supply. (a) General. There must be at least two sources of power for the electrical equipment of each fire detecting...

  14. 46 CFR 113.10-9 - Power supply.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 4 2012-10-01 2012-10-01 false Power supply. 113.10-9 Section 113.10-9 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) ELECTRICAL ENGINEERING COMMUNICATION AND ALARM SYSTEMS AND EQUIPMENT Fire and Smoke Detecting and Alarm Systems § 113.10-9 Power supply. (a)...

  15. 46 CFR 113.10-9 - Power supply.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 4 2011-10-01 2011-10-01 false Power supply. 113.10-9 Section 113.10-9 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) ELECTRICAL ENGINEERING COMMUNICATION AND ALARM SYSTEMS AND EQUIPMENT Fire and Smoke Detecting and Alarm Systems § 113.10-9 Power supply. (a)...

  16. 46 CFR 113.10-9 - Power supply.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 4 2014-10-01 2014-10-01 false Power supply. 113.10-9 Section 113.10-9 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) ELECTRICAL ENGINEERING COMMUNICATION AND ALARM SYSTEMS AND EQUIPMENT Fire and Smoke Detecting and Alarm Systems § 113.10-9 Power supply. (a)...

  17. 46 CFR 113.10-9 - Power supply.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 4 2013-10-01 2013-10-01 false Power supply. 113.10-9 Section 113.10-9 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) ELECTRICAL ENGINEERING COMMUNICATION AND ALARM SYSTEMS AND EQUIPMENT Fire and Smoke Detecting and Alarm Systems § 113.10-9 Power supply. (a)...

  18. 46 CFR 90.10-9 - Coast Guard District Commander.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 4 2010-10-01 2010-10-01 false Coast Guard District Commander. 90.10-9 Section 90.10-9 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) CARGO AND MISCELLANEOUS VESSELS GENERAL PROVISIONS Definition of Terms Used in This Subchapter § 90.10-9 Coast Guard District Commander. This...

  19. 46 CFR 90.10-9 - Coast Guard District Commander.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 4 2011-10-01 2011-10-01 false Coast Guard District Commander. 90.10-9 Section 90.10-9 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) CARGO AND MISCELLANEOUS VESSELS GENERAL PROVISIONS Definition of Terms Used in This Subchapter § 90.10-9 Coast Guard District Commander. This...

  20. 46 CFR 90.10-9 - Coast Guard District Commander.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 4 2013-10-01 2013-10-01 false Coast Guard District Commander. 90.10-9 Section 90.10-9 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) CARGO AND MISCELLANEOUS VESSELS GENERAL PROVISIONS Definition of Terms Used in This Subchapter § 90.10-9 Coast Guard District Commander. This...

  1. 46 CFR 90.10-9 - Coast Guard District Commander.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 4 2012-10-01 2012-10-01 false Coast Guard District Commander. 90.10-9 Section 90.10-9 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) CARGO AND MISCELLANEOUS VESSELS GENERAL PROVISIONS Definition of Terms Used in This Subchapter § 90.10-9 Coast Guard District Commander. This...

  2. 46 CFR 90.10-9 - Coast Guard District Commander.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 4 2014-10-01 2014-10-01 false Coast Guard District Commander. 90.10-9 Section 90.10-9 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) CARGO AND MISCELLANEOUS VESSELS GENERAL PROVISIONS Definition of Terms Used in This Subchapter § 90.10-9 Coast Guard District Commander. This...

  3. 46 CFR 188.10-9 - Chemical storeroom.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 7 2010-10-01 2010-10-01 false Chemical storeroom. 188.10-9 Section 188.10-9 Shipping... PROVISIONS Definition of Terms Used in This Subchapter § 188.10-9 Chemical storeroom. This term refers to any compartment specifically constructed or modified for the stowage of chemical stores and so designated...

  4. 46 CFR 188.10-9 - Chemical storeroom.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 7 2011-10-01 2011-10-01 false Chemical storeroom. 188.10-9 Section 188.10-9 Shipping... PROVISIONS Definition of Terms Used in This Subchapter § 188.10-9 Chemical storeroom. This term refers to any compartment specifically constructed or modified for the stowage of chemical stores and so designated...

  5. 46 CFR 188.10-9 - Chemical storeroom.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 7 2014-10-01 2014-10-01 false Chemical storeroom. 188.10-9 Section 188.10-9 Shipping... PROVISIONS Definition of Terms Used in This Subchapter § 188.10-9 Chemical storeroom. This term refers to any compartment specifically constructed or modified for the stowage of chemical stores and so designated...

  6. 46 CFR 188.10-9 - Chemical storeroom.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 7 2013-10-01 2013-10-01 false Chemical storeroom. 188.10-9 Section 188.10-9 Shipping... PROVISIONS Definition of Terms Used in This Subchapter § 188.10-9 Chemical storeroom. This term refers to any compartment specifically constructed or modified for the stowage of chemical stores and so designated...

  7. 46 CFR 188.10-9 - Chemical storeroom.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 7 2012-10-01 2012-10-01 false Chemical storeroom. 188.10-9 Section 188.10-9 Shipping... PROVISIONS Definition of Terms Used in This Subchapter § 188.10-9 Chemical storeroom. This term refers to any compartment specifically constructed or modified for the stowage of chemical stores and so designated...

  8. 19 CFR 10.9 - Articles exported for processing.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 19 Customs Duties 1 2011-04-01 2011-04-01 false Articles exported for processing. 10.9 Section 10... THE TREASURY ARTICLES CONDITIONALLY FREE, SUBJECT TO A REDUCED RATE, ETC. General Provisions Articles Exported and Returned § 10.9 Articles exported for processing. (a) Except as otherwise provided for in...

  9. 19 CFR 10.9 - Articles exported for processing.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 19 Customs Duties 1 2010-04-01 2010-04-01 false Articles exported for processing. 10.9 Section 10... THE TREASURY ARTICLES CONDITIONALLY FREE, SUBJECT TO A REDUCED RATE, ETC. General Provisions Articles Exported and Returned § 10.9 Articles exported for processing. (a) Except as otherwise provided for in...

  10. 19 CFR 10.9 - Articles exported for processing.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 19 Customs Duties 1 2014-04-01 2014-04-01 false Articles exported for processing. 10.9 Section 10... THE TREASURY ARTICLES CONDITIONALLY FREE, SUBJECT TO A REDUCED RATE, ETC. General Provisions Articles Exported and Returned § 10.9 Articles exported for processing. (a) Except as otherwise provided for in...

  11. 19 CFR 10.9 - Articles exported for processing.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 19 Customs Duties 1 2012-04-01 2012-04-01 false Articles exported for processing. 10.9 Section 10... THE TREASURY ARTICLES CONDITIONALLY FREE, SUBJECT TO A REDUCED RATE, ETC. General Provisions Articles Exported and Returned § 10.9 Articles exported for processing. (a) Except as otherwise provided for in...

  12. 19 CFR 10.9 - Articles exported for processing.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 19 Customs Duties 1 2013-04-01 2013-04-01 false Articles exported for processing. 10.9 Section 10... THE TREASURY ARTICLES CONDITIONALLY FREE, SUBJECT TO A REDUCED RATE, ETC. General Provisions Articles Exported and Returned § 10.9 Articles exported for processing. (a) Except as otherwise provided for in...

  13. 44 CFR 10.9 - Preparation of environmental assessments.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... and decision-making. (b) Content and format. The environmental assessment is a concise public document... 44 Emergency Management and Assistance 1 2010-10-01 2010-10-01 false Preparation of environmental assessments. 10.9 Section 10.9 Emergency Management and Assistance FEDERAL EMERGENCY MANAGEMENT...

  14. 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.

  15. 15 CFR 10.9 - Publication of a standard.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ..., invoices, announcements, product labels, and the like may be made to a Voluntary Product Standard published... OF VOLUNTARY PRODUCT STANDARDS § 10.9 Publication of a standard. A Voluntary Product Standard... establish, but no product may be advertised or represented in any manner which would imply or tend to...

  16. 15 CFR 10.9 - Publication of a standard.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ..., invoices, announcements, product labels, and the like may be made to a Voluntary Product Standard published... OF VOLUNTARY PRODUCT STANDARDS § 10.9 Publication of a standard. A Voluntary Product Standard... establish, but no product may be advertised or represented in any manner which would imply or tend to...

  17. 15 CFR 10.9 - Publication of a standard.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ..., invoices, announcements, product labels, and the like may be made to a Voluntary Product Standard published... OF VOLUNTARY PRODUCT STANDARDS § 10.9 Publication of a standard. A Voluntary Product Standard... establish, but no product may be advertised or represented in any manner which would imply or tend to...

  18. 46 CFR 30.10-9 - Classification requirements-TB/ALL.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 1 2013-10-01 2013-10-01 false Classification requirements-TB/ALL. 30.10-9 Section 30.10-9 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY TANK VESSELS GENERAL PROVISIONS Definitions § 30.10-9 Classification requirements—TB/ALL. The term classification requirements...

  19. 46 CFR 30.10-9 - Classification requirements-TB/ALL.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 1 2014-10-01 2014-10-01 false Classification requirements-TB/ALL. 30.10-9 Section 30.10-9 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY TANK VESSELS GENERAL PROVISIONS Definitions § 30.10-9 Classification requirements—TB/ALL. The term classification requirements...

  20. 46 CFR 30.10-9 - Classification requirements-TB/ALL.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 1 2010-10-01 2010-10-01 false Classification requirements-TB/ALL. 30.10-9 Section 30.10-9 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY TANK VESSELS GENERAL PROVISIONS Definitions § 30.10-9 Classification requirements—TB/ALL. The term classification requirements...

  1. 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. ...

  2. L1CAM in human cancer.

    PubMed

    Altevogt, Peter; Doberstein, Kai; Fogel, Mina

    2016-04-01

    L1 cell adhesion molecule (L1CAM) is one of the first neural adhesion molecules described with important functions in the development of the nervous system. Subsequent work discovered that L1CAM is expressed in many human cancers and is often associated with bad prognosis. This is most likely due to the motility and invasion promoting function of L1CAM. Here, we describe the path L1CAM has taken from a neural adhesion molecule to a recognized tumor antigen. We summarize the literature on L1CAM expression in cancers and pre-cancerous lesions. We focus on the genetic elements required for its re-expression and highlight preclinical studies for targeted therapy. The data suggest that L1CAM is a valuable diagnostic/prognostic marker and an attractive target for the therapy of several human cancers. PMID:26111503

  3. L1 Retrotransposition in Neural Progenitor Cells.

    PubMed

    Muotri, Alysson R

    2016-01-01

    Long interspersed nucleotide element 1 (LINE-1 or L1) is a family of non-LTR retrotransposons that can replicate and reintegrate into the host genome. L1s have considerably influenced mammalian genome evolution by retrotransposing during germ cell development or early embryogenesis, leading to massive genome expansion. For many years, L1 retrotransposons were viewed as a selfish DNA parasite that had no contribution in somatic cells. Historically, L1s were thought to only retrotranspose during gametogenesis and in neoplastic processes, but recent studies have shown that L1s are extremely active in the mouse, rat, and human neuronal progenitor cells (NPCs). These de novo L1 insertions can impact neuronal transcriptional expression, creating unique transcriptomes of individual neurons, possibly contributing to the uniqueness of the individual cognition and mental disorders in humans. PMID:26895053

  4. L1CAM: Cell adhesion and more.

    PubMed

    Samatov, Timur R; Wicklein, Daniel; Tonevitsky, Alexander G

    2016-08-01

    L1CAM is a cell adhesion molecule of the immunoglobulin superfamily which was originally discovered as a major player in the development of the nervous system. L1CAM was demonstrated to have prognostic value in different cancers and to be a promising target for anti-cancer therapy. Here we overview the present data on L1CAM structure and function, regulation of its expression, role in cancer and therapeutic potential. PMID:27267927

  5. 46 CFR 30.10-9 - Classification requirements-TB/ALL.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 1 2012-10-01 2012-10-01 false Classification requirements-TB/ALL. 30.10-9 Section 30... Definitions § 30.10-9 Classification requirements—TB/ALL. The term classification requirements means... classification society....

  6. 46 CFR 30.10-9 - Classification requirements-TB/ALL.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 1 2011-10-01 2011-10-01 false Classification requirements-TB/ALL. 30.10-9 Section 30... Definitions § 30.10-9 Classification requirements—TB/ALL. The term classification requirements means... classification society....

  7. 46 CFR 39.10-9 - Vessel vapor processing unit-TB/ALL.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... board must meet the requirements of 33 CFR part 154, subpart E to the satisfaction of the Commandant (CG... 46 Shipping 1 2011-10-01 2011-10-01 false Vessel vapor processing unit-TB/ALL. 39.10-9 Section 39.10-9 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY TANK VESSELS VAPOR CONTROL SYSTEMS...

  8. 46 CFR 39.10-9 - Vessel vapor processing unit-TB/ALL.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... board must meet the requirements of 33 CFR part 154, subpart E to the satisfaction of the Commandant (CG... 46 Shipping 1 2010-10-01 2010-10-01 false Vessel vapor processing unit-TB/ALL. 39.10-9 Section 39.10-9 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY TANK VESSELS VAPOR CONTROL SYSTEMS...

  9. 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

  10. 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.

  11. L1CAM whole gene deletion in a child with L1 syndrome.

    PubMed

    Chidsey, Brandalyn A; Baldwin, Erin E; Toydemir, Reha; Ahles, Lauren; Hanson, Heather; Stevenson, David A

    2014-06-01

    L1 syndrome is a group of overlapping, X-linked disorders caused by mutations in L1CAM. Clinical phenotypes within L1 syndrome include X-linked hydrocephalus with stenosis of the aqueduct of sylvius (HSAS); mental retardation, adducted thumbs, shuffling gait, and aphasia (MASA) syndrome; spastic paraplegia type 1; and agenesis of the corpus callosum. Over 200 mutations in L1CAM have been reported; however, only a few large gene deletions have been observed. We report on a 4-month-old male with a de novo whole gene deletion of L1CAM presenting with congenital hydrocephalus, aqueductal stenosis, and adducted thumbs. Initial failure of L1CAM gene sequencing suggested the possibility of a whole gene deletion of L1CAM. Further investigation through chromosome microarray analysis showed a 62Kb deletion encompassing the first exon of the PDZD4 gene and the entire L1CAM gene. Investigations into genotype-phenotype correlations have suggested that mutations leading to truncated or absent L1 protein cause more severe forms of L1 syndrome. Based on the presentation of the proband and other reported patients with whole gene deletions, we provide further evidence that L1CAM whole gene deletions result in L1 syndrome with a severe phenotype, deletions of PDZD4 do not cause additional manifestations, and that X-linked nephrogenic diabetes insipidus reported in a subset of patients with large L1CAM deletions results from the loss of AVPR2. PMID:24668863

  12. 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.

  13. euL1db: the European database of L1HS retrotransposon insertions in humans.

    PubMed

    Mir, Ashfaq A; Philippe, Claude; Cristofari, Gaël

    2015-01-01

    Retrotransposons account for almost half of our genome. They are mobile genetics elements-also known as jumping genes--but only the L1HS subfamily of Long Interspersed Nuclear Elements (LINEs) has retained the ability to jump autonomously in modern humans. Their mobilization in germline--but also some somatic tissues--contributes to human genetic diversity and to diseases, such as cancer. Here, we present euL1db, the European database of L1HS retrotransposon insertions in humans (available at http://euL1db.unice.fr). euL1db provides a curated and comprehensive summary of L1HS insertion polymorphisms identified in healthy or pathological human samples and published in peer-reviewed journals. A key feature of euL1db is its sample--wise organization. Hence L1HS insertion polymorphisms are connected to samples, individuals, families and clinical conditions. The current version of euL1db centralizes results obtained in 32 studies. It contains >900 samples, >140,000 sample-wise insertions and almost 9000 distinct merged insertions. euL1db will help understanding the link between L1 retrotransposon insertion polymorphisms and phenotype or disease.

  14. Description of the L1C signal

    USGS Publications Warehouse

    Betz, J.W.; Blanco, M.A.; Cahn, C.R.; Dafesh, P.A.; Hegarty, C.J.; Hudnut, K.W.; Kasemsri, V.; Keegan, R.; Kovach, K.; Lenahan, L.S.; Ma, H.H.; Rushanan, J.J.; Sklar, D.; Stansell, T.A.; Wang, C.C.; Yi, S.K.

    2006-01-01

    Detailed design of the modernized LI civil signal (L1C) signal has been completed, and the resulting draft Interface Specification IS-GPS-800 was released in Spring 2006. The novel characteristics of the optimized L1C signal design provide advanced capabilities while offering to receiver designers considerable flexibility in how to use these capabilities. L1C provides a number of advanced features, including: 75% of power in a pilot component for enhanced signal tracking, advanced Weilbased spreading codes, an overlay code on the pilot that provides data message synchronization, support for improved reading of clock and ephemeris by combining message symbols across messages, advanced forward error control coding, and data symbol interleaving to combat fading. The resulting design offers receiver designers the opportunity to obtain unmatched performance in many ways. This paper describes the design of L1C. A summary of LIC's background and history is provided. The signal description then proceeds with the overall signal structure consisting of a pilot component and a carrier component. The new L1C spreading code family is described, along with the logic used for generating these spreading codes. Overlay codes on the pilot channel are also described, as is the logic used for generating the overlay codes. Spreading modulation characteristics are summarized. The data message structure is also presented, showing the format for providing time, ephemeris, and system data to users, along with features that enable receivers to perform code combining. Encoding of rapidly changing time bits is described, as are the Low Density Parity Check codes used for forward error control of slowly changing time bits, clock, ephemeris, and system data. The structure of the interleaver is also presented. A summary of L 1C's unique features and their benefits is provided, along with a discussion of the plan for L1C implementation.

  15. L1C signal design options

    USGS Publications Warehouse

    Betz, J.W.; Cahn, C.R.; Dafesh, P.A.; Hegarty, C.J.; Hudnut, K.W.; Jones, A.J.; Keegan, R.; Kovach, K.; Lenahan, L.S.; Ma, H.H.; Rushanan, J.J.; Stansell, T.A.; Wang, C.C.; Yi, S.K.

    2006-01-01

    Design activities for a new civil signal centered at 1575.42 MHz, called L1C, began in 2003, and the Phase 1 effort was completed in 2004. The L1C signal design has evolved and matured during a Phase 2 design activity that began in 2005. Phase 2 has built on the initial design activity, guided by responses to international user surveys conducted during Phase 1. A common core of signal characteristics has been developed to provide advances in robustness and performance. The Phase 2 activity produced five design options, all drawing upon the core signal characteristics, while representing different blends of characteristics and capabilities. A second round of international user surveys was completed to solicit advice concerning these design options. This paper provides an update of the L1C design process, and describes the current L1C design options. Initial performance estimates are presented for each design option, displaying trades between signal tracking robustness, the speed and robustness of clock and ephemeris data, and the rate and robustness of other data message contents. Planned remaining activities are summarized, leading to optimization of the L1C design.

  16. 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.

  17. 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

  18. A Silicon d-spacing Mapping Measurement System With Resolution of 10-9

    NASA Astrophysics Data System (ADS)

    Zhang, Xiaowei; Sugiyama, Hiroshi; Fugimoto, Hiroyuki; Waseda, Atsushi; Takatomi, Toshikazu

    2010-06-01

    For determination of the Avogadro's number, a self-referenced lattice comparator established at the Photon Factory to deal with a d-spacing mapping measurement over the cross section of a 4 ˜ 5 inches FZ silicon rod. For uncertainty of 1×10-8 of the unit cell volume, it is necessary to measure lattice parameter of silicon with resolution of 3×10-9 at least. In this paper, we report the principle of our lattice comparator, characterize our measurement system, and show some mapping measurement results of FZ silicon with resolution of 3×10-9.

  19. 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).

  20. 46 CFR 111.10-9 - Ship's service supply transformers; two required.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 4 2010-10-01 2010-10-01 false Ship's service supply transformers; two required. 111.10... ENGINEERING ELECTRIC SYSTEMS-GENERAL REQUIREMENTS Power Supply § 111.10-9 Ship's service supply transformers; two required. If transformers are used to supply the ship's service distribution system required...

  1. 46 CFR 12.10-9 - Endorsement for proficiency in fast rescue boats.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 1 2013-10-01 2013-10-01 false Endorsement for proficiency in fast rescue boats. 12.10... SEAMEN REQUIREMENTS FOR RATING ENDORSEMENTS Lifeboatman § 12.10-9 Endorsement for proficiency in fast rescue boats. (a) Each person engaged or employed as a lifeboatman proficient in fast rescue boats...

  2. 46 CFR 12.10-9 - Endorsement for proficiency in fast rescue boats.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 1 2010-10-01 2010-10-01 false Endorsement for proficiency in fast rescue boats. 12.10... SEAMEN REQUIREMENTS FOR RATING ENDORSEMENTS Lifeboatman § 12.10-9 Endorsement for proficiency in fast rescue boats. (a) Each person engaged or employed as a lifeboatman proficient in fast rescue boats...

  3. 46 CFR 12.10-9 - Endorsement for proficiency in fast rescue boats.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 1 2012-10-01 2012-10-01 false Endorsement for proficiency in fast rescue boats. 12.10... SEAMEN REQUIREMENTS FOR RATING ENDORSEMENTS Lifeboatman § 12.10-9 Endorsement for proficiency in fast rescue boats. (a) Each person engaged or employed as a lifeboatman proficient in fast rescue boats...

  4. 46 CFR 12.10-9 - Endorsement for proficiency in fast rescue boats.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 1 2011-10-01 2011-10-01 false Endorsement for proficiency in fast rescue boats. 12.10... SEAMEN REQUIREMENTS FOR RATING ENDORSEMENTS Lifeboatman § 12.10-9 Endorsement for proficiency in fast rescue boats. (a) Each person engaged or employed as a lifeboatman proficient in fast rescue boats...

  5. 46 CFR 111.10-9 - Ship's service supply transformers; two required.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 4 2014-10-01 2014-10-01 false Ship's service supply transformers; two required. 111.10... ENGINEERING ELECTRIC SYSTEMS-GENERAL REQUIREMENTS Power Supply § 111.10-9 Ship's service supply transformers; two required. If transformers are used to supply the ship's service distribution system required...

  6. 46 CFR 111.10-9 - Ship's service supply transformers; two required.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 4 2012-10-01 2012-10-01 false Ship's service supply transformers; two required. 111.10... ENGINEERING ELECTRIC SYSTEMS-GENERAL REQUIREMENTS Power Supply § 111.10-9 Ship's service supply transformers; two required. If transformers are used to supply the ship's service distribution system required...

  7. 46 CFR 111.10-9 - Ship's service supply transformers; two required.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 4 2013-10-01 2013-10-01 false Ship's service supply transformers; two required. 111.10... ENGINEERING ELECTRIC SYSTEMS-GENERAL REQUIREMENTS Power Supply § 111.10-9 Ship's service supply transformers; two required. If transformers are used to supply the ship's service distribution system required...

  8. 46 CFR 111.10-9 - Ship's service supply transformers; two required.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 4 2011-10-01 2011-10-01 false Ship's service supply transformers; two required. 111.10... ENGINEERING ELECTRIC SYSTEMS-GENERAL REQUIREMENTS Power Supply § 111.10-9 Ship's service supply transformers; two required. If transformers are used to supply the ship's service distribution system required...

  9. 25 CFR 10.9 - If a person is detained or incarcerated in an Indian country detention, community residential, or...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ..., privileges, safety, protection and expected behavior would be? 10.9 Section 10.9 Indians BUREAU OF INDIAN... behavior would be? When an individual is incarcerated in an Indian country detention, community...

  10. 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

  11. MolProbity for the masses—of data

    PubMed Central

    Chen, Vincent B.; Wedell, Jonathan R.; Wenger, R. Kent; Ulrich, Eldon L.

    2015-01-01

    MolProbity is a powerful software program for validating structures of proteins and nucleic acids. Although MolProbity includes scripts for batch analysis of structures, because these scripts analyze structures one at a time, they are not well suited for the validation of a large dataset of structures. We have created a version of MolProbity (MolProbity-HTC) that circumvents these limitations and takes advantage of a high-throughput computing cluster by using the HTCondor software. MolProbity-HTC enables the longitudinal analysis of large sets of structures, such as those deposited in the PDB or generated through theoretical computation—tasks that would have been extremely time-consuming using previous versions of MolProbity. We have used MolProbity-HTC to validate the entire PDB, and have developed a new visual chart for the BioMagResBank (BMRB) website that enables users to easily ascertain the quality of each model in an NMR ensemble and to compare the quality of those models to the rest of the PDB. PMID:26195077

  12. 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

  13. 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

  14. 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...

  15. 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...

  16. 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...

  17. 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...

  18. Atomic structure of Cu-10. 9 at % Be alloys in the early stages of aging

    SciTech Connect

    Koo, Y.M.

    1987-01-01

    Diffuse x-ray scattering was employed to investigate the local atomic structure and static strains in a single crystal of a Cu-10.9 at. % Be alloy in the early stages of aging. In addition to these experiments, neutron elastic and inelastic scattering were obtained to investigate the phonon properties in the as-quenched state of this alloy. In the as-quenched state, there is a nearly regular array of small ellipsoidal Be clusters aligned along <100> directions (This produces the tweed contrast seen in TEM). The density of these clusters is 7.5 x 10/sup 26//m/sup 3/. The diffuse streaks seen in electron diffraction patterns are due largely to thermal diffuse scattering. Phonon-dispersion curves show no large differences from those of pure copper, except at (xi xi xi)/sub T/ zone boundary, where there is softening. This difference may be due to a Kohn anomaly. The elastic anisotropy of this alloy increases considerably with alloying, which probably leads to the plate-like GP zone morphology in subsequent aging treatments. The structure of the GP zones is a mixture of Be-rich single- and multi-layered zones. As aging proceeds, the zones grow in thickness.

  19. 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).

  20. 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…

  1. L1 modulates PKD1 phosphorylation in cerebellar granule neurons.

    PubMed

    Chen, Shuang-xi; Hu, Cheng-liang; Liao, Yong-hong; Zhao, Wei-jiang

    2015-01-01

    The neural cell adhesion molecule L1 (L1CAM) is crucial for the development of the nervous system, with an essential role in regulating multiple cellular activities. Protein kinase D1 (PKD1) serves as a key kinase given its diverse array of functions within the cell. Here, we investigated various aspects of the functional relationship between L1 and phosphorylated PKD1 (pPKD1) in cerebellar granule neurons. To study the relationship between L1 and PKD1 phosphorylation, human cerebellar tissue microarrays were subject to immunofluorescence staining. We observed a positive correlation between L1 protein levels and PKD1 phosphorylation. In addition, L1 also co-localized with pPKD1. To analyze the regulatory role of L1 on PKD1 phosphorylation, primary mouse cerebellar granule neurons were treated with various concentrations of rL1 for 48 h. Using Western blot, we revealed that L1 significantly increased PKD1 phosphorylation compared with vehicle control, with the maximal effect observed at 5 nM. ERK1/2 phosphorylation was significantly increased by 2.5 nM and 10nM L1, with no apparent change in SRC phosphorylation. However, SRC expression was markedly reduced by 10nM rL1. AKT1 expression and phosphorylation levels were significantly increased by rL1, with the maximal effect observed at 2.5 and 5 nM, respectively. Our combined data revealed a positive relationship between L1 and pPKD1 in both cultured cerebellar neurons and human cerebellar tissue, suggesting that L1 functions in the modulation of PKD1 phosphorylation. PMID:25445362

  2. Deep-Sea Trench Microbiology Down to 10.9 Kilometers Below the Surface

    NASA Astrophysics Data System (ADS)

    Bartlett, D. H.

    2012-12-01

    Deep-sea trenches, extending to more than 10.9 km below the sea surface, are among the most remote and infrequently sampled habitats. As a result a global perspective of microbial diversity and adaptation is lacking in these extreme settings. I will present the results of studies of deep-sea trench microbes collected in the Puerto Rico Trench (PRT), Tonga Trench, New Britain Trench and Mariana Trench. The samples collected include sediment, seawater and animals in baited traps. The analyses to be described include microbial community activity and viability measurements as a function of hydrostatic pressure, microbial culturing at high pressure under various physiological conditions, phylogenetics and metagenome and single-cell genome characterizations. Most of the results to date stem from samples recovered from the PRT. The deep-sea PRT Trench microbes have more in common at the species level with other deep-sea microbial communities previously characterized in the Pacific Ocean and the Mediterranean Sea than with the microbial populations above them in shallow waters. They also harbor larger genomes with more genes assigned to signal transduction, transcription, replication, recombination and repair and inorganic ion transport. The overrepresented transporters in the PRT metagenome include di- and tri-carboxylate transporters that correspond to the prevailing catabolic processes such as butanoate, glyoxylate and dicarboxylate metabolism. A surprisingly high abundance of sulfatases for the degradation of sulfated polysaccharides were also present in the PRT. But, perhaps the most dramatic adaptational feature of the PRT microbes is heavy metal resistance, as reflected in the high numbers of metal efflux systems present. Single-cell genomics approaches have proven particularly useful for placing PRT metagenomic data into context.

  3. L1-dependent neuritogenesis involves ankyrinB that mediates L1-CAM coupling with retrograde actin flow.

    PubMed

    Nishimura, Kazunari; Yoshihara, Fumie; Tojima, Takuro; Ooashi, Noriko; Yoon, Woohyun; Mikoshiba, Katsuhiko; Bennett, Vann; Kamiguchi, Hiroyuki

    2003-12-01

    The cell adhesion molecule L1 (L1-CAM) plays critical roles in neurite growth. Its cytoplasmic domain (L1CD) binds to ankyrins that associate with the spectrin-actin network. This paper demonstrates that L1-CAM interactions with ankyrinB (but not with ankyrinG) are involved in the initial formation of neurites. In the membranous protrusions surrounding the soma before neuritogenesis, filamentous actin (F-actin) and ankyrinB continuously move toward the soma (retrograde flow). Bead-tracking experiments show that ankyrinB mediates L1-CAM coupling with retrograde F-actin flow in these perisomatic structures. Ligation of the L1-CAM ectodomain by an immobile substrate induces L1CD-ankyrinB binding and the formation of stationary ankyrinB clusters. Neurite initiation preferentially occurs at the site of these clusters. In contrast, ankyrinB is involved neither in L1-CAM coupling with F-actin flow in growth cones nor in L1-based neurite elongation. Our results indicate that ankyrinB promotes neurite initiation by acting as a component of the clutch module that transmits traction force generated by F-actin flow to the extracellular substrate via L1-CAM.

  4. 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

  5. Enrichment of processed pseudogene transcripts in L1-ribonucleoprotein particles

    PubMed Central

    Mandal, Prabhat K.; Ewing, Adam D.; Hancks, Dustin C.; Kazazian, Haig H.

    2013-01-01

    Long INterspersed Elements (LINE-1s, L1s) are responsible for over one million retrotransposon insertions and 8000 processed pseudogenes (PPs) in the human genome. An active L1 encodes two proteins (ORF1p and ORF2p) that bind with L1 RNA and form L1-ribonucleoprotein particles (RNPs). Although it is believed that the RNA-binding property of ORF1p is critical to recruit other mobile RNAs to the RNP, the identity of recruited RNAs is largely unknown. Here, we used crosslinking and immunoprecipitation followed by deep sequencing to identify RNA components of L1-RNPs. Our results show that in addition to retrotransposed RNAs [L1, Alu and SINE-VNTR-Alu (SVA)], L1-RNPs are enriched with cellular mRNAs, which have PPs in the human genome. Using purified L1-RNPs, we show that PP-source RNAs preferentially serve as ORF2p templates in a reverse transcriptase assay. In addition, we find that exogenous ORF2p binds endogenous ORF1p, allowing reverse transcription of the same PP-source RNAs. These data demonstrate that interaction of a cellular RNA with the L1-RNP is an inside track to PP formation. PMID:23696454

  6. Immunocytological and biochemical characterization of a new neuronal cell surface component (L1 antigen) which is involved in cell adhesion.

    PubMed Central

    Rathjen, F G; Schachner, M

    1984-01-01

    Monoclonal and polyclonal L1 antibodies react by indirect immunofluorescence with the cell surface of cultured tetanus toxin-positive neurons from post-natal cerebella of mice, but not with glial fibrillary acidic protein-positive astrocytes, O4 antigen-positive oligodendrocytes or fibronectin-positive fibroblasts or fibroblast-like cells. During cerebellar development L1 antigen is detectable on tetanus toxin-positive cells as early as embryonic day 13 after 3 days in culture. In sections of the early post-natal cerebellum, L1 antigen is found on pre-migratory neurons in the internal, but not in the external part of the external granular layer. In the adult cerebellum, L1 antigen is predominantly localized in the molecular layer and around Purkinje cells. Fibers in white matter and the granular layer are also L1 antigen-positive. Granule cell bodies and synaptic glomeruli are weakly antigen-positive. Several cell lines derived from neuroblastoma C1300 also express L1 antigen. The antigen is not detectable by enzyme-linked immunosorbent assay in tissue homogenates of liver, kidney, lung, heart, sperm or thymus. With polyclonal L1 antibodies, cross-reactive determinants are found in brains of rat, guinea pig, hamster, chicken, rabbit and man, but not in frog, while monoclonal antibody reacts detectably only with mouse brain. The molecular species recognized by both monoclonal and polyclonal antibodies display two prominent bands by SDS-PAGE under reducing and non-reducing conditions with apparent mol. wts. of 140 and 200 kd. L1 antigen isolated from cultured cerebellar cells consists mainly of a band in the 200-kd range and a faint one at 140 kd. L1 antigen from neuroblastoma N2A shows two bands with slightly higher apparent mol. wts. All molecular forms of L1 antigen can be labeled by [3H]fucose and [3H]glucosamine. Ca2+-independent re-aggregation of cerebellar cells from early post-natal C57BL/6J mice and of the continuous cell line N2A derived from the murine

  7. 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…

  8. 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

  9. 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

  10. 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…

  11. 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

  12. [Use of mesquite cotyledon (Prosopis chilensis (Mol) Shuntz) in the manufacturing of cereal bars].

    PubMed

    Estévez, A M; Escobar, B; Ugarte, V

    2000-06-01

    Cereal bars with peanut and walnut has shown to be snack foods of good organoleptic characteristics and high caloric value, due to their content of protein, lipids and carbohydrates. Cotyledons of mezquite seeds have a high protein content which biological quality improves with thermal processing like toasting, microwave or moist heat under pressure. The purposes of this research were to study the use of mezquite cotyledon (Prosopis chilensis (Mol) Stuntz) in cereal bars with two different levels of peanut or walnut; and to determine the effect of two thermal treatment applied on the cotyledon upon the bar characteristics. Twelve different kind of bars were developed through the combination of two levels of peanut or walnut (15% and 18%); the use of mezquite cotyledon (0% and 6%); and the application of two thermal processing to the cotyledon (microwave and toasting). Cereal bars were analysed for chemical, physical and sensory characteristics: moisture, water activity, proximate chemical composition, sensory quality and acceptability. Moisture content of bars with peanut ranged between 10.4% and 10.9%; and for those with walnut, between 10.5% and 12.3%. Protein content was higher in the bars with mezquite cotiledon, being higher those with peanut. Thermal processing did not have any effect on the chemical composition. Bars with mezquite cotyledon treated by microwave showed a higher acceptability. PMID:11048586

  13. [Use of mesquite cotyledon (Prosopis chilensis (Mol) Shuntz) in the manufacturing of cereal bars].

    PubMed

    Estévez, A M; Escobar, B; Ugarte, V

    2000-06-01

    Cereal bars with peanut and walnut has shown to be snack foods of good organoleptic characteristics and high caloric value, due to their content of protein, lipids and carbohydrates. Cotyledons of mezquite seeds have a high protein content which biological quality improves with thermal processing like toasting, microwave or moist heat under pressure. The purposes of this research were to study the use of mezquite cotyledon (Prosopis chilensis (Mol) Stuntz) in cereal bars with two different levels of peanut or walnut; and to determine the effect of two thermal treatment applied on the cotyledon upon the bar characteristics. Twelve different kind of bars were developed through the combination of two levels of peanut or walnut (15% and 18%); the use of mezquite cotyledon (0% and 6%); and the application of two thermal processing to the cotyledon (microwave and toasting). Cereal bars were analysed for chemical, physical and sensory characteristics: moisture, water activity, proximate chemical composition, sensory quality and acceptability. Moisture content of bars with peanut ranged between 10.4% and 10.9%; and for those with walnut, between 10.5% and 12.3%. Protein content was higher in the bars with mezquite cotiledon, being higher those with peanut. Thermal processing did not have any effect on the chemical composition. Bars with mezquite cotyledon treated by microwave showed a higher acceptability.

  14. Absorptions moléculaires à grand redshift.

    NASA Astrophysics Data System (ADS)

    Combes, F.; Wiklind, T.

    L'observation de molécules en absorption est une technique pleine de promesses pour sonder le gaz froid à grand redshift. Les futurs instruments millimétriques bénéficieront de plus grandes surfaces collectrices, et un nombre bien supérieur de sources continuum deviendront accessibles, car le nombre de sources croit extre^mement rapidement à flux décroissant. D'autre part, à cause du biais de magnification gravitationnelle, on s'attend à trouver un excès de galaxies sur la ligne de visée des quasars brillants très lointains.

  15. 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

  16. 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.

  17. L1-norm-based common spatial patterns.

    PubMed

    Wang, Haixian; Tang, Qin; Zheng, Wenming

    2012-03-01

    Common spatial patterns (CSP) is a commonly used method of spatial filtering for multichannel electroencephalogram (EEG) signals. The formulation of the CSP criterion is based on variance using L2-norm, which implies that CSP is sensitive to outliers. In this paper, we propose a robust version of CSP, called CSP-L1, by maximizing the ratio of filtered dispersion of one class to the other class, both of which are formulated by using L1-norm rather than L2-norm. The spatial filters of CSP-L1 are obtained by introducing an iterative algorithm, which is easy to implement and is theoretically justified. CSP-L1 is robust to outliers. Experiment results on a toy example and datasets of BCI competitions demonstrate the efficacy of the proposed method. PMID:22147288

  18. 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

  19. 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

  20. 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

  1. Calixarene-based mol-ecular capsule from olefin metathesis.

    PubMed

    Hailu, Shimelis T; Butcher, Ray J; Hudrlik, Paul F; Hudrlik, Anne M

    2013-01-01

    The reaction of tetra-kis-(all-yloxy)calix[4]arene with the first-generation Grubbs catalyst, followed by catalytic hydrogenation, gave the novel bis-calixarene 15,20,46,51,64,69,74,79-octa-oxatridecacyclo[32.28.8.8(3,28).1(13,53).1(22,44).0(9,14).0(21,26).0(38,70).0(40,45).0(52,57).0(59,63).0(7,80).0(32,73)]octa-conta-1(63),3,5,7(80),9(14),10,12,21,23,25,28(73),29,31,34,36,38(70),40,42,44,52,54,56,59,61-tetra-cosa-ene benzene monosolvate, C72H72O8·C6H6. The structure consists of two calix[4]arene units connected by four-carbon chains at each of the four O atoms on their narrow rims, to form a cage. Each of the calix[4]arene units has a flattened cone conformation in which two of the opposite aryl groups are closer together and nearly parallel [dihedral angle between planes = 7.35 (16)°], and the other two aryl groups are splayed outward [dihedral angle between planes = 72.20 (8)°]. While the cavity contains no solvent or other guest mol-ecule, there is benzene solvent mol-ecule in the lattice. Two of the alkyl linking arms were disordered over two conformations with occupancies of 0.582 (3)/0.418 (3) and 0.33 (4)/0.467 (4). They were constrained to have similar metrical and thermal parameters. PMID:24046590

  2. Genomic alterations in BCL2L1 and DLC1 contribute to drug sensitivity in gastric cancer

    PubMed Central

    Park, Hansoo; Cho, Sung-Yup; Kim, Hyerim; Na, Deukchae; Han, Jee Yun; Chae, Jeesoo; Park, Changho; Park, Ok-Kyoung; Min, Seoyeon; Kang, Jinjoo; Choi, Boram; Min, Jimin; Kwon, Jee Young; Suh, Yun-Suhk; Kong, Seong-Ho; Lee, Hyuk-Joon; Liu, Edison T.; Kim, Jong-Il; Kim, Sunghoon; Yang, Han-Kwang; Lee, Charles

    2015-01-01

    Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. Recent high-throughput analyses of genomic alterations revealed several driver genes and altered pathways in GC. However, therapeutic applications from genomic data are limited, largely as a result of the lack of druggable molecular targets and preclinical models for drug selection. To identify new therapeutic targets for GC, we performed array comparative genomic hybridization (aCGH) of DNA from 103 patients with GC for copy number alteration (CNA) analysis, and whole-exome sequencing from 55 GCs from the same patients for mutation profiling. Pathway analysis showed recurrent alterations in the Wnt signaling [APC, CTNNB1, and DLC1 (deleted in liver cancer 1)], ErbB signaling (ERBB2, PIK3CA, and KRAS), and p53 signaling/apoptosis [TP53 and BCL2L1 (BCL2-like 1)] pathways. In 18.4% of GC cases (19/103), amplification of the antiapoptotic gene BCL2L1 was observed, and subsequently a BCL2L1 inhibitor was shown to markedly decrease cell viability in BCL2L1-amplified cell lines and in similarly altered patient-derived GC xenografts, especially when combined with other chemotherapeutic agents. In 10.9% of cases (6/55), mutations in DLC1 were found and were also shown to confer a growth advantage for these cells via activation of Rho-ROCK signaling, rendering these cells more susceptible to a ROCK inhibitor. Taken together, our study implicates BCL2L1 and DLC1 as potential druggable targets for specific subsets of GC cases. PMID:26401016

  3. Genomic alterations in BCL2L1 and DLC1 contribute to drug sensitivity in gastric cancer.

    PubMed

    Park, Hansoo; Cho, Sung-Yup; Kim, Hyerim; Na, Deukchae; Han, Jee Yun; Chae, Jeesoo; Park, Changho; Park, Ok-Kyoung; Min, Seoyeon; Kang, Jinjoo; Choi, Boram; Min, Jimin; Kwon, Jee Young; Suh, Yun-Suhk; Kong, Seong-Ho; Lee, Hyuk-Joon; Liu, Edison T; Kim, Jong-Il; Kim, Sunghoon; Yang, Han-Kwang; Lee, Charles

    2015-10-01

    Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. Recent high-throughput analyses of genomic alterations revealed several driver genes and altered pathways in GC. However, therapeutic applications from genomic data are limited, largely as a result of the lack of druggable molecular targets and preclinical models for drug selection. To identify new therapeutic targets for GC, we performed array comparative genomic hybridization (aCGH) of DNA from 103 patients with GC for copy number alteration (CNA) analysis, and whole-exome sequencing from 55 GCs from the same patients for mutation profiling. Pathway analysis showed recurrent alterations in the Wnt signaling [APC, CTNNB1, and DLC1 (deleted in liver cancer 1)], ErbB signaling (ERBB2, PIK3CA, and KRAS), and p53 signaling/apoptosis [TP53 and BCL2L1 (BCL2-like 1)] pathways. In 18.4% of GC cases (19/103), amplification of the antiapoptotic gene BCL2L1 was observed, and subsequently a BCL2L1 inhibitor was shown to markedly decrease cell viability in BCL2L1-amplified cell lines and in similarly altered patient-derived GC xenografts, especially when combined with other chemotherapeutic agents. In 10.9% of cases (6/55), mutations in DLC1 were found and were also shown to confer a growth advantage for these cells via activation of Rho-ROCK signaling, rendering these cells more susceptible to a ROCK inhibitor. Taken together, our study implicates BCL2L1 and DLC1 as potential druggable targets for specific subsets of GC cases. PMID:26401016

  4. 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

  5. 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…

  6. L1 burst fracture with associated vertebral angioma.

    PubMed

    Armaganian, G; Adetchessi, T; Pech-Gourg, G; Blondel, B; Dufour, H; Fuentes, S

    2013-04-01

    Vertebral angioma is a common bone tumor. We report a case of L1 vertebral angioma revealed by type A3.2 traumatic pathological fracture of the same vertebra. Management comprised emergency percutaneous osteosynthesis and, after stabilization of the multiple trauma, arterial embolization and percutaneous kyphoplasty.

  7. 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…

  8. 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... financing arrangements. Section 7701(l) authorizes the issuance of regulations that recharacterize any multiple-party financing transaction as a transaction directly among any two or more of such parties...

  9. 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…

  10. 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…

  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. Lexical Bundles in L1 and L2 Academic Writing

    ERIC Educational Resources Information Center

    Chen, Yu-Hua; Baker, Paul

    2010-01-01

    This paper adopts an automated frequency-driven approach to identify frequently-used word combinations (i.e., "lexical bundles") in academic writing. Lexical bundles retrieved from one corpus of published academic texts and two corpora of student academic writing (one L1, the other L2), were investigated both quantitatively and qualitatively.…

  13. 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…

  14. Least-squares RTM with L1 norm regularisation

    NASA Astrophysics Data System (ADS)

    Wu, Di; Yao, Gang; Cao, Jingjie; Wang, Yanghua

    2016-10-01

    Reverse time migration (RTM), for imaging complex Earth models, is a reversal procedure of the forward modelling of seismic wavefields, and hence can be formulated as an inverse problem. The least-squares RTM method attempts to minimise the difference between the observed field data and the synthetic data generated by the migration image. It can reduce the artefacts in the images of a conventional RTM which uses an adjoint operator, instead of an inverse operator, for the migration. However, as the least-squares inversion provides an average solution with minimal variation, the resolution of the reflectivity image is compromised. This paper presents the least-squares RTM method with a model constraint defined by an L1-norm of the reflectivity image. For solving the least-squares RTM with L1 norm regularisation, the inversion is reformulated as a ‘basis pursuit de-noise (BPDN)’ problem, and is solved directly using an algorithm called ‘spectral projected gradient for L1 minimisation (SPGL1)’. Three numerical examples demonstrate the effectiveness of the method which can mitigate artefacts and produce clean images with significantly higher resolution than the least-squares RTM without such a constraint.

  15. L1 elements, processed pseudogenes and retrogenes in mammalian genomes.

    PubMed

    Ding, Wenyong; Lin, Lin; Chen, Bing; Dai, Jianwu

    2006-12-01

    Long interspersed nuclear elements 1 (L1 elements or LINE1) are the most active autonomous retrotransposons in mammalian genomes. In addition to L1 elements themselves, other protein-coding mRNAs can also be reverse transcribed and integrated into the genome through the L1-mediated retrotransposition, leading to the formation of processed pseudogenes (PPs) and retrogenes, both of which are characterized by the lack of introns and the presence of a 3' polyA tract and flanking direct repeats. PPs are unable to encode a functional protein and have accumulated frameshift mutations and premature stop codons during evolution. A few of PPs are transcriptionally active. Retrogenes preserve undisrupted coding frames and are capable of encoding a functional protein that is identical or nearly identical to that of the progenitor gene. There is a significant excess of retrogenes that originate from the X chromosome and are retrotransposed into autosomes, and most of these retrogenes are specially expressed in male germ cells, suggesting the inactivation of X-linked genes during male meiosis provides a strong selection pressure on retrogenes originating from the X chromosome.

  16. Salmonella induces PD-L1 expression in B cells.

    PubMed

    Lopez-Medina, Marcela; Perez-Lopez, Araceli; Alpuche-Aranda, Celia; Ortiz-Navarrete, Vianney

    2015-10-01

    Salmonella persists for a long time in B cells; however, the mechanism(s) through which infected B cells avoid effector CD8 T cell responses has not been characterized. In this study, we show that Salmonella infects and survives within all B1 and B2 cell subpopulations. B cells are infected with a Salmonella typhimurium strain expressing an ovalbumin (OVA) peptide (SIINFEKL) to evaluate whether B cells process and present Salmonella antigens in the context of MHC-I molecules. Our data showed that OVA peptides are presented by MHC class I K(b)-restricted molecules and the presented antigen is generated through proteasomal degradation and vacuolar processing. In addition, Salmonella-infected B cells express co-stimulatory molecules such as CD40, CD80, and CD86 as well as inhibitory molecules such as PD-L1. Thus, the cross-presentation of Salmonella antigens and the expression of activation molecules suggest that infected B cells are able to prime and activate specific CD8(+) T cells. However, the Salmonella infection-stimulated expression of PD-L1 suggests that the PD-1/PD-L1 pathway may be involved in turning off the cytotoxic effector response during Salmonella persistent infection, thereby allowing B cells to become a reservoir for the bacteria.

  17. Vaspin promotes 3T3-L1 preadipocyte differentiation

    PubMed Central

    Liu, Ping; Wu, Jine; Zhou, Xin; Wang, Liping; Han, Wenqi; Lv, Ying; Sun, Chaofeng

    2015-01-01

    Vaspin, a novel adipocyte factor secreted from visceral adipose tissues, is associated with obesity and insulin resistance and can regulate glucose and lipid metabolism, increase insulin sensitivity, and suppress inflammation; however, the underlying mechanisms remain unknown. Proliferation and maladaptive differentiation are important pathological mechanisms underlying obesity. This study aimed to evaluate the effects of vaspin on the proliferation and differentiation of preadipocyte 3T3-L1 cells and to explore the likely mechanisms responsible for 3T3-L1 differentiation. Vaspin was added to cultured 3T3-L1 cells, and the differentiation of adipocytes was evaluated using Oil Red O staining. The AKT signaling pathway and specific differentiation factors related to the differentiation of preadipocyte 3T3-L1 cells, peroxisome proliferator-activated γ and the CCAAT/enhancer-binding protein (C/EBP) family, were evaluated using reverse transcription polymerase chain reaction (RT-PCR) and western blot analyses during the early phase of differentiation. Additionally, adiponectin mRNA, interleukin-6 mRNA (IL-6 mRNA), and glucose transporter-4 (GLUT4) protein levels were measured in the differentiated adipocytes. The results indicated that vaspin promotes the intracellular accumulation of lipids and increases differentiation-related factors, including peroxisome proliferator-activated receptor γ, C/EBPα, and free fatty acid-binding protein 4 (FABP4), in a dose-dependent manner. Additionally, vaspin (200 ng/mL) increased the mRNA and protein levels of C/EBPβ, peroxisome proliferator-activated γ, C/EBPα, and FABP4. Moreover, compared with the control, significantly smaller eight-day differentiated adipocytes were observed, and these cells exhibited decreased IL-6 mRNA and increased GLUT4 mRNA levels; these results also indicated the potential of vaspin to promote the insulin-mediated AKT signaling pathway during the early phase of differentiation. In conclusion

  18. 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

  19. 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

  20. Topiramate effects lipolysis in 3T3-L1 adipocytes

    PubMed Central

    MARTINS, GABRIELA POLTRONIERI CAMPAGNARO; SOUZA, CAMILA OLIVEIRA; MARQUES, SCHEROLIN; LUCIANO, THAIS FERNANDES; DA SILVA PIERI, BRUNO LUIZ; ROSA, JOSÉ CÉSAR; DA SILVA, ADELINO SANCHEZ RAMOS; PAULI, JOSÉ RODRIGO; CINTRA, DENNYS ESPER; ROPELLE, EDUARDO ROCHETE; RODRIGUES, BRUNO; DE LIRA, FABIO SANTOS; DE SOUZA, CLAUDIO TEODORO

    2015-01-01

    Studies have shown that topiramate (TPM)-induced weight loss can be dependent on the central nervous system (CNS). However, the direct action of TPM on adipose tissue has not been tested previously. Thus, the present study aimed to examine whether TPM modulates lipolysis in 3T3-L1. The 3T3-L1 cells were incubated in 50 µM TPM for 30 min. The β-adrenergic stimulator, isoproterenol, was used as a positive control. The release of lactate dehydrogenase, non-esterified fatty acid, glycerol and incorporation of 14C-palmitate to lipid were analyzed. The phosphorylation of protein kinase A (PKA), hormone-sensitive lipase (HSL), adipocyte triglyceride lipase (ATGL) and perilipin A, as well as the protein levels of comparative genetic identification 58 (CGI-58) were assessed. The levels of glycerol and non-esterified fatty acid increased markedly when the cells were treated with TPM. The TPM effects were similar to the isoproterenol positive control. Additionally, TPM reduced lipogenesis. These results were observed without any change in cell viability. Finally, the phosphorylation of PKA, HSL, ATGL and perilipin A, as well as the protein levels of CGI-58 were increased compared to the control cells. These results were similar to those observed in the cells treated with isoproterenol. The present results show that TPM increased the phosphorylation of pivotal lipolytic enzymes, which induced lipolysis in 3T3-L1 adipocytes, suggesting that this drug may act directly in the adipose tissue independent from its effect on the CNS. PMID:26623024

  1. Measurement of air-refractive-index fluctuation from laser frequency shift with uncertainty of order 10-9

    NASA Astrophysics Data System (ADS)

    Banh Quoc, Tuan; Ishige, Masashi; Ohkubo, Yuria; Aketagawa, Masato

    2009-12-01

    In the previous work (Ishige et al 2009 Meas. Sci. Technol. 20 084019), we presented a method of measuring the relative air-refractive-index fluctuation (Δnair) from the laser frequency shift with the measurement uncertainty of order 10-8 using a phase modulation homodyne interferometer (Basile et al 1991 Metrologia 28 455), which was supported by an ultralow thermal expansion material (ULTEM) and an external cavity laser diode (ECLD). In this paper, an improvement in the uncertainty of the Δnair measurement is presented. The improvement method is based on a Fabry-Perot cavity constructed on the ULTEM, which has a thermal expansion coefficient of 2 × 10-8 K-1 and an ECLD. The Pound-Drever-Hall method (Drever et al 1983 Appl. Phys. B 31 97) is also used to control the ECLD frequency to track the resonance of the cavity. Δnair can be derived from the ECLD frequency shift. The estimated measurement uncertainty of Δnair for a short time (~150 s) in the experiment is of order 2.5 × 10-9 or less.

  2. Aspartame downregulates 3T3-L1 differentiation.

    PubMed

    Pandurangan, Muthuraman; Park, Jeongeun; Kim, Eunjung

    2014-10-01

    Aspartame is an artificial sweetener used as an alternate for sugar in several foods and beverages. Since aspartame is 200 times sweeter than traditional sugar, it can give the same level of sweetness with less substance, which leads to lower-calorie food intake. There are reports that consumption of aspartame-containing products can help obese people lose weight. However, the potential role of aspartame in obesity is not clear. The present study investigated whether aspartame suppresses 3T3-L1 differentiation, by downregulating phosphorylated peroxisome proliferator-activated receptor γ (p-PPARγ), peroxisome proliferator-activated receptor γ (PPARγ), fatty acid-binding protein 4 (FABP4), CCAAT/enhancer-binding protein α (C/EBPα), and sterol regulatory element-binding protein 1 (SREBP1), which are critical for adipogenesis. The 3T3-L1 adipocytes were cultured and differentiated for 6 d in the absence and presence of 10 μg/ml of aspartame. Aspartame reduced lipid accumulation in differentiated adipocytes as evidenced by Oil Red O staining. qRT-PCR analysis showed that the PPARγ, FABP4, and C/EBPα mRNA expression was significantly reduced in the aspartame-treated adipocytes. Western blot analysis showed that the induction of p-PPARγ, PPARγ, SREBP1, and adipsin was markedly reduced in the aspartame-treated adipocytes. Taken together, these data suggest that aspartame may be a potent substance to alter adipocyte differentiation and control obesity. PMID:24961835

  3. Aspartame downregulates 3T3-L1 differentiation.

    PubMed

    Pandurangan, Muthuraman; Park, Jeongeun; Kim, Eunjung

    2014-10-01

    Aspartame is an artificial sweetener used as an alternate for sugar in several foods and beverages. Since aspartame is 200 times sweeter than traditional sugar, it can give the same level of sweetness with less substance, which leads to lower-calorie food intake. There are reports that consumption of aspartame-containing products can help obese people lose weight. However, the potential role of aspartame in obesity is not clear. The present study investigated whether aspartame suppresses 3T3-L1 differentiation, by downregulating phosphorylated peroxisome proliferator-activated receptor γ (p-PPARγ), peroxisome proliferator-activated receptor γ (PPARγ), fatty acid-binding protein 4 (FABP4), CCAAT/enhancer-binding protein α (C/EBPα), and sterol regulatory element-binding protein 1 (SREBP1), which are critical for adipogenesis. The 3T3-L1 adipocytes were cultured and differentiated for 6 d in the absence and presence of 10 μg/ml of aspartame. Aspartame reduced lipid accumulation in differentiated adipocytes as evidenced by Oil Red O staining. qRT-PCR analysis showed that the PPARγ, FABP4, and C/EBPα mRNA expression was significantly reduced in the aspartame-treated adipocytes. Western blot analysis showed that the induction of p-PPARγ, PPARγ, SREBP1, and adipsin was markedly reduced in the aspartame-treated adipocytes. Taken together, these data suggest that aspartame may be a potent substance to alter adipocyte differentiation and control obesity.

  4. 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.

  5. 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

  6. 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.

  7. Prognostic value and clinicopathologic characteristics of L1 cell adhesion molecule (L1CAM) in a large series of vulvar squamous cell carcinomas

    PubMed Central

    Trietsch, Marjolijn D.; Oonk, Maaike H.M.; Hawinkels, Lukas J.A.C.; Bor, Rosalie; van Eendenburg, Jaap D.H.; Ivanova, Zina; Peters, Alexander A.W.; Nijman, Hans W.; Gaarenstroom, Katja N.; Bosse, Tjalling

    2016-01-01

    Background Vulvar cancer treatment is mostly curative, but also has high morbidity rates. In a search for markers that can identify patients at risk of metastases, we investigated the prognostic value of L1-cell adhesion molecule (L1CAM) in large series of vulvar squamous cell carcinomas (VSCCs). L1CAM promotes cell motility and is an emerging prognostic factor for metastasis in many cancer subtypes. Results L1CAM expression was observed at the invasive front or in spray-patterned parts of 17% of the tumours. L1CAM-positive tumours expressed vimentin more often, but L1CAM expression was not associated with TP53 or CTNNB1 mutations. Five-year survival was worse for patients with L1CAM expression (overall survival 46.1% vs 63.6%, P=.014, disease specific survival 63.8% vs 80.0%, P=.018). Multivariate analysis indicates L1CAM expression as an independent prognostic marker (HR 2.9, 95% CI 1.10–7.68). An in vitro spheroid invasion assay showed decreased invasion of L1CAM-expressing VSCC spindle cells after treatment with L1CAM-neutralising antibodies. Materials and Methods Paraffin-embedded tumour tissue from two cohorts (N=103 and 245) of primary VSCCs were stained for L1CAM, vimentin and E-cadherin. Patients of the first cohort were tested for human papilloma virus infection and sequenced for TP53 and CTNNB1 (β-catenin) mutations. The expression of L1CAM was correlated to clinical characteristics and patient survival. Conclusion This is the first study to show high L1CAM-expression at the infiltrating margin of VSCC's. L1CAM-expressing VSCCs had a significantly worse prognosis compared to L1CAM-negative tumours. The highest expression was observed in spindle-shaped cells, where it might be correlated to their invasive capacity. PMID:27028855

  8. 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}.

  9. The role of the cytoplasmic domain of the L1 cell adhesion molecule in brain development

    PubMed Central

    Nakamura, Yukiko; Lee, Suni; Haddox, Candace L.; Weaver, Eli J.; Lemmon, Vance P.

    2011-01-01

    Mutations in the human L1CAM gene cause X-linked Hydrocephalus and MASA syndrome. In vitro studies have shown the L1 cytoplasmic domain (L1CD) is involved in L1 trafficking, neurite branching, signaling, and interactions with the cytoskeleton. L1cam knock-out (L1KO) mice have hydrocephalus, a small cerebellum, hyperfasciculation of corticothalamic tracts and abnormal peripheral nerves. To explore the function of the L1CD, we made three new mice lines in which different parts of the L1CD have been altered. In all mutant lines L1 protein is expressed and transported into the axon. Interestingly, these new L1CD mutant lines display normal brain morphology. However, the expression of L1 protein in the adult is dramatically reduced in the two L1CD mutant lines that lack the ankyrin-binding region and they show defects in motor function. Therefore, the L1CD is not responsible for the major defects observed in L1KO mice, yet it is required for continued L1 protein expression and motor function in the adult. PMID:20127821

  10. PD-L1 blockade for cancer treatment: MEDI4736.

    PubMed

    Ibrahim, Ramy; Stewart, Ross; Shalabi, Aiman

    2015-06-01

    MEDI4736 is a human immunoglobulin (Ig) G1к monoclonal antibody that blocks programmed cell death ligand-1 (PD-L1) binding to its receptors, allowing T cells to recognize and kill tumor cells. Key attributes include high affinity and selectivity for PD-L1, sustained drug exposure for up to 1 year of dosing, and engineering of the antibody to prevent antibody-dependent cell-mediated cytotoxicity. No immunogenicity impacting on the pharmacokinetics/pharmacodynamics of MEDI4736 has been reported at the 10 mg/kg every 2 weeks dose selected for further clinical development. The current safety profile and encouraging early anti-tumor activity of MEDI4736 support further clinical assessment. A broad development program for MEDI4736, both as monotherapy and in combination, is underway across a range of tumor types. This includes a large, multicenter, phase I, dose-escalation/expansion study in solid tumors (with a smaller corresponding study in Japanese patients), a phase I study in myelodysplastic syndrome, and a phase II study in advanced colorectal cancer. In addition, multiple phase I combination studies are ongoing with different agents, including those targeting MEK/BRAF in melanoma, epidermal growth factor receptor, programmed cell death-1, cytotoxic T-lymphocyte antigen-4, OX40, chemokine (C-C motif) receptor 4, and indoleamine 2,3-dioxygenase. Development is most advanced in non-small cell lung cancer, with a program currently comprising four pivotal studies and three phase I combination studies. A pivotal program for MEDI4736 in head and neck cancer began in late 2014. PMID:25965366

  11. 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

  12. Expression of PD-L1 on Canine Tumor Cells and Enhancement of IFN-γ Production from Tumor-Infiltrating Cells by PD-L1 Blockade

    PubMed Central

    Maekawa, Naoya; Konnai, Satoru; Ikebuchi, Ryoyo; Okagawa, Tomohiro; Adachi, Mami; Takagi, Satoshi; Kagawa, Yumiko; Nakajima, Chie; Suzuki, Yasuhiko; Murata, Shiro; Ohashi, Kazuhiko

    2014-01-01

    Programmed death 1 (PD-1), an immunoinhibitory receptor, and programmed death ligand 1 (PD-L1), its ligand, together induce the “exhausted” status in antigen-specific lymphocytes and are thus involved in the immune evasion of tumor cells. In this study, canine PD-1 and PD-L1 were molecularly characterized, and their potential as therapeutic targets for canine tumors was discussed. The canine PD-1 and PD-L1 genes were conserved among canine breeds. Based on the sequence information obtained, the recombinant canine PD-1 and PD-L1 proteins were constructed; they were confirmed to bind each other. Antibovine PD-L1 monoclonal antibody effectively blocked the binding of recombinant PD-1 with PD-L1–expressing cells in a dose-dependent manner. Canine melanoma, mastocytoma, renal cell carcinoma, and other types of tumors examined expressed PD-L1, whereas some did not. Interestingly, anti-PD-L1 antibody treatment enhanced IFN-γ production from tumor-infiltrating cells. These results showed that the canine PD-1/PD-L1 pathway is also associated with T-cell exhaustion in canine tumors and that its blockade with antibody could be a new therapeutic strategy for canine tumors. Further investigations are needed to confirm the ability of anti-PD-L1 antibody to reactivate canine antitumor immunity in vivo, and its therapeutic potential has to be further discussed. PMID:24915569

  13. 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

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

    PubMed

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

    2016-01-01

    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

  15. The role of L1cam in murine corticogenesis, and the pathogenesis of hydrocephalus.

    PubMed

    Itoh, Kyoko; Fushiki, Shinji

    2015-02-01

    L1cam (L1), one of the cell adhesion molecules belonging to the immunoglobulin superfamily, plays critical roles in neuronal migration, axon growth, guidance, fasciculation, and synaptic plasticity in the central as well as the peripheral nervous system. A number of X-linked forms of mental retardation have been associated with mutations in the L1 gene, including X-linked hydrocephalus in humans. Although model mice with different sites of L1 mutation have been studied, the pathogenetic mechanisms of hydrocephalus and mental retardation still remain unsolved. We herein present an overview of the function of L1 in the central nervous system and describe a human case of L1 mutation and knock-in mice that showed deleted sixth immunoglobulin of L1. Finally, we present experimental evidence showing that L1 is involved in murine neocortical histogenesis and propose a hypothetical mechanism of L1-linked hydrocephalus, with reference to corticogenesis. PMID:25641508

  16. 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

  17. Ultra-thin L1{sub 0}-FePt for perpendicular anisotropy L1{sub 0}-FePt/Ag/[Co/Pd]{sub 30} pseudo spin valves

    SciTech Connect

    Ho, Pin; Chow, Gan Moog; Chen, Jing-Sheng; Han, Guchang; He, Kaihua

    2014-05-07

    Perpendicular anisotropy L1{sub 0}-FePt/Ag/[Co/Pd]{sub 30} pseudo spin valves (PSVs) with ultra-thin L1{sub 0}-FePt alloy free layer possessing high anisotropy and thermal stability have been fabricated and studied. The thickness of the L1{sub 0}-FePt layer was varied between 2 and 4 nm. The PSV became increasingly decoupled with reduced L1{sub 0}-FePt thickness due to the larger difference between the coercivity of the L1{sub 0}-FePt and [Co/Pd]{sub 30} films. The PSV with an ultra-thin L1{sub 0}-FePt free layer of 2 nm displayed a high K{sub u} of 2.21 × 10{sup 7} ergs/cm{sup 3}, high thermal stability of 84 and a largest giant magnetoresistance of 0.54%.

  18. Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1

    PubMed Central

    Nichols, Brendan; Jog, Prachi; Lee, Jessica; Blackler, Daniel; Wilmot, Michael; D’Agati, Vivette; Markowitz, Glen; Kopp, Jeffrey; Alper, Seth L.; Pollak, Martin R.; Friedman, David J.

    2014-01-01

    Apolipoprotein L1 (APOL1) risk variants greatly elevate the risk of kidney disease in African Americans. Here we report a cohort of patients who developed collapsing focal segmental glomerulosclerosis while receiving therapeutic interferon, all of whom carried the APOL1 high-risk genotype. This finding raised the possibility that interferons and the molecular pattern recognition receptors that stimulate interferon production may contribute to APOL1-associated kidney disease. In cell culture, interferons and toll-like receptor agonists increased APOL1 expression by up to 200-fold, in some cases with the appearance of transcripts not detected under basal conditions. PolyI:C, a double-stranded RNA TLR3 agonist, increased APOL1 expression by upregulating interferons directly or through an interferon-independent, IRF-3 dependent pathway. Using pharmacological inhibitors, shRNA knockdown, and chromatin immunoprecipitation, we found that the interferon-independent TLR3 pathway relied on signaling through TBK1, NF-kB, and Jak kinases, and on binding of IRF1, IRF2, and STAT2 at the APOL1 transcription start site. We also demonstrate that overexpression of the APOL1 risk variants is more injurious to cells than overexpression of the wild-type APOL1 protein. Our study illustrates that anti-viral pathways may be an important inducer of kidney disease in individuals with the APOL1 high-risk genotype and identifies potential targets for prevention or treatment. PMID:25100047

  19. 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.

  20. 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.

  1. Very low latitude (L = 1.08) whistlers

    NASA Astrophysics Data System (ADS)

    Singh, Rajesh; Cohen, Morris B.; Maurya, Ajeet K.; Veenadhari, B.; Kumar, Sushil; Pant, P.; Said, Ryan K.; Inan, Umran S.

    2012-12-01

    For decades, whistlers observed on the ground at mid and high latitudes have been used for diagnostics of Earth's plasmasphere. Whistlers have also been observed at low latitudes however, the propagation characteristics of low latitude whistlers are poorly understood thus they have not been used effectively as a diagnostic for the low latitude ionosphere. One key limitation with past studies has been lack of knowledge of the whistler source lightning location. Here we present the first cases of low latitude ground whistlers most likely linked with their causative lightning discharges in the conjugate zone. The Global Lightning Dataset 360 (GLD360) detected lightning discharges were found to be located close to the conjugate location of the recording stations, providing direct evidence of inter-hemispheric propagation at the low latitudes. A total of 864 whistlers were observed at Allahabad, India (Geomag. lat. 16.05°N Geomag. long. 155.34°E L = 1.08) during the night of 26 January 2011. Using GLD360 network data, we show the occurrence of thunderstorm activity between 200 and 450 km from the conjugate point of Allahabad. We also report the distribution of peak currents of whistler-producing lightning, which demonstrate a cutoff at 30 kA.

  2. 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

  3. 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

  4. 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.

  5. 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

  6. 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.

  7. 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

  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.

  9. 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

  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. 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.

  12. 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.

  13. 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.

  14. 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

  15. Alliin, a Garlic (Allium sativum) Compound, Prevents LPS-Induced Inflammation in 3T3-L1 Adipocytes

    PubMed Central

    Quintero-Fabián, Saray; Ortuño-Sahagún, Daniel; Vázquez-Carrera, Manuel; López-Roa, Rocío Ivette

    2013-01-01

    Garlic (Allium sativum L.) has been used to alleviate a variety of health problems due to its high content of organosulfur compounds and antioxidant activity. The main active component is alliin (S-allyl cysteine sulfoxide), a potent antioxidant with cardioprotective and neuroprotective actions. In addition, it helps to decrease serum levels of glucose, insulin, triglycerides, and uric acid, as well as insulin resistance, and reduces cytokine levels. However its potential anti-inflammatory effect is unknown. We examined the effects of alliin in lipopolysaccharide- (LPS-) stimulated 3T3-L1 adipocytes by RT-PCR, Western blot, and microarrays analysis of 22,000 genes. Incubation of cells for 24 h with 100 μmol/L alliin prevented the increase in the expression of proinflammatory genes, IL-6, MCP-1, and Egr-1 in 3T3-L1 adipocytes exposed to 100 ng/mL LPS for 1 h. Interestingly, the phosphorylation of ERK1/2, which is involved in LPS-induced inflammation in adipocytes, was decreased following alliin treatment. Furthermore, the gene expression profile by microarrays evidentiate an upregulation of genes involved in immune response and downregulation of genes related with cancer. The present results have shown that alliin is able to suppress the LPS inflammatory signals by generating an anti-inflammatory gene expression profile and by modifying adipocyte metabolic profile. PMID:24453416

  16. Alliin, a garlic (Allium sativum) compound, prevents LPS-induced inflammation in 3T3-L1 adipocytes.

    PubMed

    Quintero-Fabián, Saray; Ortuño-Sahagún, Daniel; Vázquez-Carrera, Manuel; López-Roa, Rocío Ivette

    2013-01-01

    Garlic (Allium sativum L.) has been used to alleviate a variety of health problems due to its high content of organosulfur compounds and antioxidant activity. The main active component is alliin (S-allyl cysteine sulfoxide), a potent antioxidant with cardioprotective and neuroprotective actions. In addition, it helps to decrease serum levels of glucose, insulin, triglycerides, and uric acid, as well as insulin resistance, and reduces cytokine levels. However its potential anti-inflammatory effect is unknown. We examined the effects of alliin in lipopolysaccharide- (LPS-) stimulated 3T3-L1 adipocytes by RT-PCR, Western blot, and microarrays analysis of 22,000 genes. Incubation of cells for 24 h with 100 μmol/L alliin prevented the increase in the expression of proinflammatory genes, IL-6, MCP-1, and Egr-1 in 3T3-L1 adipocytes exposed to 100 ng/mL LPS for 1 h. Interestingly, the phosphorylation of ERK1/2, which is involved in LPS-induced inflammation in adipocytes, was decreased following alliin treatment. Furthermore, the gene expression profile by microarrays evidentiate an upregulation of genes involved in immune response and downregulation of genes related with cancer. The present results have shown that alliin is able to suppress the LPS inflammatory signals by generating an anti-inflammatory gene expression profile and by modifying adipocyte metabolic profile.

  17. 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…

  18. 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…

  19. 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.…

  20. 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…

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

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 15 2010-04-01 2010-04-01 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...

  2. 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...

  3. 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...

  4. 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...

  5. 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,…

  6. 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…

  7. The Influence of Schema and Cultural Difference on L1 and L2 Reading

    ERIC Educational Resources Information Center

    Yang, Shi-sheng

    2010-01-01

    Reading in L1 shares numerous basic elements with reading in L2, and the processes also differ greatly. Intriguing questions involve whether there are two parallel cognitive processes at work, or whether there are processing strategies that accommodate both L1 and L2. This paper examines how reading in L1 is different from and similar to reading…

  8. 26 CFR 36.3121(l)(1)-2 - Amendment of agreement.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 15 2011-04-01 2011-04-01 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...

  9. 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...

  10. 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...

  11. 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...

  12. 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...

  13. 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...

  14. 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...

  15. 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...

  16. 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...

  17. 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...

  18. 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...

  19. 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...

  20. 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...

  1. 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...

  2. 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...

  3. 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…

  4. 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.

  5. Generation, characterization and preclinical studies of a human anti-L1CAM monoclonal antibody that cross-reacts with rodent L1CAM.

    PubMed

    Cho, Seulki; Park, Insoo; Kim, Haejung; Jeong, Mun Sik; Lim, Mooney; Lee, Eung Suk; Kim, Jin Hong; Kim, Semi; Hong, Hyo Jeong

    2016-01-01

    L1 cell adhesion molecule (L1CAM) is aberrantly expressed in malignant tumors and plays important roles in tumor progression. Thus, L1CAM could serve as a therapeutic target and anti-L1CAM antibodies may have potential as anticancer agents. However, L1CAM is expressed in neural cells and the druggability of anti-L1AM antibody must be validated at the earliest stages of preclinical study. Here, we generated a human monoclonal antibody that is cross-reactive with mouse L1CAM and evaluated its pharmacokinetic properties and anti-tumor efficacy in rodent models. First, we selected an antibody (Ab4) that binds human and mouse L1CAM from the human naïve Fab library using phage display, then increased its affinity 45-fold through mutation of 3 residues in the complementarity-determining regions (CDRs) to generate Ab4M. Next, the affinity of Ab4M was increased 1.8-fold by yeast display of single-chain variable fragment containing randomly mutated light chain CDR3 to generate Ab417. The affinities (KD) of Ab417 for human and mouse L1CAM were 0.24 nM and 79.16 pM, respectively. Ab417 specifically bound the Ig5 domain of L1CAM and did not exhibit off-target activity, but bound to the peripheral nerves embedded in normal human tissues as expected in immunohistochemical analysis. In a pharmacokinetics study, the mean half-life of Ab417 was 114.49 h when a single dose (10 mg/kg) was intravenously injected into SD rats. Ab417 significantly inhibited tumor growth in a human cholangiocarcinoma xenograft nude mouse model and did not induce any adverse effect in in vivo studies. Thus, Ab417 may have potential as an anticancer agent. PMID:26785809

  6. 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

  7. 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

  8. 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).

  9. MolLoc: a web tool for the local structural alignment of molecular surfaces.

    PubMed

    Angaran, Stefano; Bock, Mary Ellen; Garutti, Claudio; Guerra, Concettina

    2009-07-01

    MolLoc stands for Molecular Local surface comparison, and is a web server for the structural comparison of molecular surfaces. Given two structures in PDB format, the user can compare their binding sites, cavities or any arbitrary residue selection. Moreover, the web server allows the comparison of a query structure with a list of structures. Each comparison produces a structural alignment that maximizes the extension of the superimposition of the surfaces, and returns the pairs of atoms with similar physicochemical properties that are close in space after the superimposition. Based on this subset of atoms sharing similar physicochemical properties a new rototranslation is derived that best superimposes them. MolLoc approach is both local and surface-oriented, and therefore it can be particularly useful when testing if molecules with different sequences and folds share any local surface similarity. The MolLoc web server is available at http://bcb.dei.unipd.it/MolLoc.

  10. Niemann-Pick C1 Like 1 (NPC1L1) an intestinal sterol transporter.

    PubMed

    Davis, Harry R; Altmann, Scott W

    2009-07-01

    Niemann-Pick C1 Like 1 (NPC1L1) has been identified and characterized as an essential protein in the intestinal cholesterol absorption process. NPC1L1 localizes to the brush border membrane of absorptive enterocytes in the small intestine. Intestinal expression of NPC1L1 is down regulated by diets containing high levels of cholesterol. While otherwise phenotypically normal, Npc1l1 null mice exhibit a significant reduction in the intestinal uptake and absorption of cholesterol and phytosterols. Characterization of the NPC1L1 pathway revealed that cholesterol absorption inhibitor ezetimibe specifically binds to an extracellular loop of NPC1L1 and inhibits its sterol transport function. Npc1l1 null mice are resistant to diet-induced hypercholesterolemia, and when crossed with apo E null mice, are completely resistant to the development of atherosclerosis. Intestinal gene expression studies in Npc1l1 null mice indicated that no exogenous cholesterol was entering enterocytes lacking NPC1L1, which resulted in an upregulation of intestinal and hepatic LDL receptor and cholesterol biosynthetic gene expression. Polymorphisms in the human NPC1L1 gene have been found to influence cholesterol absorption and plasma low density lipoprotein levels. Therefore, NPC1L1 is a critical intestinal sterol uptake transporter which influences whole body cholesterol homeostasis.

  11. 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

  12. N-Terminal Truncated UCH-L1 Prevents Parkinson's Disease Associated Damage

    PubMed Central

    Kim, Hee-Jung; Kim, Hyun Jung; Jeong, Jae-Eun; Baek, Jeong Yeob; Jeong, Jaeho; Kim, Sun; Kim, Young-Mee; Kim, Youhwa; Nam, Jin Han; Huh, Sue Hee; Seo, Jawon; Jin, Byung Kwan; Lee, Kong-Joo

    2014-01-01

    Ubiquitin C-terminal hydrolase-L1 (UCH-L1) has been proposed as one of the Parkinson's disease (PD) related genes, but the possible molecular connection between UCH-L1 and PD is not well understood. In this study, we discovered an N-terminal 11 amino acid truncated variant UCH-L1 that we called NT-UCH-L1, in mouse brain tissue as well as in NCI-H157 lung cancer and SH-SY5Y neuroblastoma cell lines. In vivo experiments and hydrogen-deuterium exchange (HDX) with tandem mass spectrometry (MS) studies showed that NT-UCH-L1 is readily aggregated and degraded, and has more flexible structure than UCH-L1. Post-translational modifications including monoubiquitination and disulfide crosslinking regulate the stability and cellular localization of NT-UCH-L1, as confirmed by mutational and proteomic studies. Stable expression of NT-UCH-L1 decreases cellular ROS levels and protects cells from H2O2, rotenone and CCCP-induced cell death. NT-UCH-L1-expressing transgenic mice are less susceptible to degeneration of nigrostriatal dopaminergic neurons seen in the MPTP mouse model of PD, in comparison to control animals. These results suggest that NT-UCH-L1 may have the potential to prevent neural damage in diseases like PD. PMID:24959670

  13. 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

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

    PubMed

    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

    2014-10-01

    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

  15. 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

  16. L1CAM stimulates glioma cell motility and proliferation through the fibroblast growth factor receptor.

    PubMed

    Mohanan, Vishnu; Temburni, Murali K; Kappes, John C; Galileo, Deni S

    2013-04-01

    The L1CAM cell adhesion/recognition molecule (L1, CD171) and fibroblast growth factor receptor (FGFR) both are expressed by human high-grade glioma cells, but their potential actions in controlling cell behavior have not been linked. L1 actions in cancer cells have been attributed mainly to integrin receptors, and we demonstrated previously that L1-stimulated glioma cell migration correlates with integrin expression, increased focal adhesion kinase activation and focal complex turnover. Our analyses of datasets revealed FGFR is overexpressed in glioma regardless of grade, while ADAM10 metalloprotease expression increases with glioma grade. Here, we used dominant-negative and short hairpin RNA approaches to inhibit the activation of FGFR1 and expression of L1, respectively. An L1 peptide that inhibits L1-FGFR interaction and PD173074, a chemical inhibitor of FGFR1 activity, also were used to elucidate the involvement of L1-FGFR interactions on glioma cell behavior. Time-lapse cell motility studies and flow cytometry cell cycle analyses showed that L1 operates to increase glioma cell motility and proliferation through FGFR activation. Shutdown of both L1 expression and FGFR activity in glioma cells resulted in a complete termination of cell migration in vitro. These studies show for the first time that soluble L1 ectodomain (L1LE) acts on glioma cells through FGFRs, and that FGFRs are used by glioma cells for increasing motility as well as proliferation in response to activation by L1LE ligand. Thus, effective treatment of high-grade glioma may require simultaneous targeting of L1, FGFRs, and integrin receptors, which would reduce glioma cell motility as well as proliferation.

  17. 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

  18. L1 stimulation of human glioma cell motility correlates with FAK activation.

    PubMed

    Yang, Muhua; Li, Yupei; Chilukuri, Kalyani; Brady, Owen A; Boulos, Magdy I; Kappes, John C; Galileo, Deni S

    2011-10-01

    The neural adhesion/recognition protein L1 (L1CAM; CD171) has been shown or implicated to function in stimulation of cell motility in several cancer types, including high-grade gliomas. Our previous work demonstrated the expression and function of L1 protein in stimulation of cell motility in rat glioma cells. However, the mechanism of this stimulation is still unclear. This study further investigated the function of L1 and L1 proteolysis in human glioblastoma multiforme (GBM) cell migration and invasion, as well as the mechanism of this stimulation. L1 mRNA was found to be present in human T98G GBM cell line but not in U-118 MG grade III human glioma cell line. L1 protein expression, proteolysis, and release were found in T98G cells and human surgical GBM cells by Western blotting. Exosome-like vesicles released by T98G cells were purified and contained full-length L1. In a scratch assay, T98G cells that migrated into the denuded scratch area exhibited upregulation of ADAM10 protease expression coincident with loss of surface L1. GBM surgical specimen cells exhibited a similar loss of cell surface L1 when xenografted into the chick embryo brain. When lentivirally introduced shRNA was used to attenuate L1 expression, such T98G/shL1 cells exhibited significantly decreased cell motility by time lapse microscopy in our quantitative Super Scratch assay. These cells also showed a decrease in FAK activity and exhibited increased focal complexes. L1 binding integrins which activate FAK were found in T98G and U-118 MG cells. Addition of L1 ectodomain-containing media (1) rescued the decreased cell motility of T98G/shL1 cells and (2) increased cell motility of U-118 MG cells but (3) did not further increase T98G cell motility. Injection of L1-attenuated T98G/shL1 cells into embryonic chick brains resulted in the absence of detectable invasion compared to control cells which invaded brain tissue. These studies support a mechanism where glioma cells at the edge of a cell mass

  19. Mechanisms for the proliferation of eosinophilic leukemia cells by FIP1L1-PDGFR{alpha}

    SciTech Connect

    Ishihara, Kenji; Kitamura, Hajime; Hiraizumi, Kenji; Kaneko, Motoko; Takahashi, Aki; Zee, OkPyo; Seyama, Toshio; Hong, JangJa; Ohuchi, Kazuo; Hirasawa, Noriyasu

    2008-02-22

    The constitutively activated tyrosine kinase Fip1-like 1 (FIP1L1)-platelet-derived growth factor receptor {alpha} (PDGFR{alpha}) causes eosinophilic leukemia EoL-1 cells to proliferate. Recently, we demonstrated that histone deacetylase inhibitors suppressed this proliferation and induced the differentiation of EoL-1 cells into eosinophils in parallel with a decrease in the level of FIP1L1-PDGFR{alpha}. In this study, we analyzed the mechanism by which FIP1L1-PDGFR{alpha} induces the proliferation and whether the suppression of cell proliferation triggers the differentiation into eosinophils. The FIP1L1-PDGFR{alpha} inhibitor imatinib inhibited the proliferation of EoL-1 cells and decreased the level of the oncoprotein c-Myc as well as the phosphorylation of extracellular signal-regulated kinase and c-Jun N-terminal kinase (JNK). The proliferation of EoL-1 cells and expression of c-Myc were also inhibited by the MEK inhibitor U0126 and JNK inhibitor SP600125. The expression of the eosinophilic differentiation marker CCR3 was not induced by imatinib. These findings suggest that FIP1L1-PDGFR{alpha} induces the proliferation of EoL-1 cells through the induction of c-Myc expression via ERK and JNK signaling pathways, but is not involved in the inhibition of differentiation toward mature eosinophils.

  20. Ezetimibe blocks the internalization of NPC1L1 and cholesterol in mouse small intestine

    PubMed Central

    Xie 谢畅, Chang; Zhou 周章森, Zhang-Sen; Li 李钠, Na; Bian 卞艳, Yan; Wang 王永建, Yong-Jian; Wang 王丽娟, Li-Juan; Li 李伯良, Bo-Liang; Song 宋保亮, Bao-Liang

    2012-01-01

    The multiple transmembrane protein Niemann-Pick C1 like1 (NPC1L1) is essential for intestinal cholesterol absorption. Ezetimibe binds to NPC1L1 and is a clinically used cholesterol absorption inhibitor. Recent studies in cultured cells have shown that NPC1L1 mediates cholesterol uptake through vesicular endocytosis that can be blocked by ezetimibe. However, how NPC1L1 and ezetimibe work in the small intestine is unknown. In this study, we found that NPC1L1 distributed in enterocytes of villi and transit-amplifying cells of crypts. Acyl-CoA cholesterol acyltransferase 2 (ACAT2), another important protein for cholesterol absorption by providing cholesteryl esters to chylomicrons, was mainly presented in the apical cytoplasm of enterocytes. NPC1L1 and ACAT2 were highly expressed in jejunum and ileum. ACAT1 presented in the Paneth cells of crypts and mesenchymal cells of villi. In the absence of cholesterol, NPC1L1 was localized on the brush border of enterocytes. Dietary cholesterol induced the internalization of NPC1L1 to the subapical layer beneath the brush border and became partially colocalized with the endosome marker Rab11. Ezetimibe blocked the internalization of NPC1L1 and cholesterol and caused their retention in the plasma membrane. This study demonstrates that NPC1L1 mediates cholesterol entering enterocytes through vesicular endocytosis and that ezetimibe blocks this step in vivo. PMID:22811412

  1. Myelin basic protein cleaves cell adhesion molecule L1 and promotes neuritogenesis and cell survival.

    PubMed

    Lutz, David; Loers, Gabriele; Kleene, Ralf; Oezen, Iris; Kataria, Hardeep; Katagihallimath, Nainesh; Braren, Ingke; Harauz, George; Schachner, Melitta

    2014-05-01

    The cell adhesion molecule L1 is a Lewis(x)-carrying glycoprotein that plays important roles in the developing and adult nervous system. Here we show that myelin basic protein (MBP) binds to L1 in a Lewis(x)-dependent manner. Furthermore, we demonstrate that MBP is released by murine cerebellar neurons as a sumoylated dynamin-containing protein upon L1 stimulation and that this MBP cleaves L1 as a serine protease in the L1 extracellular domain at Arg(687) yielding a transmembrane fragment that promotes neurite outgrowth and neuronal survival in cell culture. L1-induced neurite outgrowth and neuronal survival are reduced in MBP-deficient cerebellar neurons and in wild-type cerebellar neurons in the presence of an MBP antibody or L1 peptide containing the MBP cleavage site. Genetic ablation of MBP in shiverer mice and mutagenesis of the proteolytically active site in MBP or of the MBP cleavage site within L1 as well as serine protease inhibitors and an L1 peptide containing the MBP cleavage site abolish generation of the L1 fragment. Our findings provide evidence for novel functions of MBP in the nervous system. PMID:24671420

  2. 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

  3. PD-L1 Detection in Tumors Using [(64)Cu]Atezolizumab with PET.

    PubMed

    Lesniak, Wojciech G; Chatterjee, Samit; Gabrielson, Matthew; Lisok, Ala; Wharram, Bryan; Pomper, Martin G; Nimmagadda, Sridhar

    2016-09-21

    The programmed death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pair is a major immune checkpoint pathway exploited by cancer cells to develop and maintain immune tolerance. With recent approvals of anti-PD-1 and anti-PD-L1 therapeutic antibodies, there is an urgent need for noninvasive detection methods to quantify dynamic PD-L1 expression in tumors and to evaluate the tumor response to immune modulation therapies. To address this need, we assessed [(64)Cu]atezolizumab for the detection of PD-L1 expression in tumors. Atezolizumab (MPDL3208A) is a humanized, human and mouse cross-reactive, therapeutic PD-L1 antibody that is being investigated in several cancers. Atezolizumab was conjugated with DOTAGA and radiolabeled with copper-64. The resulting [(64)Cu]atezolizumab was assessed for in vitro and in vivo specificity in multiple cell lines and tumors of variable PD-L1 expression. We performed PET-CT imaging, biodistribution, and blocking studies in NSG mice bearing tumors with constitutive PD-L1 expression (CHO-hPD-L1) and in controls (CHO). Specificity of [(64)Cu]atezolizumab was further confirmed in orthotopic tumor models of human breast cancer (MDAMB231 and SUM149) and in a syngeneic mouse mammary carcinoma model (4T1). We observed specific binding of [(64)Cu]atezolizumab to tumor cells in vitro, correlating with PD-L1 expression levels. Specific accumulation of [(64)Cu]atezolizumab was also observed in tumors with high PD-L1 expression (CHO-hPD-L1 and MDAMB231) compared to tumors with low PD-L1 expression (CHO, SUM149). Collectively, these studies demonstrate the feasibility of using [(64)Cu]atezolizumab for the detection of PD-L1 expression in different tumor types. PMID:27458027

  4. MOLS 2.0: software package for peptide modeling and protein-ligand docking.

    PubMed

    Paul, D Sam; Gautham, N

    2016-10-01

    We previously developed an algorithm to perform conformational searches of proteins and peptides, and to perform the docking of ligands to protein receptors. In order to identify optimal conformations and docked poses, this algorithm uses mutually orthogonal Latin squares (MOLS) to rationally sample the vast conformational (or docking) space, and then analyzes this relatively small sample using a variant of mean field theory. The conformational search part of the algorithm was denoted MOLS 1.0. The docking portion of the algorithm, which allows only "flexible ligand/rigid receptor" docking, was denoted MOLSDOCK. Both are FORTRAN-based command-line-only molecular docking computer programs, though a GUI was developed later for MOLS 1.0. Both the conformational search and the rigid receptor docking parts of the algorithm have been extensively validated. We have now further enhanced the capabilities of the program by incorporating "induced fit" side-chain receptor flexibility for docking peptide ligands. Benchmarking and extensive testing is now being carried out for the flexible receptor portion of the docking. Additionally, to make both the peptide conformational search and docking algorithms (the latter including both flexible ligand/rigid receptor and flexible ligand/flexible receptor techniques) more accessible to the research community, we have developed MOLS 2.0, which incorporates a new Java-based graphical user interface (GUI). Here, we give a detailed description of MOLS 2.0. The source code and binary for MOLS 2.0 are distributed free (under a GNU Lesser General Public License) to the scientific community. They are freely available for download at https://sourceforge.net/projects/mols2-0/files/ . PMID:27638416

  5. MOLS 2.0: software package for peptide modeling and protein-ligand docking.

    PubMed

    Paul, D Sam; Gautham, N

    2016-10-01

    We previously developed an algorithm to perform conformational searches of proteins and peptides, and to perform the docking of ligands to protein receptors. In order to identify optimal conformations and docked poses, this algorithm uses mutually orthogonal Latin squares (MOLS) to rationally sample the vast conformational (or docking) space, and then analyzes this relatively small sample using a variant of mean field theory. The conformational search part of the algorithm was denoted MOLS 1.0. The docking portion of the algorithm, which allows only "flexible ligand/rigid receptor" docking, was denoted MOLSDOCK. Both are FORTRAN-based command-line-only molecular docking computer programs, though a GUI was developed later for MOLS 1.0. Both the conformational search and the rigid receptor docking parts of the algorithm have been extensively validated. We have now further enhanced the capabilities of the program by incorporating "induced fit" side-chain receptor flexibility for docking peptide ligands. Benchmarking and extensive testing is now being carried out for the flexible receptor portion of the docking. Additionally, to make both the peptide conformational search and docking algorithms (the latter including both flexible ligand/rigid receptor and flexible ligand/flexible receptor techniques) more accessible to the research community, we have developed MOLS 2.0, which incorporates a new Java-based graphical user interface (GUI). Here, we give a detailed description of MOLS 2.0. The source code and binary for MOLS 2.0 are distributed free (under a GNU Lesser General Public License) to the scientific community. They are freely available for download at https://sourceforge.net/projects/mols2-0/files/ .

  6. 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.

  7. The L1 family of cell adhesion molecules: a sickening number of mutations and protein functions.

    PubMed

    Hortsch, Michael; Nagaraj, Kakanahalli; Mualla, Rula

    2014-01-01

    L1-type proteins are transmembrane cell adhesion molecules with an evolutionary well-conserved protein domain structure of usually six immunoglobulin and five fibronectin type III domains. By engaging in many different protein-protein interactions they are involved in a multitude of molecular functions and are important players during the formation and maintenance of metazoan nervous systems. As a result, mutations in L1-type genes cause a great variety of phenotypes, most of which are neurological in nature. In humans, mutations in the L1CAM gene are responsible for L1 syndrome and other L1-type genes have been implicated in conditions as varied as mental retardation, autism, schizophrenia, multiple sclerosis, and other disorders. Equally, the overexpression of L1-type proteins appears to have deleterious effects in various types of human tumor cells, where they generally contribute to an increase in cell mobility and metastatic potential. PMID:25300138

  8. PD-1/PD-L1 expression in extra-medullary lesions of multiple myeloma.

    PubMed

    Crescenzi, Anna; Annibali, Ombretta; Bianchi, Antonella; Pagano, Anastasia; Donati, Michele; Grifoni, Alba; Avvisati, Giuseppe

    2016-10-01

    Multiple myeloma patients may develop extraosseous involvement in the course of the disease making prognosis very poor and new drugs clearly needed. The PD-1/PD-L1 axis has emerged as a master immune checkpoint in antitumor responses and recent studies investigated the role of PD-L1 in multiple myeloma cells; no data however are still available about PD-L1 expression in extramedullary localizations. We demonstrate PD-L1 expression in 4/12 cases of extraosseous myeloma suggesting that these lesions represent a specialized microenvironment. We found presence of PD-1+ infiltrating lymphocytes in all observed cases supporting the relevance of PD-1/PD-L1 checkpoint in extramedullary myeloma. We also investigated the correlation in PD1/PD-L1 staining between marrow staining and EMP lesions. PMID:27619200

  9. 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.

  10. SCWRL and MolIDE: computer programs for side-chain conformation prediction and homology modeling.

    PubMed

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

    2008-01-01

    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 on the basis of 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).

  11. Absence of canine oral papillomavirus DNA following prophylactic L1 particle-mediated immunotherapeutic delivery vaccination.

    PubMed

    Moore, R A; Nicholls, P K; Santos, E B; Gough, G W; Stanley, M A

    2002-09-01

    In the canine oral papillomavirus (COPV) model, following wart regression, COPV DNA was detected by PCR at the challenge site. However, following particle-mediated immunotherapeutic delivery (PMID) of COPV L1 and subsequent challenge, no COPV DNA could be detected. These data support PMID of COPV L1 as a protective vaccine and suggest that PMID of L1 may induce virus clearance. PMID:12185285

  12. UCH-L1 Inhibition Decreases the Microtubule-Binding Function of Tau Protein.

    PubMed

    Xie, Min; Han, Yun; Yu, Quntao; Wang, Xia; Wang, Shaohui; Liao, Xiaomei

    2015-01-01

    Ubiquitin C-terminal hydrolase L1 (UCH-L1) is critical for protein degradation and free ubiquitin recycling. In Alzheimer's disease brains, UCH-L1 is negatively related to neurofibrillary tangles whose major component is hyperphosphorylated tau protein, but the direct action of UCH-L1 on tau has not been reported. In the current study, mouse neuroblastoma Neuro2a (N2a) cells were treated by the different concentrations of UCH-L1 inhibitor LDN (2.5, 5 and 10 μM) to inhibit the hydrolase activity of UCH-L1. In addition, we also used UCH-L1 siRNA to treat the HEK293/tau441 cells to decrease the expression of UCH-L1. After LDN and UCH-L1 siRNA treatment, we used immunofluorescence, immunoprecipitation, and tau-microtubule binding assay to measure the microtubule-binding ability and post-translational modifications of tau protein. All the results presented that both inhibition of the activity and expression of UCH-L1 induced the decreased microtubule-binding ability and increased phosphorylation of tau protein. Abnormal aggregation and ubiquitination of tau protein was also observed after UCH-L1 inhibition. The above results suggested that aggregation of tau protein might be devoted to the abnormal post-translational modifications of tau protein. Our study first indicates that dysfunction of UCH-L1 most likely affected normal biological function of tau protein through decreasing degradation of ubiquitinated and hyperphosphorylated tau. PMID:26444754

  13. 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

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

    PubMed

    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

  15. 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…

  16. 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.

  17. 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

  18. An adaptive support driven reweighted L1-regularization algorithm for fluorescence molecular tomography.

    PubMed

    Shi, Junwei; Liu, Fei; Pu, Huangsheng; Zuo, Simin; Luo, Jianwen; Bai, Jing

    2014-11-01

    Fluorescence molecular tomography (FMT) is a promising in vivo functional imaging modality in preclinical study. When solving the ill-posed FMT inverse problem, L1 regularization can preserve the details and reduce the noise in the reconstruction results effectively. Moreover, compared with the regular L1 regularization, reweighted L1 regularization is recently reported to improve the performance. In order to realize the reweighted L1 regularization for FMT, an adaptive support driven reweighted L1-regularization (ASDR-L1) algorithm is proposed in this work. This algorithm has two integral parts: an adaptive support estimate and the iteratively updated weights. In the iteratively reweighted L1-minimization sub-problem, different weights are equivalent to different regularization parameters at different locations. Thus, ASDR-L1 can be considered as a kind of spatially variant regularization methods for FMT. Physical phantom and in vivo mouse experiments were performed to validate the proposed algorithm. The results demonstrate that the proposed reweighted L1-reguarization algorithm can significantly improve the performance in terms of relative quantitation and spatial resolution.

  19. 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

  20. 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

  1. 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.

  2. 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).

  3. 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

  4. Prognostic value of PD-L1 and PD-1 expression in pulmonary neuroendocrine tumors

    PubMed Central

    Fan, Yangwei; Ma, Ke; Wang, Chuying; Ning, Jing; Hu, Yuan; Dong, Danfeng; Dong, Xuyuan; Geng, Qianqian; Li, Enxiao; Wu, Yinying

    2016-01-01

    Purpose Programmed death 1 (PD-1) receptor and its ligand, programmed death ligand-1 (PD-L1), play critical roles in the immune invasion of various tumors. This study aimed to explore the clinical significance of PD-L1/PD-1 expression in the progression of pulmonary neuroendocrine tumors (PNETs). Methods The expression of PD-L1 and PD-1 in 80 patients diagnosed with PNETs were investigated. Immunohistochemical analysis was performed on 80 formalin-fixed paraffin-embedded tissue specimens from PNETs and 20 corresponding cancer-adjacent tissue specimens. Results Tissues from PNETs had higher levels of PD-L1 (58.8%) and PD-1 (51.3%) compared to the cancer-adjacent tissues (25% and 20%, respectively). Meanwhile, PD-L1 expression was associated with PD-1 expression (P=0.007). PD-L1 expression was significantly associated with histological type (P=0.014) and tumor stage (P=0.014). Univariate analyses showed that the overall survival time of PNETs patients was significantly associated with PD-L1 expression in cancer cells (P=0.003), PD-1 expression in tumor-infiltrating lymphocytes (P=0.001), tumor node metastasis stage (P<0.05), and distant metastasis (P<0.001). Additionally, multivariate analysis revealed that PD-L1 expression, PD1 expression, and distant metastasis of PNETs were independently associated with survival time. Moreover, Kaplan–Meier survival curves analysis revealed that patients with negative PD-L1 and PD-1 expression had better prognoses. Conclusion Data suggested that PD-L1 and PD-1 can be useful prognostic biomarkers for survival and can pave the way toward new immunotherapy regimens against PNETs through targeting the PD-L1/PD-1 pathway. PMID:27785054

  5. L1/2 regularization: a thresholding representation theory and a fast solver.

    PubMed

    Xu, Zongben; Chang, Xiangyu; Xu, Fengmin; Zhang, Hai

    2012-07-01

    The special importance of L1/2 regularization has been recognized in recent studies on sparse modeling (particularly on compressed sensing). The L1/2 regularization, however, leads to a nonconvex, nonsmooth, and non-Lipschitz optimization problem that is difficult to solve fast and efficiently. In this paper, through developing a threshoding representation theory for L1/2 regularization, we propose an iterative half thresholding algorithm for fast solution of L1/2 regularization, corresponding to the well-known iterative soft thresholding algorithm for L1 regularization, and the iterative hard thresholding algorithm for L0 regularization. We prove the existence of the resolvent of gradient of ||x||1/2(1/2), calculate its analytic expression, and establish an alternative feature theorem on solutions of L1/2 regularization, based on which a thresholding representation of solutions of L1/2 regularization is derived and an optimal regularization parameter setting rule is formulated. The developed theory provides a successful practice of extension of the well- known Moreau's proximity forward-backward splitting theory to the L1/2 regularization case. We verify the convergence of the iterative half thresholding algorithm and provide a series of experiments to assess performance of the algorithm. The experiments show that the half algorithm is effective, efficient, and can be accepted as a fast solver for L1/2 regularization. With the new algorithm, we conduct a phase diagram study to further demonstrate the superiority of L1/2 regularization over L1 regularization.

  6. 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

  7. 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

  8. 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

  9. 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.

  10. 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

  11. 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…

  12. 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…

  13. Development of an Analytical Rating Scale for Japanese L1 Writing.

    ERIC Educational Resources Information Center

    Sasaki, Miyuki; Hirose, Keiko

    1999-01-01

    Developed an analytic rating scale for Japanese university students' first-language (L1) expository writing. Devised a questionnaire to investigate Japanese L1 teachers' criteria for evaluating expository writing, and, based on questionnaire results, eliminated or reorganized the descriptions under six analytic criteria. (Author/VWL)

  14. Exploring a New Technique for Comparing Bilinguals' L1 and L2 Reading Speed

    ERIC Educational Resources Information Center

    Gauvin, Hanna S.; Hulstijn, Jan H.

    2010-01-01

    Is it possible to tell whether bilinguals are able to read simple text in their two languages equally fluently? Is it thus possible to distinguish balanced bilinguals from unbalanced bilinguals with respect to reading fluency in their first language (L1) and second language (L2)? In this study, we avoided making direct comparisons between L1 and…

  15. 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…

  16. 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…

  17. Image reconstruction based on L1 regularization and projection methods for electrical impedance tomography.

    PubMed

    Wang, Qi; Wang, Huaxiang; Zhang, Ronghua; Wang, Jinhai; Zheng, Yu; Cui, Ziqiang; Yang, Chengyi

    2012-10-01

    Electrical impedance tomography (EIT) is a technique for reconstructing the conductivity distribution by injecting currents at the boundary of a subject and measuring the resulting changes in voltage. Image reconstruction in EIT is a nonlinear and ill-posed inverse problem. The Tikhonov method with L(2) regularization is always used to solve the EIT problem. However, the L(2) method always smoothes the sharp changes or discontinue areas of the reconstruction. Image reconstruction using the L(1) regularization allows addressing this difficulty. In this paper, a sum of absolute values is substituted for the sum of squares used in the L(2) regularization to form the L(1) regularization, the solution is obtained by the barrier method. However, the L(1) method often involves repeatedly solving large-dimensional matrix equations, which are computationally expensive. In this paper, the projection method is combined with the L(1) regularization method to reduce the computational cost. The L(1) problem is mainly solved in the coarse subspace. This paper also discusses the strategies of choosing parameters. Both simulation and experimental results of the L(1) regularization method were compared with the L(2) regularization method, indicating that the L(1) regularization method can improve the quality of image reconstruction and tolerate a relatively high level of noise in the measured voltages. Furthermore, the projected L(1) method can also effectively reduce the computational time without affecting the quality of reconstructed images.

  18. 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…

  19. Epigenetic silencing of engineered L1 retrotransposition events in human embryonic carcinoma cells

    PubMed Central

    Garcia-Perez, Jose L.; Morell, Maria; Scheys, Joshua O.; Kulpa, Deanna A.; Morell, Santiago; Carter, Christoph C.; Hammer, Gary D.; Collins, Kathleen L.; O’Shea, K. Sue; Menendez, Pablo; Moran, John V.

    2010-01-01

    Long INterspersed Element-1 (LINE-1 or L1) retrotransposition continues to impact human genome evolution1,2. L1s can retrotranspose in the germline, during early development, and in select somatic cells3,4,5,6,7,8; however, the host response to L1 retrotransposition remains largely unexplored. Here, we show that reporter genes introduced into the genome of various human embryonic carcinoma-derived cell lines (ECs) by L1 retrotransposition are rapidly and efficiently silenced either during or immediately after their integration. Treating ECs with histone deacetylase inhibitors (IHDACs) rapidly reverses this silencing, and chromatin immunoprecipitation (ChIP) experiments revealed that reactivation of the reporter gene was correlated with changes in chromatin status at the L1 integration site. Under our assay conditions, rapid silencing also was observed when reporter genes were delivered into ECs by mouse L1s and a zebrafish LINE-2 element, but not when similar reporter genes were delivered into ECs by Moloney murine leukemia virus (MMLV) or human immunodeficiency virus (HIV), suggesting these integration events are silenced by distinct mechanisms. Finally, we demonstrate that subjecting ECs to culture conditions that promote differentiation attenuates the silencing of reporter genes delivered by L1 retrotransposition, but that differentiation, per se, is not sufficient to reactivate previously silenced reporter genes. Thus, our data suggest that ECs differ from many differentiated cells in their ability to silence reporter genes delivered by L1 retrotransposition. PMID:20686575

  20. 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…

  1. 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…

  2. Modeling the Development of L1 and EFL Writing Proficiency of Secondary School Students

    ERIC Educational Resources Information Center

    Schoonen, Rob; van Gelderen, Amos; Stoel, Reinoud D.; Hulstijn, Jan; de Glopper, Kees

    2011-01-01

    This longitudinal study investigates the development of writing proficiency in English as a foreign language (EFL), in contrast to the development of first language (L1) writing proficiency in Dutch L1, in a sample of almost 400 secondary school students in the Netherlands. Students performed several writing tasks in both languages in three…

  3. Multilingual Acquisition of Vowels in L1 Polish, L2 Danish and L3 English

    ERIC Educational Resources Information Center

    Sypianska, Jolanta

    2016-01-01

    The aim of this paper is to determine whether all languages in the linguistic repertoire of a multilingual speaker manifest cross-linguistic influence (CLI) and establish the directions of CLI on the basis of chosen vowels from the linguistic repertoire of two groups: the Bilingual group (L1 Polish/L2 Danish) and the Multilingual group (L1

  4. Long-Term Crosslinguistic Transfer of Skills from L1 to L2

    ERIC Educational Resources Information Center

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

    2009-01-01

    This study investigated the relationship of first language (L1) skills in elementary school and second language (L2) learning in high school. Students classified as high-, average-, and low-proficiency L2 learners were compared on L1 achievement measures of reading, spelling, vocabulary, phonological awareness, and listening comprehension…

  5. 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…

  6. Sidestepping Our "Scare Words": Genre as a Possible Bridge between L1 and L2 Compositionists

    ERIC Educational Resources Information Center

    Costino, Kimberly A.; Hyon, Sunny

    2011-01-01

    In light of the increasing student diversity in U.S. university composition classrooms, there is a strong need for collaboration between L1 and L2 writing specialists. Differences in the lexicons of our two fields, however, as well as the philosophical differences embedded in our word choices, can hinder productive L1-L2 communication. The purpose…

  7. 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…

  8. Simplifying and enhancing the use of PyMOL with horizontal scripts.

    PubMed

    Mooers, Blaine H M

    2016-10-01

    Scripts are used in PyMOL to exert precise control over the appearance of the output and to ease remaking similar images at a later time. We developed horizontal scripts to ease script development. A horizontal script makes a complete scene in PyMOL like a traditional vertical script. The commands in a horizontal script are separated by semicolons. These scripts are edited interactively on the command line with no need for an external text editor. This simpler workflow accelerates script development. In using PyMOL, the illustration of a molecular scene requires an 18-element matrix of view port settings. The default format spans several lines and is laborious to manually reformat for one line. This default format prevents the fast assembly of horizontal scripts that can reproduce a molecular scene. We solved this problem by writing a function that displays the settings on one line in a compact format suitable for horizontal scripts. We also demonstrate the mapping of aliases to horizontal scripts. Many aliases can be defined in a single script file, which can be useful for applying costume molecular representations to any structure. We also redefined horizontal scripts as Python functions to enable the use of the help function to print documentation about an alias to the command history window. We discuss how these methods of using horizontal scripts both simplify and enhance the use of PyMOL in research and education.

  9. 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

  10. Mol-ecular and crystal structure of gossypol tetra-methyl ether with an unknown solvate.

    PubMed

    Honkeldieva, Muhabbat; Talipov, Samat; Mardanov, Rustam; Ibragimov, Bakhtiyar

    2015-02-01

    The title compound, C34H38O8 (systematic name: 5,5'-diisopropyl-2,2',3,3'-tetra-meth-oxy-7,7'-dimethyl-2H,2'H-8,8'-bi-[naphtho-[1,8-bc]furan]-4,4'-diol), has been obtained from a gossypol solution in a mixture of dimethyl sulfate and methanol. The mol-ecule is situated on a twofold rotation axis, so the asymmetric unit contains one half-mol-ecule. In the mol-ecule, the hy-droxy groups are involved in intra-molecular O-H⋯O hydrogen bonds, and the two naphthyl fragments are inclined each to other by 83.8 (1)°. In the crystal, weak C-H⋯O and C-H⋯π inter-actions consolidate the packing, which exhibits channels with an approximate diameter of 6 Å extending along the c-axis direction. These channels are filled with highly disordered solvent mol-ecules, so their estimated scattering contribution was subtracted from the observed diffraction data using the SQUEEZE option in PLATON [Spek, A. L. (2015). Acta Cryst. C71, 9-18]. PMID:25878814

  11. Simplifying and enhancing the use of PyMOL with horizontal scripts.

    PubMed

    Mooers, Blaine H M

    2016-10-01

    Scripts are used in PyMOL to exert precise control over the appearance of the output and to ease remaking similar images at a later time. We developed horizontal scripts to ease script development. A horizontal script makes a complete scene in PyMOL like a traditional vertical script. The commands in a horizontal script are separated by semicolons. These scripts are edited interactively on the command line with no need for an external text editor. This simpler workflow accelerates script development. In using PyMOL, the illustration of a molecular scene requires an 18-element matrix of view port settings. The default format spans several lines and is laborious to manually reformat for one line. This default format prevents the fast assembly of horizontal scripts that can reproduce a molecular scene. We solved this problem by writing a function that displays the settings on one line in a compact format suitable for horizontal scripts. We also demonstrate the mapping of aliases to horizontal scripts. Many aliases can be defined in a single script file, which can be useful for applying costume molecular representations to any structure. We also redefined horizontal scripts as Python functions to enable the use of the help function to print documentation about an alias to the command history window. We discuss how these methods of using horizontal scripts both simplify and enhance the use of PyMOL in research and education. PMID:27488983

  12. Final report on international comparison CCQM-K74: Nitrogen dioxide, 10 µmol/mol

    NASA Astrophysics Data System (ADS)

    Flores, Edgar; Idrees, Faraz; Moussay, Philippe; Viallon, Joële; Wielgosz, Robert; Fernández, Teresa; Ramírez, Sergio; Rojo, Andrés; Shinji, Uehara; Waldén, Jari; Sega, Michela; Sang-Hyub, Oh; Macé, Tatiana; Couret, Cedric; Qiao, Han; Smeulders, Damian; Guenther, Franklin R.; Thorn, William J., III; Tshilongo, James; Godwill Ntsasa, Napo; Štovcík, Viliam; Valková, Miroslava; Konopelko, Leonid; Gromova, Elena; Nieuwenkamp, Gerard; Wessel, Rob M.; Milton, Martin; Harling, Alice; Vargha, Gergely; Tuma, Dirk; Kohl, Anka; Schulz, Gert

    2012-01-01

    There is a high international priority attached to activities which reduce NOx in the atmosphere. The current level of permitted emissions is typically between 50 µmol/mol and 100 µmol/mol, but lower values are expected in the future. Currently, ambient air quality monitoring regulations also require the measurement of NOx mole fractions as low as 0.2 µmol/mol. The production of accurate standards at these levels of mole fractions requires either dilution of a stable higher concentration gas standard or production by a dynamic technique, for example one based on permeation tubes. The CCQM-K74 key comparison was designed to evaluate the level of comparability of National Metrology Institutes' measurement capabilities and standards for nitrogen dioxide (NO2) at a nominal mole fraction of 10 µmol/mol. The measurements of this key comparison took place from June 2009 to May 2010. Seventeen laboratories took part in this comparison coordinated by the BIPM and VSL. The key comparison reference value was based on BIPM measurement results, and the standard measurement uncertainty of the reference value was 0.042 µmol/mol. This key comparison demonstrated that the results of the majority of the participants agreed within limits of ±3% relative to the reference value. The results of only one laboratory lay significantly outside these limits. Likewise this comparison made clear that a full interpretation of the results of the comparison needed to take into account the presence of nitric acid (in the range 100 nmol/mol to 350 nmol/mol) in the cylinders circulated as part of the comparison, as well as the possible presence of nitric acid in the primary standards used by participating laboratories. 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

  13. 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

  14. Expression profiling of Aldh1l1-precursors in the developing spinal cord reveals glial lineage-specific genes and direct Sox9-Nfe2l1 interactions.

    PubMed

    Molofsky, Anna V; Glasgow, Stacey M; Chaboub, Lesley S; Tsai, Hui-Hsin; Murnen, Alice T; Kelley, Kevin W; Fancy, Stephen P J; Yuen, Tracy J; Madireddy, Lohith; Baranzini, Sergio; Deneen, Benjamin; Rowitch, David H; Oldham, Michael C

    2013-09-01

    Developmental regulation of gliogenesis in the mammalian CNS is incompletely understood, in part due to a limited repertoire of lineage-specific genes. We used Aldh1l1-GFP as a marker for gliogenic radial glia and later-stage precursors of developing astrocytes and performed gene expression profiling of these cells. We then used this dataset to identify candidate transcription factors that may serve as glial markers or regulators of glial fate. Our analysis generated a database of developmental stage-related markers of Aldh1l1+ cells between murine embryonic day 13.5-18.5. Using these data we identify the bZIP transcription factor Nfe2l1 and demonstrate that it promotes glial fate under direct Sox9 regulatory control. Thus, this dataset represents a resource for identifying novel regulators of glial development.

  15. 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...

  16. 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

  17. 3T3-L1 adipocytes display phenotypic characteristics of multiple adipocyte lineages

    PubMed Central

    Morrison, Shona; McGee, Sean L

    2015-01-01

    Differentiated 3T3-L1 adipocytes are a widely used in vitro model of white adipocytes. In addition to classical white and brown adipocytes that are derived from different cell lineages, beige adipocytes have also been identified, which have characteristics of both white and brown adipocytes. Here we show that 3T3-L1 adipocytes display features of multiple adipocytes lineages. While the gene expression profile and basal bioenergetics of 3T3-L1 adipocytes was typical of white adipocytes, they responded acutely to catecholamines by increasing oxygen consumption in an UCP1-dependent manner, and by increasing the expression of genes enriched in brown but not beige adipocytes. Chronic exposure to catecholamines exacerbated this phenotype. However, a beige adipocyte differentiation procedure did not induce a beige adipocyte phenotype in 3T3-L1 fibroblasts. These multiple lineage features should be considered when interpreting data from experiments utilizing 3T3-L1 adipocytes. PMID:26451286

  18. Improved sparse reconstruction for fluorescence molecular tomography with L1/2 regularization

    PubMed Central

    Guo, Hongbo; Yu, Jingjing; He, Xiaowei; Hou, Yuqing; Dong, Fang; Zhang, Shuling

    2015-01-01

    Fluorescence molecular tomography (FMT) is a promising imaging technique that allows in vivo visualization of molecular-level events associated with disease progression and treatment response. Accurate and efficient 3D reconstruction algorithms will facilitate the wide-use of FMT in preclinical research. Here, we utilize L1/2-norm regularization for improving FMT reconstruction. To efficiently solve the nonconvex L1/2-norm penalized problem, we transform it into a weighted L1-norm minimization problem and employ a homotopy-based iterative reweighting algorithm to recover small fluorescent targets. Both simulations on heterogeneous mouse model and in vivo experiments demonstrated that the proposed L1/2-norm method outperformed the comparative L1-norm reconstruction methods in terms of location accuracy, spatial resolution and quantitation of fluorescent yield. Furthermore, simulation analysis showed the robustness of the proposed method, under different levels of measurement noise and number of excitation sources. PMID:26137370

  19. Identification of a new gene, molR, essential for utilization of molybdate by Escherichia coli.

    PubMed Central

    Lee, J H; Wendt, J C; Shanmugam, K T

    1990-01-01

    A mutation in a new gene, molR, prevented the synthesis in Escherichia coli of molybdoenzymes, including the two formate dehydrogenase isoenzymes, nitrate reductase and trimethylamine-N-oxide reductase. This phenotype was suppressed by supplementing the media with molybdate. Thus, the molR mutant was phenotypically similar to previously described chlD mutants, thought to be defective in molybdate transport. The molR gene is located at 65.3 min in the E. coli chromosome, in contrast to the chlD gene, which maps at 17 min and thus can be readily distinguished. The molR gene is also cotransducible with a hitherto unidentified gene essential for the production of 2-oxoglutarate from isocitrate, designated icdB (located at 66 min). The molR mutant strain SE1100 also failed to produce the hydrogenase component of formate hydrogenlyase (HYD3) in molybdate-unsupplemented media. The amount of molybdate required by strain SE1100 for the production of parental levels of formate hydrogenlyase activity was dependent on the growth medium. In Luria-Bertani medium, this value was about 100 microM, and in glucose-minimal medium, 1.0 microM was sufficient. In low-sulfur medium, this value decreased to about 50 nM. The addition of sulfate or selenite increased the amount of molybdate needed for the production of formate hydrogenlyase activity. These data suggest that in the absence of the high-affinity molybdate transport system, E. coli utilizes sulfate and selenite transport systems for transporting molybdate, preferring sulfate transport over the selenite transport system. PMID:2156810

  20. Phosphorylation of ORF1p is required for L1 retrotransposition

    PubMed Central

    Cook, Pamela R.; Jones, Charles E.; Furano, Anthony V.

    2015-01-01

    Although members of the L1 (LINE-1) clade of non-LTR retrotransposons can be deleterious, the L1 clade has remained active in most mammals for ∼100 million years and generated almost 40% of the human genome. The details of L1–host interaction are largely unknown, however. Here we report that L1 activity requires phosphorylation of the protein encoded by the L1 ORF1 (ORF1p). Critical phospho-acceptor residues (two serines and two threonines) reside in four conserved proline-directed protein kinase (PDPK) target sites. The PDPK family includes mitogen-activated protein kinases and cyclin-dependent kinases. Mutation of any PDPK phospho-acceptor inhibits L1 retrotransposition. The phosphomimetic aspartic acid can restore activity at the two serine sites, but not at either threonine site, where it is strongly inhibitory. ORF1p also contains conserved PDPK docking sites, which promote specific interaction of PDPKs with their targets. As expected, mutations in these sites also inhibit L1 activity. PDPK mutations in ORF1p that inactivate L1 have no significant effect on the ability of ORF1p to anneal RNA in vitro, an important biochemical property of the protein. We show that phosphorylated PDPK sites in ORF1p are required for an interaction with the peptidyl prolyl isomerase 1 (Pin1), a critical component of PDPK-mediated regulation. Pin1 acts via isomerization of proline side chains at phosphorylated PDPK motifs, thereby affecting substrate conformation and activity. Our demonstration that L1 activity is dependent on and integrated with cellular phosphorylation regulatory cascades significantly increases our understanding of interactions between L1 and its host. PMID:25831499

  1. Phosphorylation of ORF1p is required for L1 retrotransposition.

    PubMed

    Cook, Pamela R; Jones, Charles E; Furano, Anthony V

    2015-04-01

    Although members of the L1 (LINE-1) clade of non-LTR retrotransposons can be deleterious, the L1 clade has remained active in most mammals for ∼100 million years and generated almost 40% of the human genome. The details of L1-host interaction are largely unknown, however. Here we report that L1 activity requires phosphorylation of the protein encoded by the L1 ORF1 (ORF1p). Critical phospho-acceptor residues (two serines and two threonines) reside in four conserved proline-directed protein kinase (PDPK) target sites. The PDPK family includes mitogen-activated protein kinases and cyclin-dependent kinases. Mutation of any PDPK phospho-acceptor inhibits L1 retrotransposition. The phosphomimetic aspartic acid can restore activity at the two serine sites, but not at either threonine site, where it is strongly inhibitory. ORF1p also contains conserved PDPK docking sites, which promote specific interaction of PDPKs with their targets. As expected, mutations in these sites also inhibit L1 activity. PDPK mutations in ORF1p that inactivate L1 have no significant effect on the ability of ORF1p to anneal RNA in vitro, an important biochemical property of the protein. We show that phosphorylated PDPK sites in ORF1p are required for an interaction with the peptidyl prolyl isomerase 1 (Pin1), a critical component of PDPK-mediated regulation. Pin1 acts via isomerization of proline side chains at phosphorylated PDPK motifs, thereby affecting substrate conformation and activity. Our demonstration that L1 activity is dependent on and integrated with cellular phosphorylation regulatory cascades significantly increases our understanding of interactions between L1 and its host. PMID:25831499

  2. Production and Characterization of ZFP36L1 Antiserum against Recombinant Protein from Escherichia coli

    PubMed Central

    Cao, Heping; Lin, Rui; Ghosh, Sanjukta; Anderson, Richard A.; Urban, Joseph F.

    2009-01-01

    Tristetraprolin/zinc finger protein 36 (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 production in rabbits. The antiserum recognized nanograms of the antigen on immunoblots. This antiserum and another antiserum developed against recombinant mouse TTP were used to detect ZFP36L1 and TTP in mouse 3T3-L1 adipocytes and RAW264.7 macrophages. Immunoblotting showed that ZFP36L1 was stably expressed with a size corresponding to the lower mass size of ZFP36L1 expressed in transfected human embryonic kidney 293 cells, but TTP was induced by cinnamon extract and not by lipopolysaccharide (LPS) in adipocytes. In contrast, ZFP36L1 was undetectable but TTP was strongly induced in LPS-stimulated RAW cells. Quantitative real-time polymerase chain reaction confirmed the higher levels of ZFP36L1 mRNA in adipocytes and TTP mRNA in RAW cells. Low levels of ZFP36L1 expression were also confirmed by northern blotting in mouse embryonic fibroblasts. These results demonstrate that ZFP36L1 antiserum is useful in the detection of this protein and that TTP and ZFP36L1 are differentially expressed and regulated at the mRNA and protein levels in mouse adipocytes and macrophages. PMID:18302406

  3. SREBP2 mediates the modulation of intestinal NPC1L1 expression by curcumin.

    PubMed

    Kumar, Pradeep; Malhotra, Pooja; Ma, Ke; Singla, Amika; Hedroug, Omar; Saksena, Seema; Dudeja, Pradeep K; Gill, Ravinder K; Alrefai, Waddah A

    2011-07-01

    Curcumin, the major phenolic compound in the spice turmeric, exhibits numerous biological effects, including lowering plasma cholesterol and preventing diet-induced hypercholesterolemia. The mechanisms underlying the hypocholesterolemic effect of curcumin are not fully understood. In this regard, intestinal Niemann-Pick C1-like 1 (NPC1L1) cholesterol transporter, the molecular target of intestinal cholesterol absorption inhibitor ezetimibe, plays an essential role in the maintenance of cholesterol homeostasis. The current studies were designed to investigate the effect of curcumin on NPC1L1 function, expression, and promoter activity in intestinal Caco-2 monolayers. NPC1L1 function was evaluated by the measurement of ezetimibe-sensitive [(3)H]cholesterol esterification. Relative abundance of NPC1L1 mRNA and protein was evaluated by real-time PCR and Western blotting, respectively. Luciferase assays were used to measure NPC1L1 promoter activity. Our results showed that curcumin significantly inhibited ezetimibe-sensitive cholesterol esterification in a dose-dependent manner with a maximum decrease (by 52% compared with control) occurring at 50 μM concentration. Curcumin treatment of Caco-2 monolayers also significantly decreased NPC1L1 mRNA and protein expression. Similarly, the promoter activity of the NPC1L1 gene was inhibited significantly (55%) by 50 μM curcumin. The decrease in NPC1L1 promoter activity by curcumin was associated with a reduction in the expression and the DNA-binding activity of the sterol response element-binding protein 2 (SREBP2) transcription factor. Furthermore, the overexpression of active SREBP2 protected NPC1L1 from the inhibitory effect of curcumin. Our studies demonstrate that curcumin directly modulates intestinal NPC1L1 expression via transcriptional regulation and the involvement of SREBP2 transcription factor.

  4. 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

  5. PD-L1 expression in non-small cell lung cancer: Correlations with genetic alterations.

    PubMed

    Scheel, Andreas H; Ansén, Sascha; Schultheis, Anne M; Scheffler, Matthias; Fischer, Rieke N; Michels, Sebastian; Hellmich, Martin; George, Julie; Zander, Thomas; Brockmann, Michael; Stoelben, Erich; Groen, Harry; Timens, Wim; Perner, Sven; von Bergwelt-Baildon, Michael; Büttner, Reinhard; Wolf, Jürgen

    2016-05-01

    Inhibition of the PD-1/PD-L1 pathway may induce anticancer immune responses in non-small cell lung cancer (NSCLC). Two PD-L1 immunohistochemistry (IHC) assays have been approved as companion diagnostic tests for therapeutic anti-PD-1 antibodies. However, many aspects of PD-L1 prevalence and association with genetically defined subtypes have not been addressed systematically. Here, we analyzed PD-L1 expression in 436 genetically annotated NSCLC specimens enriched for early stages using PD-L1 antibody 5H1. Expression of PD-L1 was detected in the tumor cells (TC) (34% of cases) and in associated immune cells (IC) (49%) across all stages of NSCLC, either alone or in combination. PD-L1 IHC-positive TC, but not IC showed significantly higher PD-L1 RNA expression levels. Expression in TC was associated with TP53, KRAS and STK11 mutational status in adenocarcinomas (AD) and with NFE2L2 mutations in squamous cell carcinomas (SQ). No correlations with histological subtype, clinical characteristics and overall survival were found. The presence of PD-L1-positive IC was significantly associated with patients' smoking status in AD. The findings are in agreement with the emerging concept that tumors with high mutational burden are more likely to benefit from immunotherapy, since TP53 and KRAS mutations are linked to smoking, increased numbers of somatic mutations and expression of neoantigens. Current clinical studies focus on stage IIIB and IV NSCLC; however, PD-L1 expression occurs in earlier stages and might be a predictive biomarker in clinical trials testing (neo-) adjuvant strategies. PMID:27467949

  6. PD-L1 is an independent prognostic predictor in gastric cancer of Western patients

    PubMed Central

    Böger, Christine; Behrens, Hans-Michael; Mathiak, Micaela; Krüger, Sandra; Kalthoff, Holger; Röcken, Christoph

    2016-01-01

    Targeting the PD-1/PD-L1 immune checkpoint signaling is a novel promising treatment strategy in several tumor entities, and it is suggested that PD-L1/PD-1 expression is predictive for a PD-1/PD-L1 checkpoint inhibitor treatment response. We investigated the expression of PD-L1 and PD-1 by immunohistochemistry in a large and well characterized gastric cancer (GC) cohort of Caucasian patients, consisting of 465 GC samples and 15 corresponding liver metastases. Staining results were correlated with clinico-pathological characteristics and survival. PD-L1 expression was found in tumor cells of 140 GCs (30.1%) and 9 liver metastases (60%) respectively in immune cells of 411 GCs (88.4%) and 11 liver metastases (73.3%). PD-1 was expressed in tumor infiltrating lymphocytes in 250 GCs (53.8%) and in 11 liver metastases (73.3%). PD-L1 expression was significantly more prevalent in men, GCs of the proximal stomach, unclassified, papillary, Her2/neu-positive, Epstein-Barr-virus-positive, microsatellite instable, and PIK3CA-mutated GCs. A high PD-L1/PD-1 expression was associated with a significantly better patient outcome, and PD-L1 turned out to be an independent survival prognosticator. The correlation of PD-L1/PD-1 expression with distinct clinico-pathological patient characteristics may serve as a surrogate marker of PD-L1-positive GCs and may direct the use of immune checkpoint treatment strategies. PMID:27009855

  7. Scanning tunneling microscopy and electrochemical study of the surface structure of Pt(10,10,9) and Pt(11,10,10) electrodes prepared under different cooling conditions

    NASA Astrophysics Data System (ADS)

    Herrero, Enrique; Orts, José M.; Aldaz, Antonio; Feliu, Juan M.

    1999-10-01

    The effect of three surface electrochemical preparation techniques for single crystal surfaces on two platinum stepped surfaces [Pt(10,10,9) and Pt(11,10,10)] has been investigated by scanning tunneling microscopy and cyclic voltammetry. The preparation techniques consisted of a thermal treatment followed by a cooling step in (a) a hydrogen+argon atmosphere, (b) air (c) iodine vapor+air. For Pt(10,10,9) and Pt(11,10,10) surfaces, the hydrogen+argon treatment provides surfaces that have a very narrow distribution of terrace widths around the nominal value and monatomic steps. On the other hand, facetted surfaces with terrace widths and steps four to five times their nominal values are obtained when the cooling is in the presence of iodine vapor. The air treatment generates surfaces in which the terrace width is not as uniform as in the H 2+Ar case and some kink sites are created. The changes in the surface topography can be followed in the voltammetric profile of the surfaces recorded in a sulfuric acid solution.

  8. 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

  9. Mutation in the sixth immunoglobulin domain of L1CAM is associated with migrational brain anomalies

    PubMed Central

    Shieh, Christine; Moser, Franklin; Graham, John M.; Watiker, Valerie

    2015-01-01

    Objective: To describe the phenotype of a patient with classical features of X-linked L1 syndrome associated with novel brain malformations. Methods: Diagnostic analysis included physical and dysmorphology examinations, MRI of the brain, and exome sequencing of the family trio. Results: We report a 2.5-year-old boy with developmental delay, dysmorphic facies, and adducted thumbs. MRI of the brain showed a truncated corpus callosum and periventricular heterotopias associated with polymicrogyria (PMG). Variant segregation analysis with exome sequencing discovered a novel maternally derived hemizygous variant in exon 14 of the L1CAM gene (c.1759 G>C; p.G587R). Conclusions: This novel L1CAM mutation was located in the protein's sixth immunoglobin domain and involved glycine-587, a key residue in the structure of L1CAM because of its interactions with lysine-606, which indicates that any mutation at this site would likely affect the secondary structure and function of the protein. The replacement of the small nonpolar glycine residue with a large basic arginine would have an even more dramatic result. The presentation of periventricular nodular heterotopias with overlying PMG is very uncommon, and its association with L1CAM may provide insight into other similar cases. Furthermore, this presentation indicates the important role that L1CAM plays in neuronal migration and brain development and extends the phenotype associated with L1CAM-associated disorders. PMID:27066571

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

    PubMed Central

    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

  11. Novel functions for the endocytic regulatory proteins MICAL-L1 and EHD1 in mitosis.

    PubMed

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

    2015-01-01

    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.

  12. Sarcomatoid lung carcinomas show high levels of Programmed death Ligand-1 (PD-L1)

    PubMed Central

    Velcheti, Vamsidhar; Rimm, David L.; Schalper, Kurt A.

    2013-01-01

    Programmed death-1 (PD-1) is a co-inhibitory inducible receptor present on T-cells and macrophages. Tumor cells with increased programmed death ligand-1 (PD-L1) are believed to escape immunity through activation of PD-1/PD-L1 pathway and suppression of effector immune responses. Recent strategies targeting the PD-1/PD-L1 axis have shown promising results in patients with several tumors types, including lung carcinomas. Preliminary data suggests that PD-L1 protein expression might predictive response to such therapies. Sarcomatoid carcinomas (SCs) of the lung include rare subtypes of poorly differentiated non-small cell lung carcinomas (NSCLC) of high grade and aggressive behavior. The biology of these neoplasms is poorly understood and they frequently show increased local inflammatory and lymphocytic infiltration. Here, we report the expression of PD-L1 in 13 SCs from two large retrospective lung cancer cohorts. Using automated quantitative immunofloresence (aqIF/AQUA®) and a mouse monoclonal antibody directed against the extra-cellular domain of PD-L1, we show that 9 of 13 (69.2%) patients with SCs are positive for PD-L1 and their levels are higher than in conventional NSCLC. These results provide rationale for the potential use of targeted immunetherapy in lung SCs. PMID:23676558

  13. 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

  14. A novel L1CAM mutation in a fetus detected by prenatal diagnosis.

    PubMed

    Piccione, Maria; Matina, Federico; Fichera, Marco; Lo Giudice, Mariangela; Damiani, Gianfranca; Jakil, Maria Cristina; Corsello, Giovanni

    2010-04-01

    X-linked hydrocephalus is due to mutations in the L1 neuronal cell adhesion molecule (L1CAM) gene. L1 protein plays a key role in neurite outgrowth, axonal guidance, and pathfinding during the development of the nervous system. We report on a familial case diagnosed by prenatal ultrasonographic examination, with cerebellar hypoplasia, agenesis of the corpus callosum, and the bilateral overlapping of the second and third fingers of the hand. Sequencing of the L1CAM gene showed a novel missense mutation in exon 14: transition of a guanine to cytosine at position 1777 (c.1777G>C), which led to an amino acid change of alanine to proline at position 593 (Ala593Pro) in the sixth immunoglobulin domain of the L1 protein. The L1CAM mutation testing should be considered in fetuses with ultrasonographic signs of hydrocephalus and a positive family history compatible with X-linked inheritance. We agree with previous reports that suggest also considering limb abnormalities other than adducted thumbs in addition to classical neurological disgenesis, as characteristic for L1-disease.

  15. 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

  16. 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…

  17. 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…

  18. Human Papillomavirus Type16- L1 VLP Production in Insect Cells

    PubMed Central

    Abdoli, Asghar; Soleimanjahi, Hoorieh; Fotouhi, Fatemeh; Teimoori, Ali; Pour Beiranvand, Shahram; Kianmehr, Zahra

    2013-01-01

    Objective(s): Infection by high-risk papillomavirus is regarded as the major risk factor in the development of cervical cancer. Recombinant DNA technology allows expression of the L1 major capsid protein of HPV in different expression systems, which has intrinsic capacity to self-assemble into viral-like particles (VLP). VLPS are non-infectious, highly immunogenic and can elicit neutralizing antibodies. VLP-based HPV vaccines can prevent persistent HPV infections and cervical cancer. In this study recombinant HPV-16 L1 protein was produced in Sf9 insect cells and VLP formation was confirmed. Materials and Methods: Complete HPV-16 L1 gene was inserted into pFast HTa plasmid and transformed into DH10BAC Escherichia coli containing bacmid and helper plasmid. The recombinant Bacmid colonies turned to white and non-recombinant colonies harboring L1 gene remained blue in the presence of X-gal and IPTG in colony selection strategy. To confirm the recombinant bacmid production, PCR was applied using specific L1 primers. To produce recombinant baculovirus, the recombinant bacmid DNA was extracted and transfected into Sf9 cells using Cellfectin. The expression of L1 in Sf9 cells was identified through SDS-PAGE and western blot analysis using specific L1 monoclonal antibody. Self-assembled HPV16L-VLPs in Sf9 cells was confirmed by electron microscopy. Results: The recombinant protein L1 was predominantly ~60 KD in SDS-PAGE with distinct immunoreactivity in western blot analysis and formed VLPS as confirmed by electron microscopy. Conclusion: Application of recombinant baculovirus containing HPV-16 L1 gene will certainly prove to be a constructive tool in production of VLPs for prophylactic vaccine development as well as diagnostic tests. PMID:24106591

  19. 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.

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

    SciTech Connect

    Lai, Peng-Yeh; Tsai, Chong-Bin; 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.

  1. The ExoMol database: Molecular line lists for exoplanet and other hot atmospheres

    NASA Astrophysics Data System (ADS)

    Tennyson, Jonathan; Yurchenko, Sergei N.; Al-Refaie, Ahmed F.; Barton, Emma J.; Chubb, Katy L.; Coles, Phillip A.; Diamantopoulou, S.; Gorman, Maire N.; Hill, Christian; Lam, Aden Z.; Lodi, Lorenzo; McKemmish, Laura K.; Na, Yueqi; Owens, Alec; Polyansky, Oleg L.; Rivlin, Tom; Sousa-Silva, Clara; Underwood, Daniel S.; Yachmenev, Andrey; Zak, Emil

    2016-09-01

    The ExoMol database (www.exomol.com) provides extensive line lists of molecular transitions which are valid over extended temperatures ranges. The status of the current release of the database is reviewed and a new data structure is specified. This structure augments the provision of energy levels (and hence transition frequencies) and Einstein $A$ coefficients with other key properties, including lifetimes of individual states, temperature-dependent cooling functions, Land\\'e $g$-factors, partition functions, cross sections, $k$-coefficients and transition dipoles with phase relations. Particular attention is paid to the treatment of pressure broadening parameters. The new data structure includes a definition file which provides the necessary information for utilities accessing ExoMol through its application programming interface (API). Prospects for the inclusion of new species into the database are discussed.

  2. 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

  3. 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.

  4. Towards J/mol Accuracy for the Cohesive Energy of Solid Argon.

    PubMed

    Schwerdtfeger, Peter; Tonner, Ralf; Moyano, Gloria E; Pahl, Elke

    2016-09-26

    The cohesive energies of argon in its cubic and hexagonal closed packed structures are computed with an unprecedented accuracy of about 5 J mol(-1) (corresponding to 0.05 % of the total cohesive energy). The same relative accuracy with respect to experimental data is also found for the face-centered cubic lattice constant deviating by ca. 0.003 Å. This level of accuracy was enabled by using high-level theoretical, wave-function-based methods within a many-body decomposition of the interaction energy. Static contributions of two-, three-, and four-body fragments of the crystal are all individually converged to sub-J mol(-1) accuracy and complemented by harmonic and anharmonic vibrational corrections. Computational chemistry is thus achieving or even surpassing experimental accuracy for the solid-state rare gases. PMID:27593519

  5. 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.

  6. 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.

  7. 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.

  8. 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

  9. Ins-4 and daf-28 function redundantly to regulate C. elegans L1 arrest.

    PubMed

    Chen, Yutao; Baugh, L Ryan

    2014-10-15

    Caenorhabditis elegans larvae reversibly arrest development in the first larval stage in response to starvation (L1 arrest or L1 diapause). Insulin-like signaling is a critical regulator of L1 arrest. However, the C. elegans genome encodes 40 insulin-like peptides, and it is unknown which peptides participate in nutritional control of L1 development. Work in other contexts has revealed that insulin-like genes can promote development ("agonists") or developmental arrest ("antagonists"), suggesting that such agonists promote L1 development in response to feeding. We measured mRNA expression dynamics with high temporal resolution for all 40 insulin-like genes during entry into and recovery from L1 arrest. Nutrient availability influences expression of the majority of insulin-like genes, with variable dynamics suggesting complex regulation. We identified thirteen candidate agonists and eight candidate antagonists based on expression in response to nutrient availability. We selected ten candidate agonists (daf-28, ins-3, ins-4, ins-5, ins-6, ins-7, ins-9, ins-26, ins-33 and ins-35) for further characterization in L1 stage larvae. We used destabilized reporter genes to determine spatial expression patterns. Expression of candidate agonists is largely overlapping in L1 stage larvae, suggesting a role of the intestine, chemosensory neurons ASI and ASJ, and the interneuron PVT in control of L1 development. Transcriptional regulation of candidate agonists is most significant in the intestine, as if internal nutrient status is a more important influence on transcription than sensory perception. Phenotypic analysis of single and compound deletion mutants did not reveal effects on L1 developmental dynamics, though simultaneous disruption of ins-4 and daf-28 increases survival of L1 arrest. Furthermore, overexpression of ins-4, ins-6 or daf-28 alone decreases survival and promotes cell division during starvation. These results suggest extensive functional overlap among insulin

  10. MolProbity: all-atom structure validation for macromolecular crystallography

    SciTech Connect

    Chen, Vincent B.; Arendall, W. Bryan III; Headd, Jeffrey J.; Keedy, Daniel A.; Immormino, Robert M.; Kapral, Gary J.; Murray, Laura W.; Richardson, Jane S.; Richardson, David C.

    2010-01-01

    MolProbity structure validation will diagnose most local errors in macromolecular crystal structures and help to guide their correction. MolProbity is a structure-validation web service that provides broad-spectrum solidly based evaluation of model quality at both the global and local levels for both proteins and nucleic acids. It relies heavily on the power and sensitivity provided by optimized hydrogen placement and all-atom contact analysis, complemented by updated versions of covalent-geometry and torsion-angle criteria. Some of the local corrections can be performed automatically in MolProbity and all of the diagnostics are presented in chart and graphical forms that help guide manual rebuilding. X-ray crystallography provides a wealth of biologically important molecular data in the form of atomic three-dimensional structures of proteins, nucleic acids and increasingly large complexes in multiple forms and states. Advances in automation, in everything from crystallization to data collection to phasing to model building to refinement, have made solving a structure using crystallography easier than ever. However, despite these improvements, local errors that can affect biological interpretation are widespread at low resolution and even high-resolution structures nearly all contain at least a few local errors such as Ramachandran outliers, flipped branched protein side chains and incorrect sugar puckers. It is critical both for the crystallographer and for the end user that there are easy and reliable methods to diagnose and correct these sorts of errors in structures. MolProbity is the authors’ contribution to helping solve this problem and this article reviews its general capabilities, reports on recent enhancements and usage, and presents evidence that the resulting improvements are now beneficially affecting the global database.

  11. Azahar: a PyMOL plugin for construction, visualization and analysis of glycan molecules.

    PubMed

    Arroyuelo, Agustina; Vila, Jorge A; Martin, Osvaldo A

    2016-08-01

    Glycans are key molecules in many physiological and pathological processes. As with other molecules, like proteins, visualization of the 3D structures of glycans adds valuable information for understanding their biological function. Hence, here we introduce Azahar, a computing environment for the creation, visualization and analysis of glycan molecules. Azahar is implemented in Python and works as a plugin for the well known PyMOL package (Schrodinger in The PyMOL molecular graphics system, version 1.3r1, 2010). Besides the already available visualization and analysis options provided by PyMOL, Azahar includes 3 cartoon-like representations and tools for 3D structure caracterization such as a comformational search using a Monte Carlo with minimization routine and also tools to analyse single glycans or trajectories/ensembles including the calculation of radius of gyration, Ramachandran plots and hydrogen bonds. Azahar is freely available to download from http://www.pymolwiki.org/index.php/Azahar and the source code is available at https://github.com/agustinaarroyuelo/Azahar . PMID:27549814

  12. 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

  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.

  14. Various amenability properties of the L1-algebra of polynomial hypergroups and applications

    NASA Astrophysics Data System (ADS)

    Lasser, R.

    2009-12-01

    We investigate amenability, weak amenability and [alpha]t-amenability of the L1-algebra of polynomial hypergroups, and derive from these properties some applications for the corresponding orthogonal polynomials.

  15. 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.

  16. 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

  17. Polymorphic L1 retrotransposons are frequently in strong linkage disequilibrium with neighboring SNPs.

    PubMed

    Higashino, Saneyuki; Ohno, Tomoyuki; Ishiguro, Koichi; Aizawa, Yasunori

    2014-05-10

    L1 retrotransposons have been the major driver of structural variation of the human genome. L1 insertion polymorphism (LIP)-mediated genomic variation can alter the transcriptome and contribute to the divergence of human phenotypes. To assess this possibility, a genome-wide association study (GWAS) including LIPs is required. Toward this ultimate goal, the present study examined linkage disequilibrium between six LIPs and their neighboring single nucleotide polymorphisms (SNPs). Genomic PCR and sequencing of L1-plus and -minus alleles from different donors revealed that all six LIPs were in strong linkage disequilibrium with at least one SNP. In addition, comparison of syntenic regions containing the identified SNP nucleotides was performed among modern humans (L1-plus and -minus alleles), archaic humans and non-human primates, revealing two different evolutionary schemes that might have resulted in the observed strong SNP-LIP linkage disequilibria. This study provides an experimental framework and guidance for a future SNP-LIP integrative GWAS.

  18. 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.

  19. Structural and magnetic properties of L1(0)/A1, FePt nanocomposites

    SciTech Connect

    Giannopoulos, G; Speliotis, T; Li, WF; Hadjipanayis, G; Niarchos, D

    2013-01-01

    In this work structural and magnetic properties of (L1(0)-FePt/A1-FePt) exchange coupled nanocomposites are presented. Semi spherical "dome-like" nanocomposites with L1(0) FePt isolated nanoparticles and A1 FePt (fcc) cap layers were obtained by depositing A1-FePt on type L1(0) FePt nanoparticles in order to understand the influence of the soft magnetic layer thickness on the magnetic properties of the system. Epitaxial growth is confirmed by X-ray diffraction and TEM, while the coercivity decreases dramatically for the L1(0)/A1-FePt system when the thickness of the A1-FePt cap layers is increased. This result can be used to realize ultrahigh magnetic recording media with tunable coercivity, suitable for conventional write heads. (C) 2012 Elsevier B.V. All rights reserved.

  20. Polymorphism of the capsid L1 gene of human papillomavirus types 31, 33, and 35.

    PubMed

    Cornut, Gilbert; Gagnon, Simon; Hankins, Catherine; Money, Deborah; Pourreaux, Karina; Franco, Eduardo L; Coutlée, François

    2010-07-01

    The L1 gene encodes for the major capsid protein of human papillomaviruses (HPV). There is limited information on the polymorphism of L1 for types related to HPV-16. This report explores the polymorphism of L1 in phylogenetically related types 31, 33, and 35 compared to HPV-16. Genital specimens collected from 732 HIV-seropositive and 323 HIV-seronegative women were screened for HPV DNA with consensus L1 PCR. Cervical samples positive for HPV-16 (n = 74), HPV-31 (n = 78), HPV-33 (n = 37), and HPV-35 (n = 58) were further characterized by PCR-sequencing of the complete L1 gene. The number of nucleotide substitutions within L1 ranged from 19 for HPV-33 to 52 for HPV-31. The ratio of the number of variants/number of isolates tested was higher for HPV-31 (56.4%, P = 0.05) and HPV-35 (60.3%, P = 0.04) compared to HPV-16 (40.5%), while this ratio was lower for HPV-33 (24.3%), although not significantly (P = 0.14). The maximal distance between HPV variants was greater in the five putative surface-exposed loops of L1 than in sequences outside the loops (P < 0.01). Synonymous variations were encountered in 1.7% (95% CI 1.1-2.3) of nucleotides inside the L1 loops and 2.4% (95% CI1.2-3.7) of nucleotides outside the L1 loops. Non-synonymous variations were encountered in 1.8% (95% CI 1.1-2.5) of nucleotides within the L1 loops and 0.2% (95% CI 0-0.4) of nucleotides outside the loops. dN/dS ratios were below 1.0 in extra-loop and intra-loop regions, but they were lower in extra-loop regions. These results suggest that sequences within and outside the hypervariable loops of L1 were under selective constraint.

  1. 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

  2. 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

  3. 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

  4. Glial cells suppress postencephalitic CD8+ T lymphocytes through PD-L1.

    PubMed

    Schachtele, Scott J; Hu, Shuxian; Sheng, Wen S; Mutnal, Manohar B; Lokensgard, James R

    2014-10-01

    Engagement of the programmed death (PD)-1 receptor on activated cells by its ligand (PD-L1) is a mechanism for suppression of activated T-lymphocytes. Microglia, the resident inflammatory cells of the brain, are important for pathogen detection and initiation of innate immunity, however, a novel role for these cells as immune regulators has also emerged. PD-L1 on microglia has been shown to negatively regulate T-cell activation in models of multiple sclerosis and acute viral encephalitis. In this study, we investigated the role of glial cell PD-L1 in controlling encephalitogenic CD8(+) T-lymphocytes, which infiltrate the brain to manage viral infection, but remain to produce chronic neuroinflammation. Using a model of chronic neuroinflammation following murine cytomegalovirus (MCMV)-induced encephalitis, we found that CD8(+) T-cells persisting within the brain expressed PD-1. Conversely, activated microglia expressed PD-L1. In vitro, primary murine microglia, which express low basal levels of PD-L1, upregulated the co-inhibitory ligand on IFN-γ-treatment. Blockade of the PD-1: PD-L1 pathway in microglial: CD8(+) T-cell co-cultures increased T-cell IFN-γ and interleukin (IL)-2 production. We observed a similar phenomenon following blockade of this co-inhibitory pathway in astrocyte: CD8(+) T-cell co-cultures. Using ex vivo cultures of brain leukocytes, including microglia and CD8(+) T-cells, obtained from mice with MCMV-induced chronic neuroinflammation, we found that neutralization of either PD-1 or PD-L1 increased IFN-γ production from virus-specific CD8(+) T-cells stimulated with MCMV IE1168-176 peptide. These data demonstrate that microglia and astrocytes control antiviral T-cell responses and suggest a therapeutic potential of PD1: PD-L1 modulation to manage the deleterious consequences of uncontrolled neuroinflammation.

  5. Intonational differences between L1 and L2 english in South Africa.

    PubMed

    Swerts, Marc; Zerbian, Sabine

    2010-01-01

    Previous studies have shown that characteristics of a person's first language (L1) may transfer to a second language (L2). The current study looks at the extent to which this holds for aspects of intonation as well. More specifically, we investigate to what extent traces of the L1 can be discerned in the way intonation is used in the L2 for two functions: (1) to highlight certain words by making them sound more prominent and (2) to signal continuation or finality in a list by manipulating the speech melody. To this end, the article presents an explorative study into the way focus and boundaries are marked prosodically in Zulu, and it also compares such prosodic functions in two variants of English in South Africa, i.e., English spoken as an L1, and English spoken as an L2/additional language by speakers who have Zulu as their L1. The latter language is commonly referred to as Black South African English. This comparison is interesting from a typological perspective, as Zulu is intonationally different from English, especially in the way prosody is exploited for signalling informationally important stretches of speech. Using a specific elicitation procedure, we found in a first study that speakers of South African English (as L1) mark focused words and position within a list by intonational means, just as in other L1 varieties of English, whereas Zulu only uses intonation for marking continuity or finality. A second study focused on speakers of Black South African English, and compared the prosody of proficient versus less proficient speakers. We found that the proficient speakers were perceptually equivalent to L1 speakers of English in their use of intonation for marking focus and boundaries. The less proficient speakers marked boundaries in a similar way as L1 speakers of English, but did not use prosody for signalling focus, analogous to what is typical of their native language. Acoustic observations match these perceptual results.

  6. 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

  7. 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

  8. Fucoxanthin and its metabolite, fucoxanthinol, suppress adipocyte differentiation in 3T3-L1 cells.

    PubMed

    Maeda, Hayato; Hosokawa, Masashi; Sashima, Tokutake; Takahashi, Nobuyuki; Kawada, Teruo; Miyashita, Kazuo

    2006-07-01

    Fucoxanthin is a major carotenoid found in edible seaweed such as Undaria pinnatifida and Hijikia fusiformis. We investigated the suppressive effects of fucoxanthin and its metabolite, fucoxanthinol, on the differentiation of 3T3-L1 preadipocytes to adipocytes. Fucoxanthin inhibited intercellular lipid accumulation during adipocyte differentiation of 3T3-L1 cells. Furthermore, fucoxanthin was converted to fucoxanthinol in 3T3-L1 cells. Fucoxanthinol also exhibited suppressive effects on lipid accumulation and decreased glycerol-3-phosphate dehydrogenase activity, an indicator of adipocyte differentiation. The suppressive effect of fucoxanthinol was stronger than that of fucoxanthin. In addition, in 3T3-L1 cells treated with fucoxanthin and fucoxanthinol, peroxisome proliferator-activated receptor gamma (PPARgamma), which regulates adipogenic gene expression, was down-regulated in a dose-dependent manner. These results suggest that fucoxanthin and fucoxanthinol inhibit the adipocyte differentiation of 3T3-L1 cells through down-regulation of PPARgamma. Fucoxanthinol had stronger suppressive effects than fucoxanthin on adipocyte differentiation in 3T3-L1 cells. PMID:16786166

  9. Immunization with a pentameric L1 fusion protein protects against papillomavirus infection.

    PubMed

    Yuan, H; Estes, P A; Chen, Y; Newsome, J; Olcese, V A; Garcea, R L; Schlegel, R

    2001-09-01

    The prophylactic papillomavirus vaccines currently in clinical trials are composed of viral L1 capsid protein that is synthesized in eukaryotic expression systems and purified in the form of virus-like particles (VLPs). To evaluate whether VLPs are necessary for effective vaccination, we expressed the L1 protein as a glutathione S-transferase (GST) fusion protein in Escherichia coli and assayed its immunogenic activity in an established canine oral papillomavirus (COPV) model that previously validated the efficacy of VLP vaccines. The GST-COPV L1 fusion protein formed pentamers, but these capsomere-like structures did not assemble into VLPs. Despite the lack of VLP formation, the GST-COPV L1 protein retained its native conformation as determined by reactivity with conformation-specific anti-COPV antibodies. Most importantly, the GST-COPV L1 pentamers completely protected dogs from high-dose viral infection of their oral mucosa. L1 fusion proteins expressed in bacteria represent an economical alternative to VLPs as a human papillomavirus vaccine. PMID:11483728

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

    PubMed

    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

    1995-12-01

    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. PMID:8524802

  11. Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in mice

    PubMed Central

    Deng, Liufu; Liang, Hua; Burnette, Byron; Beckett, Michael; Darga, Thomas; Weichselbaum, Ralph R.; Fu, Yang-Xin

    2014-01-01

    High-dose ionizing irradiation (IR) results in direct tumor cell death and augments tumor-specific immunity, which enhances tumor control both locally and distantly. Unfortunately, local relapses often occur following IR treatment, indicating that IR-induced responses are inadequate to maintain antitumor immunity. Therapeutic blockade of the T cell negative regulator programmed death–ligand 1 (PD-L1, also called B7-H1) can enhance T cell effector function when PD-L1 is expressed in chronically inflamed tissues and tumors. Here, we demonstrate that PD-L1 was upregulated in the tumor microenvironment after IR. Administration of anti–PD-L1 enhanced the efficacy of IR through a cytotoxic T cell–dependent mechanism. Concomitant with IR-mediated tumor regression, we observed that IR and anti–PD-L1 synergistically reduced the local accumulation of tumor-infiltrating myeloid-derived suppressor cells (MDSCs), which suppress T cells and alter the tumor immune microenvironment. Furthermore, activation of cytotoxic T cells with combination therapy mediated the reduction of MDSCs in tumors through the cytotoxic actions of TNF. Our data provide evidence for a close interaction between IR, T cells, and the PD-L1/PD-1 axis and establish a basis for the rational design of combination therapy with immune modulators and radiotherapy. PMID:24382348

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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.

  17. BET Bromodomain Inhibition Promotes Anti-tumor Immunity by Suppressing PD-L1 Expression.

    PubMed

    Zhu, Hengrui; Bengsch, Fee; Svoronos, Nikolaos; Rutkowski, Melanie R; Bitler, Benjamin G; Allegrezza, Michael J; Yokoyama, Yuhki; Kossenkov, Andrew V; Bradner, James E; Conejo-Garcia, Jose R; Zhang, Rugang

    2016-09-13

    Restoration of anti-tumor immunity by blocking PD-L1 signaling through the use of antibodies has proven to be beneficial in cancer therapy. Here, we show that BET bromodomain inhibition suppresses PD-L1 expression and limits tumor progression in ovarian cancer. CD274 (encoding PD-L1) is a direct target of BRD4-mediated gene transcription. In mouse models, treatment with the BET inhibitor JQ1 significantly reduced PD-L1 expression on tumor cells and tumor-associated dendritic cells and macrophages, which correlated with an increase in the activity of anti-tumor cytotoxic T cells. The BET inhibitor limited tumor progression in a cytotoxic T-cell-dependent manner. Together, these data demonstrate a small-molecule approach to block PD-L1 signaling. Given the fact that BET inhibitors have been proven to be safe with manageable reversible toxicity in clinical trials, our findings indicate that pharmacological BET inhibitors represent a treatment strategy for targeting PD-L1 expression. PMID:27626654

  18. 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

  19. 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

  20. 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.

  1. 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.

  2. 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.

  3. CHLORHEXIDINE INHIBITS L1 CELL ADHESION MOLECULE MEDIATED NEURITE OUTGROWTH IN VITRO

    PubMed Central

    Milstone, Aaron M.; Bamford, Penny; Aucott, Susan W.; Tang, Ningfeng; White, Kimberly R.; Bearer, Cynthia F.

    2013-01-01

    Background Chlorhexidine is a skin disinfectant that reduces skin and mucous membrane bacterial colonization and inhibits organism growth. Despite numerous studies assessing chlorhexidine safety in term infants, residual concerns have limited its use in hospitalized neonates, especially low birth weight preterm infants. The aim of this study was to assess the potential neurotoxicity of chlorhexidine on the developing central nervous system using a well-established in vitro model of neurite outgrowth that includes laminin and L1 cell adhesion molecule (L1) as neurite outgrowth promoting substrates. Methods Cerebellar granule neurons are plated on either poly L-lysine, L1 or laminin. Chlorhexidine, hexachlorophene or their excipients are added to the media. Neurons are grown for 24 h, then fixed and neurite length measured. Results Chlorhexidine significantly reduced the length of neurites grown on L1 but not laminin. Chlorhexidine concentrations as low as 125 ng/ml statistically significantly reduced neurite length on L1. Hexachlorophene did not affect neurite length. Conclusion Chlorhexidine at concentrations detected in the blood following topical applications in preterm infants specifically inhibited L1 mediated neurite outgrowth of cerebellar granule neurons. It is now vital to determine whether the blood brain barrier is permeable to chlorhexidine in preterm infants. PMID:24126818

  4. Expression of HPV-11 L1 protein in transgenic Arabidopsis thaliana and Nicotiana tabacum

    PubMed Central

    Kohl, Thomas O; Hitzeroth, Inga I; Christensen, Neil D; Rybicki, Edward P

    2007-01-01

    Background We have investigated the possibility and feasibility of producing the HPV-11 L1 major capsid protein in transgenic Arabidopsis thaliana ecotype Columbia and Nicotiana tabacum cv. Xanthi as potential sources for an inexpensive subunit vaccine. Results Transformation of plants was only achieved with the HPV-11 L1 gene with the C-terminal nuclear localization signal (NLS-) encoding region removed, and not with the full-length gene. The HPV-11 L1 NLS- gene was stably integrated and inherited through several generations of transgenic plants. Plant-derived HPV-11 L1 protein was capable of assembling into virus-like particles (VLPs), although resulting particles displayed a pleomorphic phenotype. Neutralising monoclonal antibodies binding both surface-linear and conformation-specific epitopes bound the A. thaliana-derived particles and – to a lesser degree – the N. tabacum-derived particles, suggesting that plant-derived and insect cell-derived VLPs displayed similar antigenic properties. Yields of up to 12 μg/g of HPV-11 L1 NLS- protein were harvested from transgenic A. thaliana plants, and 2 μg/g from N. tabacum plants – a significant increase over previous efforts. Immunization of New Zealand white rabbits with ~50 μg of plant-derived HPV-11 L1 NLS- protein induced an antibody response that predominantly recognized insect cell-produced HPV-11 L1 NLS- and not NLS+ VLPs. Evaluation of the same sera concluded that none of them were able to neutralise pseudovirion in vitro. Conclusion We expressed the wild-type HPV-11 L1 NLS- gene in two different plant species and increased yields of HPV-11 L1 protein by between 500 and 1000-fold compared to previous reports. Inoculation of rabbits with extracts from both plant types resulted in a weak immune response, and antisera neither reacted with native HPV-11 L1 VLPs, nor did they neutralise HPV-11 pseudovirion infectivity. This has important and potentially negative implications for the production of HPV-11

  5. ExoMol: Molecular Line List for Exoplanets and Other Atmospheres

    NASA Astrophysics Data System (ADS)

    Tennyson, Jonathan; Yurchenko, Sergei N.; Polyansky, Oleg

    2016-06-01

    The discovery of extrasolar planets is one of the major scientific advances of the last two decades. Thousands of planets have now been detected and astronomers are beginning to characterize their composition and physical characteristics. To do this requires a huge quantity of spectroscopic data most of which are not available from laboratory studies. The ExoMol project [1] is generating a comprehensive solution to this problem by providing spectroscopic data on all the molecular transitions of importance in the atmospheres of exoplanets. These data are widely applicable to other problems such studies on cool stars, brown dwarfs and circumstellar environments as well as industrial and technological problems on earth. ExoMol employs a mixture of first principles and empirically tuned quantum mechanical methods to compute comprehensive and very large rotation-vibration and rovibronic line lists. Results span a variety of closed (NaH, SiO, PN, NaCl, KCl, CS) and open (BeH, MgH, CaH, AlO, VO) shell diatomics to triatomics (HCN/HNC, SO_2, H_2S, H_3^+), tetratomics (H_2CO, PH_3, SO_3, H_2O_2), plus methane [2] and nitric acid [3]. This has led directly to the detection of new species in the atmospheres of exoplanets [4]. A new comprehensive data release has just been completed [5]. Progress on and future prospects of the project will be summarised. J. Tennyson, S. N. Yurchenko, Mon. Not. R. astr. Soc., 425, 21, 2012. S. N. Yurchenko, J. Tennyson, J. Bailey, M. D. J. Hollis, G Tinetti, Proc. Nat. Acad. Sci., 111, 9379, 2014. A. I. Pavlyuchko, S. N. Yurchenko, J. Tennyson, Mon. Not. R. astr. Soc., 452, 1702, 2015. A. Tsiaras et al, Astrophys. J., in press. J. Tennyson et al, J. Mol. Spectrosc., in press.

  6. 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).

  7. 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

  8. 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.

  9. PD-1, PD-L1 and PD-L2 expression in mouse prostate cancer.

    PubMed

    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.

  10. L1-norm locally linear representation regularization multi-source adaptation learning.

    PubMed

    Tao, Jianwen; Wen, Shiting; Hu, Wenjun

    2015-09-01

    In most supervised domain adaptation learning (DAL) tasks, one has access only to a small number of labeled examples from target domain. Therefore the success of supervised DAL in this "small sample" regime needs the effective utilization of the large amounts of unlabeled data to extract information that is useful for generalization. Toward this end, we here use the geometric intuition of manifold assumption to extend the established frameworks in existing model-based DAL methods for function learning by incorporating additional information about the target geometric structure of the marginal distribution. We would like to ensure that the solution is smooth with respect to both the ambient space and the target marginal distribution. In doing this, we propose a novel L1-norm locally linear representation regularization multi-source adaptation learning framework which exploits the geometry of the probability distribution, which has two techniques. Firstly, an L1-norm locally linear representation method is presented for robust graph construction by replacing the L2-norm reconstruction measure in LLE with L1-norm one, which is termed as L1-LLR for short. Secondly, considering the robust graph regularization, we replace traditional graph Laplacian regularization with our new L1-LLR graph Laplacian regularization and therefore construct new graph-based semi-supervised learning framework with multi-source adaptation constraint, which is coined as L1-MSAL method. Moreover, to deal with the nonlinear learning problem, we also generalize the L1-MSAL method by mapping the input data points from the input space to a high-dimensional reproducing kernel Hilbert space (RKHS) via a nonlinear mapping. Promising experimental results have been obtained on several real-world datasets such as face, visual video and object.

  11. 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

  12. 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

  13. 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

  14. The Carbon Isotopic Record from Hulu Cave, China and C3/C4 Vegetation History from 75 to 10.9 ka

    NASA Astrophysics Data System (ADS)

    Smith, E. A.; Wang, Y.; Cheng, H.; Carpenter, S.; Dorale, J. A.; Edwards, R. L.

    2003-12-01

    We present a carbon isotopic record for eastern China, from a nearly continuous sequence of stalagmites (MSD, MSL, YT, H82) from Hulu Cave (32° N, 119° E). The record corresponds to the oxygen isotopic record of Wang et al. (2001), with ages from 74.9 to 10.9 ka (based on 230Th dates). δ 13C values range from -11.75 to -1.52‰ (VPDB). From 75 to 60 ka, the δ 13C is relatively light (mean = -8.5 +/- 1.4‰ ), excluding a 2 ky δ 13C excursion ˜71 ka. From 60 to 25 ka, the δ 13C alternates between heavy to intermediate values (range = -1.7 to -7.9‰ ). From 25 to 10.9 ka, δ 13C is light compared to the preceding interval except a 2‰ positive shift synchronous with the Bolling/Allerod. The carbon record of the four stalagmites replicate suggesting that factors such as changes in the hydrologic characteristics of individual drip pathways, amount of carbonate bedrock dissolved, or kinetic fractionation, do not affect δ 13C significantly. Similarly, it is unlikely that variability is caused by changes in the proportion of atmospheric to soil-produced CO2. If that was the case, one would expect high δ 13C during cold, dry intervals, which is exactly the opposite of what we observe. Therefore, we conclude that the δ 13C variations are likely caused by variation in the ratio of C3 to C4 vegetation above the cave. From 40 ka to 10.9 ka, the stalagmite δ 13C values are broadly consistent with known vegetation patterns based on pollen records (Liu et al., 1992; Sun et al., 1997; Winkler and Wang, 1993). Hulu Cave δ 18O has features similar to Greenland ice core δ 18O, with warmer temperatures during Greenland interstadials (heavy δ 18O) correlated with stronger summer monsoons in China (light δ 18O). Between 69-14.5 ka, Hulu Cave δ 18O and δ 13C are significantly anti-correlated (R = -0.80). During periods of stronger summer monsoons, suggestive of warmer temperatures and higher evapotranspiration, the record shows a greater abundance of C4 vegetation

  15. 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.

  16. 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

  17. 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

  18. 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

  19. Differential L1 regulation in pluripotent stem cells of humans and apes.

    PubMed

    Marchetto, Maria C N; Narvaiza, Iñigo; Denli, Ahmet M; Benner, Christopher; Lazzarini, Thomas A; Nathanson, Jason L; Paquola, Apuã C M; Desai, Keval N; Herai, Roberto H; Weitzman, Matthew D; Yeo, Gene W; Muotri, Alysson R; Gage, Fred H

    2013-11-28

    Identifying cellular and molecular differences between human and non-human primates (NHPs) is essential to the basic understanding of the evolution and diversity of our own species. Until now, preserved tissues have been the main source for most comparative studies between humans, chimpanzees (Pan troglodytes) and bonobos (Pan paniscus). However, these tissue samples do not fairly represent the distinctive traits of live cell behaviour and are not amenable to genetic manipulation. We propose that induced pluripotent stem (iPS) cells could be a unique biological resource to determine relevant phenotypical differences between human and NHPs, and that those differences could have potential adaptation and speciation value. Here we describe the generation and initial characterization of iPS cells from chimpanzees and bonobos as new tools to explore factors that may have contributed to great ape evolution. Comparative gene expression analysis of human and NHP iPS cells revealed differences in the regulation of long interspersed element-1 (L1, also known as LINE-1) transposons. A force of change in mammalian evolution, L1 elements are retrotransposons that have remained active during primate evolution. Decreased levels of L1-restricting factors APOBEC3B (also known as A3B) and PIWIL2 (ref. 7) in NHP iPS cells correlated with increased L1 mobility and endogenous L1 messenger RNA levels. Moreover, results from the manipulation of A3B and PIWIL2 levels in iPS cells supported a causal inverse relationship between levels of these proteins and L1 retrotransposition. Finally, we found increased copy numbers of species-specific L1 elements in the genome of chimpanzees compared to humans, supporting the idea that increased L1 mobility in NHPs is not limited to iPS cells in culture and may have also occurred in the germ line or embryonic cells developmentally upstream to germline specification during primate evolution. We propose that differences in L1 mobility may have

  20. 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

  1. Polymerization and nucleic acid-binding properties of human L1 ORF1 protein.

    PubMed

    Callahan, Kathryn E; Hickman, Alison B; Jones, Charles E; Ghirlando, Rodolfo; Furano, Anthony V

    2012-01-01

    The L1 (LINE 1) retrotransposable element encodes two proteins, ORF1p and ORF2p. ORF2p is the L1 replicase, but the role of ORF1p is unknown. Mouse ORF1p, a coiled-coil-mediated trimer of ∼42-kDa monomers, binds nucleic acids and has nucleic acid chaperone activity. We purified human L1 ORF1p expressed in insect cells and made two findings that significantly advance our knowledge of the protein. First, in the absence of nucleic acids, the protein polymerizes under the very conditions (0.05 M NaCl) that are optimal for high (∼1 nM)-affinity nucleic acid binding. The non-coiled-coil C-terminal half mediates formation of the polymer, an active conformer that is instantly resolved to trimers, or multimers thereof, by nucleic acid. Second, the protein has a biphasic effect on mismatched double-stranded DNA, a proxy chaperone substrate. It protects the duplex from dissociation at 37°C before eventually melting it when largely polymeric. Therefore, polymerization of ORF1p seemingly affects its interaction with nucleic acids. Additionally, polymerization of ORF1p at its translation site could explain the heretofore-inexplicable phenomenon of cis preference-the favored retrotransposition of the actively translated L1 transcript, which is essential for L1 survival. PMID:21937507

  2. 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.

  3. CCL3L1 copy number, HIV load, and immune reconstitution in sub-Saharan Africans

    PubMed Central

    2013-01-01

    Background The role of copy number variation of the CCL3L1 gene, encoding MIP1α, in contributing to the host variation in susceptibility and response to HIV infection is controversial. Here we analyse a sub-Saharan African cohort from Tanzania and Ethiopia, two countries with a high prevalence of HIV-1 and a high co-morbidity of HIV with tuberculosis. Methods We use a form of quantitative PCR called the paralogue ratio test to determine CCL3L1 gene copy number in 1134 individuals and validate our copy number typing using array comparative genomic hybridisation and fiber-FISH. Results We find no significant association of CCL3L1 gene copy number with HIV load in antiretroviral-naïve patients prior to initiation of combination highly active anti-retroviral therapy. However, we find a significant association of low CCL3L1 gene copy number with improved immune reconstitution following initiation of highly active anti-retroviral therapy (p = 0.012), replicating a previous study. Conclusions Our work supports a role for CCL3L1 copy number in immune reconstitution following antiretroviral therapy in HIV, and suggests that the MIP1α -CCR5 axis might be targeted to aid immune reconstitution. PMID:24219137

  4. Epac, not PKA catalytic subunit, is required for 3T3-L1 preadipocyte differentiation

    PubMed Central

    Ji, Zhenyu; Mei, Fang C.; Cheng, Xiaodong

    2009-01-01

    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

  5. The L(1/2) regularization approach for survival analysis in the accelerated failure time model.

    PubMed

    Chai, Hua; Liang, Yong; Liu, Xiao-Ying

    2015-09-01

    The analysis of high-dimensional and low-sample size microarray data for survival analysis of cancer patients is an important problem. It is a huge challenge to select the significantly relevant bio-marks from microarray gene expression datasets, in which the number of genes is far more than the size of samples. In this article, we develop a robust prediction approach for survival time of patient by a L(1/2) regularization estimator with the accelerated failure time (AFT) model. The L(1/2) regularization could be seen as a typical delegate of L(q)(0L(1/2) regularized AFT model by the coordinate descent algorithm with a renewed half thresholding operator. The results of the simulation experiment showed that we could obtain more accurate and sparse predictor for survival analysis by the L(1/2) regularized AFT model compared with other L1 type regularization methods. The proposed procedures are applied to five real DNA microarray datasets to efficiently predict the survival time of patient based on a set of clinical prognostic factors and gene signatures.

  6. Maturational conversion of dendritic early endosomes and their roles in L1-mediated axon growth.

    PubMed

    Lasiecka, Zofia M; Yap, Chan Choo; Katz, Joshua; Winckler, Bettina

    2014-10-29

    The function of endosomes is intricately linked to cellular function in all cell types, including neurons. Intriguingly, neurons express cell type-specific proteins that localize to endosomes, but little is known about how these neuronal proteins interface with canonical endosomes and ubiquitously expressed endosomal components, such as EEA1 (Early Endosomal Antigen 1). NEEP21 (Neuronal Early Endosomal Protein 21 kDa) localizes to somatodendritic endosomes, and downregulation of NEEP21 perturbs the correct trafficking of multiple receptors, including glutamate receptors (GluA2) during LTP and amyloidogenic processing of βAPP. Our own work implicated NEEP21 in correct trafficking of the axonal cell adhesion molecule L1/neuron-glia cell adhesion molecule (NgCAM). NEEP21 dynamically localizes with EEA1-positive early endosomes but is also found in EEA1-negative endosomes. Live imaging reveals that NEEP21-positive, EEA1-negative endosomes arise as a consequence of maturational conversion of EEA1/NEEP21 double-positive endosomes. Interfering with EEA1 function causes missorting of L1/NgCAM, axon outgrowth defects on the L1 substrate, and disturbance of NEEP21 localization. Last, we uncover evidence that functional interference with NEEP21 reduces axon and dendrite growth of primary rat hippocampal neurons on L1 substrate but not on N-cadherin substrate, thus implicating endosomal trafficking through somatodendritic early endosomes in L1-mediated axon growth. PMID:25355216

  7. 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.

  8. [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.

  9. Research and implementation of MODIS L1B data process based on grid computing

    NASA Astrophysics Data System (ADS)

    Tao, Liang; Chen, Deqing; Meng, Lingkui; Li, Jiyuan; Wang, Zhanfeng

    2008-12-01

    MODIS (Moderate Resolution Imaging Spectroradiometer, Moderate Resolution Imaging Spectroradiometer) is carrying on a major satellite remote sensing sensors of EOS series in the United States. MODIS remote sensing data is the new generation of satellite remote sensing information sources; it has broad application prospects in ecological research, environmental monitoring, global climate change and agricultural resources survey and other studies. MODIS data has featured a large volume of data and dealing with complex. In this paper Grid Computing technology brought to the processing of MODIS L1B Data is in order to improve the efficiency. First of all, this paper gives a brief introduction of MODIS L1B data and its application status, also talks about gird computing. Then the structure of MODIS L1B Data Process Based on Grid Computing (MLDPGRID) on logic is given, also explain the function of three tiers. In the realization section, receiving of MODIS L1B data, Grid Platform, software environment and network architecture, processing of MODIS L1B data and portal of MLDPGRID are all discussed. Finally, the paper gives the evaluation and conclusion of the MLDPGRID, meanwhile the optimization strategy and future work are discussed.

  10. Crystal structure of the RNA binding ribosomal protein L1 from Thermus thermophilus.

    PubMed Central

    Nikonov, S; Nevskaya, N; Eliseikina, I; Fomenkova, N; Nikulin, A; Ossina, N; Garber, M; Jonsson, B H; Briand, C; Al-Karadaghi, S; Svensson, A; Aevarsson, A; Liljas, A

    1996-01-01

    L1 has a dual function as a ribosomal protein binding rRNA and as a translational repressor binding mRNA. The crystal structure of L1 from Thermus thermophilus has been determined at 1.85 angstroms resolution. The protein is composed of two domains with the N- and C-termini in domain I. The eight N-terminal residues are very flexible, as the quality of electron density map shows. Proteolysis experiments have shown that the N-terminal tail is accessible and important for 23S rRNA binding. Most of the conserved amino acids are situated at the interface between the two domains. They probably form the specific RNA binding site of L1. Limited non-covalent contacts between the domains indicate an unstable domain interaction in the present conformation. Domain flexibility and RNA binding by induced fit seems plausible. Images PMID:8635468

  11. 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

  12. 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

  13. 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.

  14. Toward the direct deposition of L1{sub 0} FePt nanoparticles

    SciTech Connect

    Qiu Jiaoming; Judy, Jack H.; Weller, Dieter; Wang Jianping

    2005-05-15

    In this paper we report a technique that can directly fabricate L1{sub 0} phase FePt nanoparticles. FePt nanoparticles were generated through gas-phase aggregation using a magnetron-sputtering-based nanocluster source. Following the source chamber, an online halogen-lamp heater was used for the L1{sub 0} phase formation during the particles' flight in vacuum. Transmission electron microscopy and vibrating-sample magnetometer data verified the successful fabrication of the L1{sub 0} phase FePt nanoparticles. The coercivity value at 300 K is 1100 Oe for the nanoparticles with online heating. Neon carrier gas was applied to manipulate FePt nanoparticle size and to enhance particle size uniformity. The size dependence of nanoparticle ordering was investigated.

  15. Cranberries (Oxycoccus quadripetalus) inhibit adipogenesis and lipogenesis in 3T3-L1 cells.

    PubMed

    Kowalska, Katarzyna; Olejnik, Anna; Rychlik, Joanna; Grajek, Włodzimierz

    2014-04-01

    Cranberries (Oxycoccus quadripetalus) are a valuable source of bioactive substances with high antioxidant potential and well documented beneficial health properties. In the present study, the activity of cranberries, in terms of the inhibiting effects of adipogenesis, was investigated using the 3T3-L1 cell line. The obtained results showed that cranberries reduced proliferation and viability of 3T3-L1 preadipocytes in a dose-dependent manner. Treatment with cranberries decreased the number of adipocytes and reduced lipid accumulation in maturing 3T3-L1 preadipocytes, demonstrating an inhibitory effect on lipogenesis. Moreover, it was found that cranberries directly induced lipolysis in adipocytes and down-regulated the expression of major transcription factors of the adipogenesis pathway, such as PPARγ, C/EBPα and SREBP1. These findings indicate that cranberries are capable of suppressing adipogenesis and therefore they seem to be natural bioactive factors effective in adipose tissue mass modulation.

  16. Phytic acid and myo-inositol support adipocyte differentiation and improve insulin sensitivity in 3T3-L1 cells.

    PubMed

    Kim, Jin Nam; Han, Sung Nim; Kim, Hye-Kyeong

    2014-08-01

    Phytic acid, also known as myo-inositol hexaphosphate, has been shown to lower blood glucose levels and to improve insulin sensitivity in rodents. We investigated the effects of phytic acid and myo-inositol on differentiation, insulin-stimulated glucose uptake, and lipolysis of adipocytes to test the hypothesis that the antidiabetic properties of phytic acid and myo-inositol are mediated directly through adipocytes. 3T3-L1 cells were treated with 10, 50, or 200 μmol/L of phytic acid or myo-inositol. Oil Red O staining and an intracellular triacylglycerol assay were used to determine lipid accumulation during adipocyte differentiation. Immunoblotting and real-time polymerase chain reaction (PCR) were performed to evaluate expression of transcription factors, a target protein, and insulin signaling molecules. Phytic acid and myo-inositol exposures increased lipid accumulation in a dose-dependent manner (P < .01). The expression of key transcription factors associated with adipocyte differentiation, such as peroxisome proliferator-activated receptor γ (PPARγ) and sterol regulatory element-binding protein 1c, and the expression of fatty acid synthase increased upon treatments with phytic acid and myo-inositol (P < .05). Insulin-stimulated glucose uptake in mature adipocytes increased with phytic acid and myo-inositol treatments (P < .01). In addition, mRNA levels of insulin receptor substrate 1 (IRS1), mRNA levels of glucose transporter 4, and phosphorylation of tyrosine in IRS1 increased upon phytic acid and myo-inositol treatments. In fully differentiated adipocytes, phytic acid and myo-inositol reduced basal lipolysis dose dependently (P < .01). These results suggest that phytic acid and myo-inositol increase insulin sensitivity in adipocytes by increasing lipid storage capacity, improving glucose uptake, and inhibiting lipolysis.

  17. 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

  18. 26 CFR 36.3121(l)(1)-1 - Agreements entered into by domestic corporations with respect to foreign subsidiaries.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 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)...

  19. The N-terminal Domain of NPC1L1 Protein Binds Cholesterol and Plays Essential Roles in Cholesterol Uptake*

    PubMed Central

    Zhang, Jin-Hui; Ge, Liang; Qi, Wei; Zhang, Liqing; Miao, Hong-Hua; Li, Bo-Liang; Yang, Maojun; Song, Bao-Liang

    2011-01-01

    Niemann-Pick C1-like 1 (NPC1L1) is a multitransmembrane protein playing a crucial role in dietary and biliary cholesterol absorption. Cholesterol promotes the formation and endocytosis of NPC1L1-flotillin-cholesterol membrane microdomains, which is an early step in cholesterol uptake. How cholesterol is sensed in this step is unknown. Here, we find that the N-terminal domain (NTD) of NPC1L1 binds cholesterol. Mutation of residue Leu-216 in NPC1L1-NTD eliminates cholesterol binding, decreases the formation of NPC1L1-flotillin-cholesterol membrane microdomains, and prevents NPC1L1-mediated cholesterol uptake in culture cells and mice livers. NPC1L1-NTD specifically binds cholesterol but not plant sterols, which may account for the selective cholesterol absorption in intestine. Furthermore, 25- or 27-hydroxycholesterol competes with cholesterol to bind NPC1L1-NTD and inhibits the cholesterol induced endocytosis of NPC1L1. Together, these results demonstrate that plasma membrane-localized NPC1L1 binds exogenous cholesterol via its NTD, and facilitates the formation of NPC1L1-flotillin-cholesterol membrane microdomains that are then internalized into cells through the clathrin-AP2 pathway. Our study uncovers the mechanism of cholesterol sensing by NPC1L1 and proposes a mechanism for selective cholesterol absorption. PMID:21602275

  20. 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...

  1. 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...

  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... subsidiary. See § 36.3121(l)(8)-1, relating to the definition of foreign subsidiary. Except as provided...

  3. 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....

  4. The Effects of Giving and Receiving Marginal L1 Glosses on L2 Vocabulary Learning by Upper Secondary Learners

    ERIC Educational Resources Information Center

    Samian, Hosein Vafadar; Foo, Thomas Chow Voon; Mohebbi, Hassan

    2016-01-01

    This paper reports the findings of a study that investigated the effect of giving and receiving marginal L1 glosses on L2 vocabulary learning. To that end, forty nine Iranian learners of English were assigned to three different experimental conditions including marginal L1 glosses Giver (n = 17), marginal L1 glosses Receiver (n = 17), and no…

  5. 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....

  6. 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....

  7. 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...

  8. 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....

  9. 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....

  10. 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...

  11. 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...

  12. 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....

  13. 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....

  14. 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...

  15. 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...

  16. 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...

  17. 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...

  18. 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....

  19. 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…

  20. 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.

  1. 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

  2. Who's in control? Proficiency and L1 influence on L2 processing.

    PubMed

    Elston-Güttler, Kerrie E; Paulmann, Silke; Kotz, Sonja A

    2005-10-01

    We report three reaction time (RT)/event-related brain potential (ERP) semantic priming lexical decision experiments that explore the following in relation to L1 activation during L2 processing: (1) the role of L2 proficiency, (2) the role of sentence context, and (3) the locus of L1 activations (orthographic vs. semantic). All experiments used German (L1) homonyms translated into English (L2) to form prime-target pairs (pine-jaw for Kiefer) to test whether the L1 caused interference in an all-L2 experiment. Both RTs and ERPs were measured on targets. Experiment 1 revealed reversed priming in the N200 component and RTs for low-proficiency learners, but only RT interference for high-proficiency participants. Experiment 2 showed that once the words were processed in sentence context, the low-proficiency participants still showed reversed N200 and RT priming, whereas the high-proficiency group showed no effects. Experiment 3 tested native English speakers with the words in sentence context and showed a null result comparable to the high-proficiency group. Based on these results, we argue that cognitive control relating to translational activation is modulated by (1) L2 proficiency, as the early interference in the N200 was observed only for low-proficiency learners, and (2) sentence context, as it helps high-proficiency learners control L1 activation. As reversed priming was observed in the N200 and not the N400 component, we argue that (3) the locus of the L1 activations was orthographic. Implications in terms of bilingual word recognition and the functional role of the N200 ERP component are discussed.

  3. Cloning and sequencing of the L1 gene of canine oral papillomavirus.

    PubMed

    Isegawa, N; Nakano, K; Ohta, M; Shirasawa, H; Tokita, H; Simizu, B

    1994-09-01

    Canine oral papillomavirus (COPV) DNA was isolated from two different sources. One of these DNAs was molecularly cloned and its physical map was determined. Hybridization analyses using subgenomic fragments of bovine papillomavirus type 1 (BPV-1) and human papillomavirus type 16 (HPV16) as probes revealed that the cloned COPV shared moderate homology within the E1 and L1 regions of BPV-1 and HPV16, whereas homology in other regions of BPV-1 and HPV16 was low. The putative L1 gene of COPV was sequenced and several conserved regions, including antigenic epitopes which are common in other known papillomaviruses, were analyzed. PMID:8076829

  4. Observation of an unstable l =1 diocotron mode on a hollow electron column

    SciTech Connect

    Driscoll, C.F. )

    1990-02-05

    Stable and unstable diocotron modes varying as {ital e}{sup {ital il}{theta}}, with {ital l}=1, are measured on a magnetized, partially hollow electron column. The unstable mode is observed to grow exponentially over several decades, in contradiction to present 2 D fluid theory. This {ital l}=1 instability can dominate the evolution well into the nonlinear regime, resulting in cross-field transport to a stable, monotonically decreasing density profile. To the extent this process is described by 2D {bold E}{times}{bold B} drifts, it is isomorphic to the Kelvin-Helmholtz shear-flow instability of inviscid fluids.

  5. A compressed primal-dual method for generating bivariate cubic L1 splines

    NASA Astrophysics Data System (ADS)

    Wang, Yong; Fang, Shu-Cherng; Lavery, John E.

    2007-04-01

    In this paper, we develop a compressed version of the primal-dual interior point method for generating bivariate cubic L1 splines. Discretization of the underlying optimization model, which is a nonsmooth convex programming problem, leads to an overdetermined linear system that can be handled by interior point methods. Taking advantage of the special matrix structure of the cubic L1 spline problem, we design a compressed primal-dual interior point algorithm. Computational experiments indicate that this compressed primal-dual method is robust and is much faster than the ordinary (uncompressed) primal-dual interior point algorithm.

  6. 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.

  7. 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.

  8. 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.

  9. 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

  10. 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

  11. Crystal structure of a mutant of archaeal ribosomal protein L1 from Methanococcus jannaschii

    NASA Astrophysics Data System (ADS)

    Sarskikh, A. V.; Gabdulkhakov, A. G.; Kostareva, O. S.; Shklyaeva, A. A.; Tishchenko, S. V.

    2014-05-01

    The crystal structure of a mutant of archaeal ribosomal protein L1 from Methanococcus jannaschii with the deletion of a nonconserved positively charged cluster consisting of eight C-terminal amino acid residues is determined by the molecular replacement method at 1.75 Å resolution. This mutant is shown to form more stable and ordered crystals belonging to a space group other than that of the wild-type protein crystals. The positively charged C-terminal region has only a slight effect on the interaction between protein L1 and RNA molecules. Hence, this mutant can be used to prepare protein-RNA complexes and obtain their crystals.

  12. 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.

  13. 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).

  14. Moléculas orgánicas no-rígidas

    NASA Astrophysics Data System (ADS)

    Senent Díez, M. L.

    Se destaca la importancia del estudio espectroscópico ab initio de una serie de moléculas no-rígidas detectadas en el medio interestelar (acetona, dimetil-eter, etanol, metanol, metilamina, ldots), así como los últimos avances del desarrollo de la metodología para el tratamiento teórico de estas especies. Se describe, a modo de ejemplo, el análisis del espectro roto-torsional de la molécula de glicoaldehido que ha sido recientemente detectada en el centro Galáctico Sagitario B2 (N) [1]. Esta especie presenta dos movimientos de gran amplitud que interaccionan, descansan en el Infrarrojo Lejano y le confiere propiedades no-rígidas. La molécula puede existir en posiciones cis y trans y presenta cinco confórmeros estables, tres de simetría Cs (I, II y IV) y un doble mínimo trans de simetría C1 (III) . La conformación favorita, I, presenta simetría Cs y se estabiliza por la formación de un puente de hidrógeno entre los grupos OH y C=O. Los mínimos secundarios II, III, y IV se han determinado a 1278.2 cm-1 (trans, Cs), 1298.8 cm-1 (trans, C1) y 1865.2 cm-1 (cis, Cs) con cálculos MP4/cc-pVQZ que incluyen sustituciones triples. Para determinar que vibraciones interaccionan con las torsiones, se ha realizado un análisis armónico en los mínimos. Las frecuencias fundamentales armónicas correspondientes al mínimo I se han calculado en 213.4 cm-1 (torsión C-C) y 425.7 cm-1 (torsión OH). Es de esperar que tan sólo dos vibraciones, la flexión del grupo C-C-O y el aleteo del hidrógeno del grupo aldehídico puedan desplazar el espectro torsional de la molécula aislada. Para determinar el espectro torsional, se ha determinado la superficie de potencial en dos dimensiones mediante el cálculo ab initio de las geometrías y energías de 74 conformaciones seleccionadas. Estas últimas se han ajustado a un doble serie de Fourier. A partir de la PES y de los parámetros cinéticos del Hamiltoniano vibracional se han obtenido frecuencias e intensidades

  15. W4 theory for computational thermochemistry : in pursuit of confident sub-kJ/mol predictions.

    SciTech Connect

    Karton, A.; Rabinovich, E.; Martin, J. M. L.; Ruscic, B.; Chemistry; Weizmann Institute of Science

    2006-01-01

    In an attempt to improve on our earlier W3 theory [A. D. Boese et al., J. Chem. Phys. 120, 4129 (2004)] we consider such refinements as more accurate estimates for the contribution of connected quadruple excitations ({cflx T}{sub 4}), inclusion of connected quintuple excitations ({cflx T}{sub 5}), diagonal Born-Oppenheimer corrections (DBOC), and improved basis set extrapolation procedures. Revised experimental data for validation purposes were obtained from the latest version of the Active Thermochemical Tables thermochemical network. The recent CCSDT(Q) method offers a cost-effective way of estimating {cflx T}{sub 4} but is insufficient by itself if the molecule exhibits some nondynamical correlation. The latter considerably slows down basis set convergence for {cflx T}{sub 4}, and anomalous basis set convergence in highly polar systems makes two-point extrapolation procedures unusable. However, we found that the CCSDTQ-CCSDT(Q) difference converges quite rapidly with the basis set, and that the formula 1.10[CCSDT(Q)/cc-pVTZ+CCSDTQ/cc-pVDZ-CCSDT(Q)/cc-pVDZ] offers a very reliable as well as fairly cost-effective estimate of the basis set limit {cflx T}{sub 4} contribution. The {cflx T}{sub 5} contribution converges very rapidly with the basis set, and even a simple double-zeta basis set appears to be adequate. The largest {cflx T}{sub 5} contribution found in the present work is on the order of 0.5 kcal/mol (for ozone). DBOCs are significant at the 0.1 kcal/mol level in hydride systems. Post-CCSD(T) contributions to the core-valence correlation energy are only significant at that level in systems with severe nondynamical correlation effects. Based on the accumulated experience, a new computational thermochemistry protocol for first- and second-row main-group systems, to be known as W4 theory, is proposed. Its computational cost is not insurmountably higher than that of the earlier W3 theory, while performance is markedly superior. Our W4 atomization energies for

  16. 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.

  17. Rotation moléculaire en temps réel dans l'eau liquide

    NASA Astrophysics Data System (ADS)

    Amir, W.; Lascoux, N.; Gallot, G.; Gale, G.; Pommeret, S.; Leicknam, J.-Ci.; Bratos, S.

    2002-06-01

    La connaissance déjà acquise sur la dynamique de la liaison hydrogène dans l'eau liquide grâce au développement de laser délivrant des impulsions ultra-courtes dans l'infrarouge moyen nous permet de filmer la rotation de molécules HDO dans une solution D2O. L'expérience réalisée au laboratoire est basée sur la technique de spectroscopie pompe sonde résolue en polarisation. L'anisotropie mesurée permet de détecter en temps réel l'angle de déflexion du moment dipolaire de transition dont le point de départ est la direction du faisceau laser de pompe.

  18. Calixarene-based mol­ecular capsule from olefin metathesis

    PubMed Central

    Hailu, Shimelis T.; Butcher, Ray J.; Hudrlik, Paul F.; Hudrlik, Anne M.

    2013-01-01

    The reaction of tetra­kis­(all­yloxy)calix[4]arene with the first-generation Grubbs catalyst, followed by catalytic hydrogenation, gave the novel bis-calixarene 15,20,46,51,64,69,74,79-octa­oxatridecacyclo[32.28.8.83,28.113,53.122,44.09,14.021,26.038,70.040,45.052,57.059,63.07,80.032,73]octa­conta-1(63),3,5,7(80),9(14),10,12,21,23,25,28(73),29,31,34,36,38(70),40,42,44,52,54,56,59,61-tetra­cosa­ene benzene monosolvate, C72H72O8·C6H6. The structure consists of two calix[4]arene units connected by four-carbon chains at each of the four O atoms on their narrow rims, to form a cage. Each of the calix[4]arene units has a flattened cone conformation in which two of the opposite aryl groups are closer together and nearly parallel [dihedral angle between planes = 7.35 (16)°], and the other two aryl groups are splayed outward [dihedral angle between planes = 72.20 (8)°]. While the cavity contains no solvent or other guest mol­ecule, there is benzene solvent mol­ecule in the lattice. Two of the alkyl linking arms were disordered over two conformations with occupancies of 0.582 (3)/0.418 (3) and 0.33 (4)/0.467 (4). They were constrained to have similar metrical and thermal parameters. PMID:24046590

  19. 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.

  20. Antibody therapy to human L1CAM in a transgenic mouse model blocks local tumor growth but induces EMT.

    PubMed

    Doberstein, Kai; Harter, Patrick N; Haberkorn, Uwe; Bretz, Niko P; Arnold, Bernd; Carretero, Rafael; Moldenhauer, Gerhard; Mittelbronn, Michel; Altevogt, Peter

    2015-03-01

    L1 cell adhesion molecule (L1CAM) is overexpressed in many human cancers, confers bad prognosis and augments cell motility, invasion and metastasis. Results from xenograft mouse models suggested that L1CAM antibodies might be promising tools for cancer therapy. Here, we generated human L1CAM-transgenic mice to study therapeutic efficacy and putative side effects in a model system. We established three transgenic lines (M2, M3 and F4) expressing the human L1CAM transgene in brain, kidney and colon with decreasing intensity (M2, M3 > F4). The expression pattern was similar to that of L1CAM in humans. No interference of the transgene with the expression of endogenous L1CAM was observed. Immunohistochemical analysis revealed correct expression of the transgene in mouse cortex and collective duct of the kidney. Injection of (125)I-labeled L1CAM antibodies resulted in specific enrichment in the kidney but not in the brain. The injection of the therapeutic anti-human L1CAM mAb L1-9.3/2a into transgenic mice even at high doses did not cause behavioral changes or other side effects. Similar results were obtained using a mouse specific L1CAM mAb in normal mice. Tumor therapy experiments were performed using syngeneic mouse tumor cells (RET melanoma and Panc02 pancreatic adenocarcinoma) transduced with human L1CAM. MAb L1-9.3/2a efficiently and specifically attenuated local tumor growth in both model systems without apparent side effects. The therapeutic effect was dependent on immune effector mechanisms. Analysis of Panc02-huL1CAM tumors after therapy showed elevated levels of EGF and evidence of immune-induced epithelial-mesenchymal transition. The results suggest that our transgenic mice are valuable tools to study L1CAM-based antibody therapy. PMID:25230579

  1. 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.

  2. 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

  3. 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

  4. Characterization of HPV16 L1 loop domains in the formation of a type-specific, conformational epitope

    PubMed Central

    Olcese, Vanessa A; Chen, Yan; Schlegel, Richard; Yuan, Hang

    2004-01-01

    Background Virus-like particles (VLPs) formed by the human papillomavirus (HPV) L1 capsid protein are currently being tested in clinical trials as prophylactic vaccines against genital warts and cervical cancer. The efficacy of these vaccines is critically dependent upon L1 type-specific conformational epitopes. To investigate the molecular determinants of the HPV16 L1 conformational epitope recognized by monoclonal antibody 16A, we utilized a domain-swapping approach to generate a series of L1 proteins composed of a canine oral papillomavirus (COPV) L1 backbone containing different regions of HPV16 L1. Results Gross domain swaps, which did not alter the ability of L1 to assemble into VLPs, demonstrated that the L1 N-terminus encodes at least a component of the 16A antigenic determinant. Finer epitope mapping, using GST-L1 fusion proteins, mapped the 16A epitope to the L1 variable regions I and possibly II within the N-terminus. Conclusions These results suggest that non-contiguous loop regions of L1 display critical components of a type-specific, conformational epitope. PMID:15260888

  5. TOLUENE DISRUPTION OF THE FUNCTIONS OF L1 CELL ADHESION MOLECULE AT CONCENTRATIONS ASSOCIATED WITH OCCUPATIONAL EXPOSURES

    PubMed Central

    White, Kimberly M.R.; Sabatino, Julia A.; He, Min; Davis, Natalie; Tang, Ningfeng; Bearer, Cynthia F

    2016-01-01

    Background Prenatal toluene exposure can cause neurodevelopmental disabilities similar to fetal alcohol syndrome. Both share neuroanatomic pathologies similar to children with mutations in L1 cell adhesion molecule (L1). L1 mediates neurite outgrowth (NOG) via signaling through ERK1/2 which require trafficking of L1 through lipid rafts. Our objective is to determine if (1) toluene inhibits L1-mediated NOG and (2) toluene inhibits L1 signaling at concentrations achieved during occupational exposure. Methods Concentrations of toluene reflective of blood concentrations achieved in solvent abusers and occupational settings are used. Cerebellar granule neurons (CGN) harvested from postnatal day 6 rat pups are plated on coverslips coated with poly-L-lysine (PLL) alone or PLL followed by laminin. L1 is added to the media of CGN plated on PLL alone. Toluene is added 2 hours after plating. Cells are fixed at 24 h and neurite length is measured. ERK1/2 activation by L1 in CGN is analyzed by immunoblot. Results Toluene significantly reduced mean neurite length of CGN exposed to L1 but not laminin. Toluene significantly reduced L1-mediated ERK1/2 phosphorylation. Conclusion Results suggest that toluene inhibits L1-lipid raft interactions at occupationally relevant concentrations and may lead to a fetal solvent spectrum disorder similar to fetal alcohol spectrum disorder. PMID:27027721

  6. 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

  7. 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

  8. Adenovirus L1 52- and 55-kilodalton proteins are required for assembly of virions.

    PubMed Central

    Hasson, T B; Soloway, P D; Ornelles, D A; Doerfler, W; Shenk, T

    1989-01-01

    A variant of adenovirus type 5 that contained a mutation within the L1 52- and 55-kilodalton (52/55K) protein-coding region was isolated. The mutant, termed ts369, produced L1 52/55K proteins with a two-amino-acid substitution and was temperature sensitive. Temperature-shift experiments indicated that the ts369 defect was late in the viral growth cycle. DNA replication and synthesis of late proteins occurred normally in ts369-infected cells at the nonpermissive temperature, but mature virions were not produced. Rather, capsidlike particles associated with the left-terminal region of the viral chromosome accumulated. These incomplete particles could not be chased into mature virions when the infected cells were shifted to the permissive temperature. However, previously synthesized proteins could be assembled into virions in the presence of a protein synthesis inhibitor upon shiftdown from the nonpermissive temperature, suggesting that the inactivation of the L1 52/55K proteins was reversible. These results indicate that the adenovirus L1 52/55K proteins play a role in the assembly of infectious virus particles. Images PMID:2760976

  9. Cdk5 disruption attenuates tumor PD-L1 expression and promotes antitumor immunity

    PubMed Central

    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.

    2016-01-01

    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. Computational Assessment of Lexical Differences in L1 and L2 Writing

    ERIC Educational Resources Information Center

    Crossley, Scott A.; McNamara, Danielle S.

    2009-01-01

    The purpose of this paper is to provide a detailed analysis of how lexical differences related to cohesion and connectionist models can distinguish first language (L1) writers of English from second language (L2) writers of English. Key to this analysis is the use of the computational tool Coh-Metrix, which measures cohesion and text difficulty at…

  11. 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

  12. 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…

  13. 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.

  14. 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:…

  15. 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…

  16. Resistin regulates the expression of plasminogen activator inhibitor-1 in 3T3-L1 adipocytes.

    PubMed

    Ikeda, Yoshito; Tsuchiya, Hiroyuki; Hama, Susumu; Kajimoto, Kazuaki; Kogure, Kentaro

    2014-05-30

    Resistin and plasminogen activator inhibitor-1 (PAI-1) are adipokines, which are secreted from adipocytes. Increased plasma resistin and PAI-1 levels aggravate metabolic syndrome through exacerbation of insulin resistance and induction of chronic inflammation. However, the relationship between resistin and PAI-1 gene expression remains unclear. Previously, we found that resistin regulates lipid metabolism via carbohydrate responsive element-binding protein (ChREBP) during adipocyte maturation (Ikeda et al., 2013) [6]. In this study, to clarify the relationship between expression of resistin and PAI-1, PAI-1 expression in differentiated 3T3-L1 adipocytes was measured after transfection with anti-resistin siRNA. We found that PAI-1 gene expression and secreted PAI-1 protein were significantly decreased by resistin knockdown. Furthermore, phosphorylation of Akt, which can inhibit PAI-1 expression, was accelerated and the activity of protein phosphatase 2A (PP2A) was suppressed in resistin knockdown 3T3-L1 adipocytes. In addition, the expression of glucose transporter type 4, a ChREBP target gene, was reduced and was associated with inhibition of PP2A. The addition of culture medium collected from COS7 cells transfected with a resistin expression plasmid rescued the suppression of PAI-1 expression in resistin knockdown 3T3-L1 adipocytes. Our findings suggest that resistin regulates PAI-1 expression in 3T3-L1 adipocytes via Akt phosphorylation.

  17. 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.

  18. The Effect of L1 Orthography on Non-Native Vowel Perception

    ERIC Educational Resources Information Center

    Escudero, Paola; Wanrooij, Karin

    2010-01-01

    Previous research has shown that orthography influences the learning and processing of spoken non-native words. In this paper, we examine the effect of L1 orthography on non-native sound perception. In Experiment 1, 204 Spanish learners of Dutch and a control group of 20 native speakers of Dutch were asked to classify Dutch vowel tokens by…

  19. Using L1 to Enhance the Grammar Learning and Having Only English Policy in EFL Classes

    ERIC Educational Resources Information Center

    Uyar, Yusuf

    2012-01-01

    The purpose of this study is to determine the differences of grammar learning, if any, between the EFL classes in which native language (L1) is sometimes used and only target language (L2) is used. Participants were 42 prep year students from one of the universities in Turkey. They have been studying English for 9 months, and now they are in level…

  20. 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 ...

  1. Translation, L1 Writing, and L2 Writing of Japanese ESL Learners.

    ERIC Educational Resources Information Center

    Uzawa, Kozue

    1994-01-01

    In this Canadian college study, 22 Japanese, English-as-a-Second-Language (ESL) learners' translation processes and writings were examined and contrasted with the same group's first-language (L1) and second-language (L2) writing performance. All subjects (aged 19-23 years) had been educated in Japan in Japanese prior to attending English-language…

  2. The Development of Morphological Awareness in Young Bilinguals: Effects of Age and L1 Background

    ERIC Educational Resources Information Center

    Lam, Boji Pak-Wing; Sheng, Li

    2016-01-01

    Purpose: Current understanding about the effect of first language (L1) background on morphological awareness (MA) development in those who are bilingual is largely limited to school-aged second-language learners. This study examined the development of MA in bilingual Mandarin-English (ManEngBi) and Spanish-English (SpaEngBi) children ages 4 to 7…

  3. 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

  4. L1 Influence on the Acquisition Order of English Grammatical Morphemes

    ERIC Educational Resources Information Center

    Murakami, Akira; Alexopoulou, Theodora

    2016-01-01

    We revisit morpheme studies to evaluate the long-standing claim for a universal order of acquisition. We investigate the L2 acquisition order of six English grammatical morphemes by learners from seven L1 groups across five proficiency levels. Data are drawn from approximately 10,000 written exam scripts from the Cambridge Learner Corpus. The…

  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. Selectivity in L1 Attrition: Differential Object Marking in Spanish Near-Native Speakers of English

    ERIC Educational Resources Information Center

    Chamorro, Gloria; Sturt, Patrick; Sorace, Antonella

    2016-01-01

    Previous research has shown L1 attrition to be restricted to structures at the interfaces between syntax and pragmatics, but not to occur with syntactic properties that do not involve such interfaces ("Interface Hypothesis", Sorace and Filiaci in "Anaphora resolution in near-native speakers of Italian." "Second Lang…

  7. 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…

  8. 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…

  9. 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

  10. 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

  11. 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

  12. 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,…

  13. 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

  14. Loanwords and Vocabulary Size Test Scores: A Case of Different Estimates for Different L1 Learners

    ERIC Educational Resources Information Center

    Laufer, Batia; McLean, Stuart

    2016-01-01

    The article investigated how the inclusion of loanwords in vocabulary size tests affected the test scores of two L1 groups of EFL learners: Hebrew and Japanese. New BNC- and COCA-based vocabulary size tests were constructed in three modalities: word form recall, word form recognition, and word meaning recall. Depending on the test modality, the…

  15. The Use of Paraphrase in Summary Writing: A Comparison of L1 and L2 Writers

    ERIC Educational Resources Information Center

    Keck, Casey

    2006-01-01

    Paraphrasing is considered by many to be an important skill for academic writing, and some have argued that the teaching of paraphrasing might help students avoid copying from source texts. Few studies, however, have investigated the ways in which both L1 and L2 academic writers already use paraphrasing as a textual borrowing strategy when…

  16. 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.

  17. CATS-ISS_L1B_N-M7.1-V2-07

    Atmospheric Science Data Center

    2016-10-24

    CATS-ISS_L1B_N-M7.1-V2-07 The Cloud-Aerosol Transport System (CATS) is a three wavelength, polarization-sensitive ... Injection Heights Cloud Vertical Extent Aerosol Vertical Extent Volume Depolarization Ratio Profiles Attenuated ...

  18. CATS-ISS_L1B_D-M7.1-V2-07

    Atmospheric Science Data Center

    2016-10-25

    CATS-ISS_L1B_D-M7.1-V2-07 The Cloud-Aerosol Transport System (CATS) is a three wavelength, polarization-sensitive ... Injection Heights Cloud Vertical Extent Aerosol Vertical Extent Volume Depolarization Ratio Profiles Attenuated ...

  19. 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.

  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. 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. 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…

  3. Raspberry ketone increases both lipolysis and fatty acid oxidation in 3T3-L1 adipocytes.

    PubMed

    Park, Kyoung Sik

    2010-10-01

    Raspberry ketone (RK) is a natural phenolic compound of the red raspberry. The dietary administration of RK to male mice has been reported to prevent high-fat diet-induced elevation in body weight and to increase lipolysis in white adipocytes. To elucidate a possible mechanism for the antiobesity action of RK, its effects on the expression and the secretion of adiponectin, lipolysis, and fatty acid oxidation in 3T3-L1 were investigated. Treatment with 10 µM of RK increased lipolysis significantly in differentiated 3T3-L1 cells. An immunoassay showed that RK increased both the expression and the secretion of adiponectin, an adipocytokine mainly expressed and secreted by adipose tissue. In addition, treatment with 10 µM of RK increased the fatty acid oxidation and suppressed lipid accumulation in 3T3-L1 adipocytes. These findings suggest that RK holds great promise as an herbal medicine since its biological activities alter the lipid metabolism in 3T3-L1 adipocytes.

  4. Inhibitory effects of Fucoidan in 3T3-L1 adipocyte differentiation.

    PubMed

    Kim, Mi-Ja; Chang, Un-Jae; Lee, Jin-Sil

    2009-01-01

    Fucoidan is a group of sulfated fucose-containing polysaccharides that derived from non-mammalian origin such as marine brown algae, the jelly coat from sea urchin eggs, and the sea cucumber body wall. However, potential biological activities against obesity from fucoidan were not reported in the literature. The objective of this study was to evaluate protective effect of fucoidan in 3T3-L1 adipocyte differentiation. Preadipocyte 3T3-L1 was treated with 100 and 200 microg/ml fucoidan during adipogenesis. Adipogenesis was determined through Oil Red O staining method and the expression of adipogenic genes aP2, ACC, and PPARgamma. Adipogenesis of 3T3-L1 treated with 100 and 200 microg/ml fucoidan were significantly inhibited at 32.8% and 39.7% using Oil Red O staining method, respectively (P < 0.05). Treating the 3T3-L1 cells with 100 and 200 microg/ml fucoidan significantly decreased the expression of aP2 gene by 6.2% and 27.2%, respectively, of ACC gene by 22.2% and 38.2%, respectively, and of PPARgamma gene by 44.2% and 69.4%, respectively, compared to adipocyte controls (P < 0.05). The results suggest that fucoidan could be used for inhibiting fat accumulation, which is mediated by decreasing aP2, ACC, and PPARgamma gene expression.

  5. CATS-ISS_L1B_N-M7.2-V2-07

    Atmospheric Science Data Center

    2016-10-24

    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:  ...

  6. CATS-ISS_L1B_D-M7.2-V2-07

    Atmospheric Science Data Center

    2016-10-24

    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:  ...

  7. 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

  8. CTLA-4 and PD-L1 checkpoint blockade enhances oncolytic measles virus therapy.

    PubMed

    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

    2014-11-01

    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

  9. Advanced Learners' L1 (Swedish) versus L2 (English) Inferencing

    ERIC Educational Resources Information Center

    Karlsson, Monica

    2014-01-01

    Research shows that the most important skill to possess when learning a previously unknown word is to be able to interpret its meaning based on the context in which it is found (Nation, 2001). This is especially true for L1 learners, but regrettably, research shows, not as true for students learning a second language (Nation, 2001). The aim of the…

  10. 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

    2016-01-08

    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.

  11. 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

  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. 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.

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

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 15 2013-04-01 2013-04-01 false Determination and disclosure of marital status... TREASURY (CONTINUED) EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE Collection of Income Tax at Source § 31.3402(l)-1 Determination...

  15. 26 CFR 31.3402(l)-1 - Determination and disclosure of marital status.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 15 2011-04-01 2011-04-01 false Determination and disclosure of marital status... TREASURY (CONTINUED) EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE Collection of Income Tax at Source § 31.3402(l)-1 Determination...

  16. 26 CFR 31.3402(l)-1 - Determination and disclosure of marital status.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 15 2012-04-01 2012-04-01 false Determination and disclosure of marital status... TREASURY (CONTINUED) EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE Collection of Income Tax at Source § 31.3402(l)-1 Determination...

  17. 26 CFR 31.3402(l)-1 - Determination and disclosure of marital status.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 15 2014-04-01 2014-04-01 false Determination and disclosure of marital status... TREASURY (CONTINUED) EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE Collection of Income Tax at Source § 31.3402(l)-1 Determination...

  18. Mobility pathways for vertebrate L1, L2, CR1, and RTE clade retrotransposons.

    PubMed

    Ichiyanagi, Kenji; Okada, Norihiro

    2008-06-01

    Autonomous non-long terminal repeat retrotransposons (NLRs) are ubiquitous mobile genetic elements that insert their DNA copies at new locations by retrotransposition. In vertebrates, there are 4 NLR clades, L1, L2, CR1, and RTE, which diverged in the Precambrian era. It has been demonstrated that retrotransposition of L1 and L2 members proceeds via coordinated reactions of targeted DNA cleavage and reverse transcription catalyzed by the NLR-encoded proteins, which are followed by the joining of the 5' (upstream) junction. However, the study on the mobility pathways for vertebrate NLRs is so far limited to L1 and L2. In this report, using target analysis of nested transposons for genomic copies, we studied retrotransposition pathways for a variety of vertebrate NLRs, including those of the L1, L2, CR1, and RTE clades in the human, cow, opossum, chicken, and zebrafish genomes. Thus, this study constitutes the first comprehensive analysis of NLR retrotransposition products in vertebrates. Our data revealed that these elements share similar mechanisms for the cleavages of the 2 target DNA strands and for the initiation of reverse transcription. Possible endonuclease-independent insertions were also identified. Overall, our results suggest the existence of multiple retrotransposition pathways that are conserved among the diverse NLR clades in various vertebrate hosts. PMID:18343891

  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. 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'…

  2. 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

  3. 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…

  4. 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…

  5. 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…

  6. 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 &…

  7. 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

  8. 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

  9. 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.

  10. 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…

  11. 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…

  12. 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:  ...

  13. 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.

  14. Identification of dynamical hinge points of the L1 ligase molecular switch.

    PubMed

    Giambasu, George M; Lee, Tai-Sung; Sosa, Carlos P; Robertson, Michael P; Scott, William G; York, Darrin M

    2010-04-01

    The L1 ligase is an in vitro selected ribozyme that uses a noncanonically base-paired ligation site to catalyze regioselectively and regiospecifically the 5' to 3' phosphodiester bond ligation, a reaction relevant to origin of life hypotheses that invoke an RNA world scenario. The L1 ligase crystal structure revealed two different conformational states that were proposed to represent the active and inactive forms. It remains an open question as to what degree these two conformers persist as stable conformational intermediates in solution, and along what pathway are they able to interconvert. To explore these questions, we have performed a series of molecular dynamics simulations in explicit solvent of the inactive-active conformational switch in L1 ligase. Four simulations were performed departing from both conformers in both the reactant and product states, in addition to a simulation where local unfolding in the active state was induced. From these simulations, along with crystallographic data, a set of four virtual torsion angles that span two evolutionarily conserved and restricted regions were identified as dynamical hinge points in the conformational switch transition. The ligation site visits three distinct states characterized by hydrogen bond patterns that are correlated with the formation of specific contacts that may promote catalysis. The insights gained from these simulations contribute to a more detailed understanding of the coupled catalytic/conformational switch mechanism of L1 ligase that may facilitate the design and engineering of new catalytic riboswitches.

  15. 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.

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

    PubMed

    Tubio, Jose M C; Li, Yilong; Ju, Young Seok; 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; van't Veer, Laura; 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

    2014-08-01

    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.

  17. L1 cell adhesion molecule induces melanoma cell motility by activation of mitogen-activated protein kinase pathways.

    PubMed

    Yi, Young-Su; Baek, Kwang-Soo; Cho, Jae Youl

    2014-06-01

    L1 cell adhesion molecule (L1CAM) is highly expressed in various types of cancer cells and has been implicated in the control of cell proliferation and motility. Recently, L1CAM was reported to induce the motility of melanoma cells, but the mechanism of this induction remains poorly understood. In this study, we investigated the molecular mechanisms by which L1CAM induces the motility of melanoma cells. Unlike other types of cancer cells, B16F10 melanoma cells highly expressed L1CAM at both the RNA and protein levels, and the expression of L1CAM induced AP-1 activity. In accordance to AP-1 activation, MAPK signaling pathways were activated by L1CAM. Inhibition of L1CAM expression by L1CAM-specific siRNA suppressed the activation of MAPKs such as ERK and p38. However, no significant change was observed in JNK activation. As expected, upstream MAP2K, MKK3/6, MAP3K, and TAK1 were also deactivated by the inhibition of L1CAM expression. L1CAM induced the motility of B16F10 cells. Inhibition of L1CAM expression suppressed migration and invasion of B16F10 cells, but no suppressive effect was observed on their proliferation and anti-apoptotic resistance. Treatment of B16F10 cells with U0126, an ERK inhibitor, or SB203580, a p38 inhibitor, suppressed the migration and invasion abilities of B16F10 cells. Taken together, our results suggest that L1CAM induces the motility of B16F10 melanoma cells via the activation of MAPK pathways. This finding provides a more detailed molecular mechanism of L1CAM-mediated induction of melanoma cell motility. PMID:24974583

  18. 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

  19. 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

  20. Effects of leukemia inhibitory factor on 3T3-L1 adipocytes.

    PubMed

    Hogan, Jessica C; Stephens, Jacqueline M

    2005-06-01

    Leukemia inhibitory factor (LIF) is a member of the gp130 cytokine family and signals through the receptor complex of gp130 and the LIF receptor (LIFR) to activate the JAK/STAT signaling cascade. Since LIF activates STATs 1 and 3 in adipocytes, we examined the effects of LIF on 3T3-L1 adipocytes. Our studies clearly demonstrate that LIF treatment had minimal effects on adipocyte differentiation as judged by marker gene expression, but did inhibit triacylglyceride (TAG) accumulation during adipogenesis. Acute treatment with LIF resulted in increased expression of suppressors of cytokine signaling-3 (SOCS3) and CCAAT/enhancer-binding protein-delta (C/EBPdelta) mRNA in 3T3-L1 adipocytes. Moreover, the upregulation of C/EBPdelta correlated with binding to three sites in the C/EBPdelta promoter by LIF-activated protein complexes that contained STAT1 and not STAT3. Chronic treatment with LIF resulted in decreased protein levels of sterol regulatory element binding protein-1 (SREBP1) and fatty acid synthase (FAS), but had no effect on the expression of other adipocyte marker proteins or on TAG levels in mature 3T3-L1 adipocytes. LIF had a small effect on insulin-stimulated glucose uptake in 3T3-L1 adipocytes, but did not cause insulin resistance following chronic treatment. These findings indicate that LIF has similar and distinct effects in comparison with the effects of other gp130 cytokines on cultured fat cells. In summary, our results support a role for LIF in the regulation of proteins involved in lipid synthesis and in the modulation of signal transduction pathways in 3T3-L1 adipocytes.

  1. 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

  2. Role of miR-34a as a suppressor of L1CAM in endometrial carcinoma.

    PubMed

    Schirmer, Uwe; Doberstein, Kai; Rupp, Anne-Kathleen; Bretz, Niko P; Wuttig, Daniela; Kiefel, Helena; Breunig, Christian; Fiegl, Heidi; Müller-Holzner, Elisabeth; Zeillinger, Robert; Schuster, Eva; Zeimet, Alain G; Sültmann, Holger; Altevogt, Peter

    2014-01-30

    L1CAM promotes cell motility, invasion and metastasis formation in various human cancers and can be considered as a driver of tumor progression. Knowledge about genetic processes leading to the presence of L1CAM in cancers is of considerable importance. Experimentally, L1CAM expression can be achieved by various means. Over-expression of the transcription factor SLUG or treatment of cells with TGF-β1 can induce or augment L1CAM levels in cancer cells. Likewise, hypomethylation of the L1CAM promoter on the X chromosome correlates with L1CAM expression. However, presently no mechanisms that might control transcriptional activity are known. Here we have identified miR-34a as a suppressor of L1CAM. We observed that L1CAM positive endometrial carcinoma (EC) cell lines HEC1B and SPAC1L lost L1CAM protein and mRNA by treatment with demethylating agents or knock-down of the DNA-methyltransferase-1 (DNMT1). Concomitantly, several miRNAs were up-regulated. Using miRNA profiling, luciferase reporter assays and mutagenesis, we identified miR-34a as a putative binder to the L1CAM-3'UTR. Over-expression of miR-34a in HEC1B cells blocked L1CAM expression and inhibited cell migration. In ECC1 cells (wildtype p53) the activation of p53 caused miR-34a up-regulation and loss of L1CAM expression that was miR-34a dependent. We observed an inverse correlation between L1CAM and miR-34a levels in EC cell lines. In primary tumor sections areas expressing high amounts of L1CAM had less miR-34a expression than those with low L1CAM levels. Our data suggest that miR-34a can regulate L1CAM expression by targeting L1CAM mRNA for degradation. These findings shed new light on the complex regulation of L1CAM in human tumors. PMID:24497324

  3. Role of miR-34a as a suppressor of L1CAM in endometrial carcinoma

    PubMed Central

    Schirmer, Uwe; Doberstein, Kai; Rupp, Anne-Kathleen; Bretz, Niko P.; Wuttig, Daniela; Kiefel, Helena; Breunig, Christian; Fiegl, Heidi; Müller-Holzner, Elisabeth; Zeillinger, Robert; Eva, Heidi; Zeimet, Alain G.; SÜltmann, Holger; Altevogt, Peter

    2014-01-01

    L1CAM promotes cell motility, invasion and metastasis formation in various human cancers and can be considered as a driver of tumor progression. Knowledge about genetic processes leading to the presence of L1CAM in cancers is of considerable importance. Experimentally, L1CAM expression can be achieved by various means. Overexpression of the transcription factor SLUG or treatment of cells with TGF-ß1 can induce or augment L1CAM levels in cancer cells. Likewise, hypomethylation of the L1CAM promoter on the X chromosome correlates with L1CAM expression. However, presently no mechanisms that might control transcriptional activity are known. Here we have identified miR-34a as a suppressor of L1CAM. We observed that L1CAM positive endometrial carcinoma (EC) cell lines HEC1B and SPAC1L lost L1CAM protein and mRNA by treatment with demethylating agents or knock-down of the DNA-methyltransferase-1 (DNMT1). Concomitantly, several miRNAs were up-regulated. Using miRNA profiling, luciferase reporter assays and mutagenesis, we identified miR-34a as a putative binder to the L1CAM-3'UTR. Overexpression of miR-34a in HEC1B cells blocked L1CAM expression and inhibited cell migration. In ECC1 cells (wildtype p53) the activation of p53 caused miR-34a up-regulation and loss of L1CAM expression that was miR-34a dependent. We observed an inverse correlation between L1CAM and miR-34a levels in EC cell lines. In primary tumor sections areas expressing high amounts of L1CAM had less miR-34a expression than those with low L1CAM levels. Our data suggest that miR-34a can regulate L1CAM expression by targeting L1CAM mRNA for degradation. These findings shed new light on the complex regulation of L1CAM in human tumors. PMID:24497324

  4. Porphyrins Containing a Triphenylamine Donor and up to Eight Alkoxy Chains for Dye-Sensitized Solar Cells: A High Efficiency of 10.9%.

    PubMed

    Tang, Yunyu; Wang, Yueqiang; Li, Xin; Ågren, Hans; Zhu, Wei-Hong; Xie, Yongshu

    2015-12-23

    Porphyrins are promising DSSC sensitizers due to their structural similarity to chlorophylls as well as their tunable strong absorption. Herein, a novel D-π-A porphyrin dye XW14 containing a strongly electron-donating triphenylamine moiety as the electron donor was designed and synthesized. To avoid undesirably decreased Voc caused by dye aggregation effect, two methoxy or hexyloxy chains were introduced to the para positions of the triphenylamine moiety to afford XW15 and XW16, respectively. To further extend the absorption to a longer wavelength, a benzothiadiazole unit was introduced as an auxiliary acceptor to furnish XW17. Compared with XW14, the introduction of additional methoxy or hexyloxy groups in XW15 and XW16 red-shift the onset wavelengths from 760 to 780 and 790 nm, respectively. More impressively, XW17 has a more extended π-conjugation framework, and thus, it exhibits a much broader IPCE spectrum with an extremely red-shifted onset wavelength of 830 nm, resulting in the highest Jsc (18.79 mA cm(-2)). On the other hand, the hexyloxy chains are favorable for suppressing the dye aggregation effect, and thus XW16 shows the highest Voc of 734 mV. As a result, XW16 and XW17 demonstrate photovoltaic efficiencies of 9.1 and 9.5%, respectively, higher than those of XW14 (8.6%) and XW15 (8.7%), and obviously higher than that of 7.94% for our previously reported dye, XW4. On the basis of optimized porphyrin dye XW17, we used a nonporphyrin dye with a high Voc and strong absorption around 500 nm (WS-5) as the cosensitizer to improve the Voc from 700 to 748 mV, with synergistical Jsc enhancement from 18.79 to 20.30 mA cm(-2). Thus, the efficiency was dramatically enhanced to 10.9%, which is among the highest efficiencies obtained for the DSSCs based on traditional iodine electrolyte. In addition, the DSSCs based on XW17 + WS-5 exhibit good photostability, which is beneficial for practical applications. PMID:26606858

  5. Cell recognition molecule L1 promotes embryonic stem cell differentiation through the regulation of cell surface glycosylation

    SciTech Connect

    Li, Ying; Huang, Xiaohua; An, Yue; Ren, Feng; Yang, Zara Zhuyun; Zhu, Hongmei; Zhou, Lei; He, Xiaowen; Schachner, Melitta; Xiao, Zhicheng; Ma, Keli; Li, Yali

    2013-10-25

    Highlights: •Down-regulating FUT9 and ST3Gal4 expression blocks L1-induced neuronal differentiation of ESCs. •Up-regulating FUT9 and ST3Gal4 expression in L1-ESCs depends on the activation of PLCγ. •L1 promotes ESCs to differentiate into neuron through regulating cell surface glycosylation. -- Abstract: Cell recognition molecule L1 (CD171) plays an important role in neuronal survival, migration, differentiation, neurite outgrowth, myelination, synaptic plasticity and regeneration after injury. Our previous study has demonstrated that overexpressing L1 enhances cell survival and proliferation of mouse embryonic stem cells (ESCs) through promoting the expression of FUT9 and ST3Gal4, which upregulates cell surface sialylation and fucosylation. In the present study, we examined whether sialylation and fucosylation are involved in ESC differentiation through L1 signaling. RNA interference analysis showed that L1 enhanced differentiation of ESCs into neurons through the upregulation of FUT9 and ST3Gal4. Furthermore, blocking the phospholipase Cγ (PLCγ) signaling pathway with either a specific PLCγ inhibitor or knockdown PLCγ reduced the expression levels of both FUT9 and ST3Gal4 mRNAs and inhibited L1-mediated neuronal differentiation. These results demonstrate that L1 promotes neuronal differentiation from ESCs through the L1-mediated enhancement of FUT9 and ST3Gal4 expression.

  6. Ataxia telangiectasia mutated (ATM) modulates long interspersed element-1 (L1) retrotransposition in human neural stem cells

    PubMed Central

    Coufal, Nicole G.; Garcia-Perez, Josè Luis; Peng, Grace E.; Marchetto, Maria C. N.; Muotri, Alysson R.; Mu, Yangling; Carson, Christian T.; Macia, Angela; Moran, John V.; Gage, Fred H.

    2011-01-01

    Long interspersed element-1 (L1) retrotransposons compose ∼20% of the mammalian genome, and ongoing L1 retrotransposition events can impact genetic diversity by various mechanisms. Previous studies have demonstrated that endogenous L1 retrotransposition can occur in the germ line and during early embryonic development. In addition, recent data indicate that engineered human L1s can undergo somatic retrotransposition in human neural progenitor cells and that an increase in human-specific L1 DNA content can be detected in the brains of normal controls, as well as in Rett syndrome patients. Here, we demonstrate an increase in the retrotransposition efficiency of engineered human L1s in cells that lack or contain severely reduced levels of ataxia telangiectasia mutated, a serine/threonine kinase involved in DNA damage signaling and neurodegenerative disease. We demonstrate that the increase in L1 retrotransposition in ataxia telangiectasia mutated-deficient cells most likely occurs by conventional target-site primed reverse transcription and generate either longer, or perhaps more, L1 retrotransposition events per cell. Finally, we provide evidence suggesting an increase in human-specific L1 DNA copy number in postmortem brain tissue derived from ataxia telangiectasia patients compared with healthy controls. Together, these data suggest that cellular proteins involved in the DNA damage response may modulate L1 retrotransposition. PMID:22159035

  7. Ataxia telangiectasia mutated (ATM) modulates long interspersed element-1 (L1) retrotransposition in human neural stem cells.

    PubMed

    Coufal, Nicole G; Garcia-Perez, Josè Luis; Peng, Grace E; Marchetto, Maria C N; Muotri, Alysson R; Mu, Yangling; Carson, Christian T; Macia, Angela; Moran, John V; Gage, Fred H

    2011-12-20

    Long interspersed element-1 (L1) retrotransposons compose ∼20% of the mammalian genome, and ongoing L1 retrotransposition events can impact genetic diversity by various mechanisms. Previous studies have demonstrated that endogenous L1 retrotransposition can occur in the germ line and during early embryonic development. In addition, recent data indicate that engineered human L1s can undergo somatic retrotransposition in human neural progenitor cells and that an increase in human-specific L1 DNA content can be detected in the brains of normal controls, as well as in Rett syndrome patients. Here, we demonstrate an increase in the retrotransposition efficiency of engineered human L1s in cells that lack or contain severely reduced levels of ataxia telangiectasia mutated, a serine/threonine kinase involved in DNA damage signaling and neurodegenerative disease. We demonstrate that the increase in L1 retrotransposition in ataxia telangiectasia mutated-deficient cells most likely occurs by conventional target-site primed reverse transcription and generate either longer, or perhaps more, L1 retrotransposition events per cell. Finally, we provide evidence suggesting an increase in human-specific L1 DNA copy number in postmortem brain tissue derived from ataxia telangiectasia patients compared with healthy controls. Together, these data suggest that cellular proteins involved in the DNA damage response may modulate L1 retrotransposition.

  8. Cell adhesion molecule L1 contributes to neuronal excitability regulating the function of voltage-gated Na+ channels.

    PubMed

    Valente, Pierluigi; Lignani, Gabriele; Medrihan, Lucian; Bosco, Federica; Contestabile, Andrea; Lippiello, Pellegrino; Ferrea, Enrico; Schachner, Melitta; Benfenati, Fabio; Giovedì, Silvia; Baldelli, Pietro

    2016-05-01

    L1 (also known as L1CAM) is a trans-membrane glycoprotein mediating neuron-neuron adhesion through homophilic and heterophilic interactions. Although experimental evidence has implicated L1 in axonal outgrowth, fasciculation and pathfinding, its contribution to voltage-gated Na(+) channel function and membrane excitability has remained unknown. Here, we show that firing rate, single cell spiking frequency and Na(+) current density are all reduced in hippocampal excitatory neurons from L1-deficient mice both in culture and in slices owing to an overall reduced membrane expression of Na(+) channels. Remarkably, normal firing activity was restored when L1 was reintroduced into L1-deficient excitatory neurons, indicating that abnormal firing patterns are not related to developmental abnormalities, but are a direct consequence of L1 deletion. Moreover, L1 deficiency leads to impairment of action potential initiation, most likely due to the loss of the interaction of L1 with ankyrin G that produces the delocalization of Na(+) channels at the axonal initial segment. We conclude that L1 contributes to functional expression and localization of Na(+) channels to the neuronal plasma membrane, ensuring correct initiation of action potential and normal firing activity. PMID:26985064

  9. molSimplify: A toolkit for automating discovery in inorganic chemistry.

    PubMed

    Ioannidis, Efthymios I; Gani, Terry Z H; Kulik, Heather J

    2016-08-15

    We present an automated, open source toolkit for the first-principles screening and discovery of new inorganic molecules and intermolecular complexes. Challenges remain in the automatic generation of candidate inorganic molecule structures due to the high variability in coordination and bonding, which we overcome through a divide-and-conquer tactic that flexibly combines force-field preoptimization of organic fragments with alignment to first-principles-trained metal-ligand distances. Exploration of chemical space is enabled through random generation of ligands and intermolecular complexes from large chemical databases. We validate the generated structures with the root mean squared (RMS) gradients evaluated from density functional theory (DFT), which are around 0.02 Ha/au across a large 150 molecule test set. Comparison of molSimplify results to full optimization with the universal force field reveals that RMS DFT gradients are improved by 40%. Seamless generation of input files, preparation and execution of electronic structure calculations, and post-processing for each generated structure aids interpretation of underlying chemical and energetic trends. © 2016 Wiley Periodicals, Inc. PMID:27364957

  10. Stimulation of glioma cell motility by expression, proteolysis, and release of the L1 neural cell recognition molecule

    PubMed Central

    Yang, Muhua; Adla, Shalini; Temburni, Murali K; Patel, Vivek P; Lagow, Errin L; Brady, Owen A; Tian, Jing; Boulos, Magdy I; Galileo, Deni S

    2009-01-01

    Background Malignant glioma cells are particularly motile and can travel diffusely through the brain parenchyma, apparently without following anatomical structures to guide their migration. The neural adhesion/recognition protein L1 (L1CAM; CD171) has been implicated in contributing to stimulation of motility and metastasis of several non-neural cancer types. We explored the expression and function of L1 protein as a stimulator of glioma cell motility using human high-grade glioma surgical specimens and established rat and human glioma cell lines. Results L1 protein expression was found in 17 out of 18 human high-grade glioma surgical specimens by western blotting. L1 mRNA was found to be present in human U-87/LacZ and rat C6 and 9L glioma cell lines. The glioma cell lines were negative for surface full length L1 by flow cytometry and high resolution immunocytochemistry of live cells. However, fixed and permeablized cells exhibited positive staining as numerous intracellular puncta. Western blots of cell line extracts revealed L1 proteolysis into a large soluble ectodomain (~180 kDa) and a smaller transmembrane proteolytic fragment (~32 kDa). Exosomal vesicles released by the glioma cell lines were purified and contained both full-length L1 and the proteolyzed transmembrane fragment. Glioma cell lines expressed L1-binding αvβ5 integrin cell surface receptors. Quantitative time-lapse analyses showed that motility was reduced significantly in glioma cell lines by 1) infection with an antisense-L1 retroviral vector and 2) L1 ectodomain-binding antibodies. Conclusion Our novel results support a model of autocrine/paracrine stimulation of cell motility in glioma cells by a cleaved L1 ectodomain and/or released exosomal vesicles containing L1. This mechanism could explain the diffuse migratory behavior of high-grade glioma cancer cells within the brain. PMID:19874583

  11. miR-21-3p is a positive regulator of L1CAM in several human carcinomas.

    PubMed

    Doberstein, Kai; Bretz, Niko P; Schirmer, Uwe; Fiegl, Heidi; Blaheta, Roman; Breunig, Christian; Müller-Holzner, Elisabeth; Reimer, Dan; Zeimet, Alain G; Altevogt, Peter

    2014-11-28

    Expression of L1 cell adhesion molecule (L1CAM) occurs frequently in human cancers and is associated with poor prognosis in cancers such as ovarian, endometrial, breast, renal cell carcinoma and pancreatic ductal adenocarcinoma. L1CAM promotes cell motility, invasion, chemoresistance and metastasis formation. Elucidating genetic processes involved in the expression of L1CAM in cancers is of considerable importance. Transcription factors such as SLUG, β-catenin/TCF-LEF, PAX8 and VHL have been implicated in the re-activation of L1CAM in various types of cancers. There is increasing evidence that micro-RNAs can also have strong effects on gene expression. Here we have identified miR-21-3p as a positive regulator of L1CAM expression. Over-expression of miR-21-3p (miR-21*) but not the complementary sequence miR-21-5p (miR-21) could strongly augment L1CAM expression in renal, endometrial and ovarian carcinoma derived cell lines by an unknown mechanism involving transcriptional activation of the L1CAM gene. In patient cohorts from renal, endometrial and ovarian cancers we observed a strong positive correlation of L1CAM and miR-21-3p expressions. Although L1CAM alone was a reliable marker for overall and disease free survival, the combination of L1CAM and miR-21-3p expressions strongly enhanced the predictive power. Our findings shed new light on the complex regulation of L1CAM in cancers and advocate the use of L1CAM/miR-21-3p for diagnostic application. PMID:25149066

  12. Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced Cancer

    PubMed Central

    Brahmer, Julie R.; Tykodi, Scott S.; Chow, Laura Q.M.; Hwu, Wen-Jen; Topalian, Suzanne L.; Hwu, Patrick; Drake, Charles G.; Camacho, Luis H.; Kauh, John; Odunsi, Kunle; Pitot, Henry C.; Hamid, Omid; Bhatia, Shailender; Martins, Renato; Eaton, Keith; Chen, Shuming; Salay, Theresa M.; Alaparthy, Suresh; Grosso, Joseph F.; Korman, Alan J.; Parker, Susan M.; Agrawal, Shruti; Goldberg, Stacie M.; Pardoll, Drew M.; Gupta, Ashok; Wigginton, Jon M.

    2013-01-01

    BACKGROUND Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of tumor cells to evade the host’s immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models. METHODS In this multicenter phase 1 trial, we administered intravenous anti–PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per kilogram of body weight) to patients with selected advanced cancers. Anti–PD-L1 antibody was administered every 14 days in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression. RESULTS As of February 24, 2012, a total of 207 patients — 75 with non–small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer — had received anti–PD-L1 antibody. The median duration of therapy was 12 weeks (range, 2 to 111). Grade 3 or 4 toxic effects that investigators considered to be related to treatment occurred in 9% of patients. Among patients with a response that could be evaluated, an objective response (a complete or partial response) was observed in 9 of 52 patients with melanoma, 2 of 17 with renal-cell cancer, 5 of 49 with non–small-cell lung cancer, and 1 of 17 with ovarian cancer. Responses lasted for 1 year or more in 8 of 16 patients with at least 1 year of follow-up. CONCLUSIONS Antibody-mediated blockade of PD-L1 induced durable tumor regression (objective response rate of 6 to 17%) and prolonged stabilization of disease (rates of 12 to 41% at 24 weeks) in patients with advanced cancers, including non–small-cell lung cancer, melanoma, and renal-cell cancer. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00729664.) PMID:22658128

  13. Improved L0 Gradient Minimization with L1 Fidelity for Image Smoothing

    PubMed Central

    Pang, Xueshun; Zhang, Suqi; Gu, Junhua; Li, Lingling; Liu, Boying; Wang, Huaibin

    2015-01-01

    Edge-preserving image smoothing is one of the fundamental tasks in the field of computer graphics and computer vision. Recently, L0 gradient minimization (LGM) has been proposed for this purpose. In contrast to the total variation (TV) model which employs the L1 norm of the image gradient, the LGM model adopts the L0 norm and yields much better results for the piecewise constant image. However, as an improvement of the total variation (TV) model, the LGM model also suffers, even more seriously, from the staircasing effect and is not robust to noise. In order to overcome these drawbacks, in this paper, we propose an improvement of the LGM model by prefiltering the image gradient and employing the L1 fidelity. The proposed improved LGM (ILGM) behaves robustly to noise and overcomes the staircasing artifact effectively. Experimental results show that the ILGM is promising as compared with the existing methods. PMID:26383869

  14. Focus detection from digital in-line holograms based on spectral l1 norms.

    PubMed

    Li, Weichang; Loomis, Nick C; Hu, Qiao; Davis, Cabell S

    2007-10-01

    A rapid focus-detection technique based directly on the spectral content of digital holograms is developed. It differs from previous approaches in that it does not need a full reconstruction of the image. The technique uses l(1) norms of object spectral components associated with the real and imaginary parts of the reconstruction kernel. Further, the l(1) norms can be computed efficiently in the spatial frequency domain using a polar coordinate system, yielding a drastic speedup of approximately 2 orders of magnitude compared with image-based focus detection. Significant computational savings are achieved when subsequent image reconstructions are done selectively over the detected focus distances. Focus-detection results from holograms of plankton are demonstrated that show the technique is both accurate and robust. PMID:17912295

  15. Tcf7l1 protects the anterior neural fold from adopting the neural crest fate.

    PubMed

    Mašek, Jan; Machoň, Ondřej; Kořínek, Vladimír; Taketo, M Mark; Kozmik, Zbyněk

    2016-06-15

    The neural crest (NC) is crucial for the evolutionary diversification of vertebrates. NC cells are induced at the neural plate border by the coordinated action of several signaling pathways, including Wnt/β-catenin. NC cells are normally generated in the posterior neural plate border, whereas the anterior neural fold is devoid of NC cells. Using the mouse model, we show here that active repression of Wnt/β-catenin signaling is required for maintenance of neuroepithelial identity in the anterior neural fold and for inhibition of NC induction. Conditional inactivation of Tcf7l1, a transcriptional repressor of Wnt target genes, leads to aberrant activation of Wnt/β-catenin signaling in the anterior neuroectoderm and its conversion into NC. This reduces the developing prosencephalon without affecting the anterior-posterior neural character. Thus, Tcf7l1 defines the border between the NC and the prospective forebrain via restriction of the Wnt/β-catenin signaling gradient. PMID:27302397

  16. L1, L2, and L3 subshell fluorescence yields: Updated database and new empirical values

    NASA Astrophysics Data System (ADS)

    Sahnoune, Y.; Kahoul, A.; Kasri, Y.; Deghfel, B.; Medjadi, D. E.; Khalfallah, F.; Daoudi, S.; Aylikçi, V.; Küp Aylikçi, N.; Nekkab, M.

    2016-08-01

    In this paper, a summary of experimental data published in the period of time between 1955 to february-2016 was presented in a tabular form for Li subshell fluorescence yields (ωL1 ,ωL2 andωL3) taken from different sources. First, a critical examination of these data using the weighted average valuesωLi-W was presented. Then, an interpolation using the famous analytical function (ωLi-W / (1 -ωLi-W)) 1 / 4 vs the atomic number Z was proformed to deduce a new empirical Li subshell fluorescence yields for elements in the range 40≤Z≤96 for ωL1 and ωL2 and 23≤Z≤96 for ωL3 . At last, our calculated empirical Li subshell fluorescence yields have been compared with other theoretical and empirical values reported in the literature.

  17. Earth to Moon Transfer: Direct vs Via Libration Points (L1, L2)

    NASA Technical Reports Server (NTRS)

    Condon, Gerald L.; Wilson, Samuel W.

    2004-01-01

    For some three decades, the Apollo-style mission has served as a proven baseline technique for transporting flight crews to the Moon and back with expendable hardware. This approach provides an optimal design for expeditionary missions, emphasizing operational flexibility in terms of safely returning the crew in the event of a hardware failure. However, its application is limited essentially to low-latitude lunar sites, and it leaves much to be desired as a model for exploratory and evolutionary programs that employ reusable space-based hardware. This study compares the performance requirements for a lunar orbit rendezvous mission type with one using the cislunar libration point (L1) as a stopover and staging point for access to arbitrary sites on the lunar surface. For selected constraints and mission objectives, it contrasts the relative uniformity of performance cost when the L1 staging point is used with the wide variation of cost for the Apollo-style lunar orbit rendezvous.

  18. Perpendicular magnetic anisotropy and spin reorientation transition in L1{sub 0} FePt films

    SciTech Connect

    Ahn, Jae Young; Lee, Nyun Jong; Kim, Tae Hee; Lee, J.-H.; Michel, Anny; Eyidi, Dominique

    2011-04-01

    We investigated the thickness and composition dependence of perpendicular magnetic anisotropy (PMA) in L1{sub 0} Fe{sub 1-x}Pt{sub x} (x = 0.4, 0.5, and 0.55) films. The FePt films with different thicknesses of 35 and 70 A were grown at the substrate temperature T{sub s} = 300 deg. C by molecular beam epitaxy coevaporation technique. A (001)-oriented epitaxial L1{sub 0} FePt film was grown on the thin (001)-oriented fcc Pt layer, while a poorly crystallized FePt film was formed on the (111)-textured Pt layer. Our results showed that, at a fixed thickness of 70 A, the PMA of FePt alloy films is enhanced as Pt content increases from 40% to 55%.

  19. Spiroimidazolidinone NPC1L1 inhibitors. Part 2: structure-activity studies and in vivo efficacy.

    PubMed

    Howell, Kobporn L; DeVita, Robert J; Garcia-Calvo, Margarita; Meurer, Roger D; Lisnock, JeanMarie; Bull, Herbert G; McMasters, Daniel R; McCann, Margaret E; Mills, Sander G

    2010-12-01

    Ezetimibe (Zetia®), a cholesterol-absorption inhibitor (CAI) approved by the FDA for the treatment of hypercholesterolemia, is believed to target the intestine protein Niemann-Pick C1-Like 1 (NPC1L1) or its pathway. A spiroimidazolidinone NPC1L1 inhibitor identified by virtual screening showed moderate binding activity but was not efficacious in an in vivo rodent model of cholesterol absorption. Synthesis of analogs established the structure-activity relationships for binding activity, and resulted in compounds with in vivo efficacy, including 24, which inhibited plasma cholesterol absorption by 67% in the mouse, thereby providing proof-of-concept that non-β-lactams can be effective CAIs.

  20. L1-Penalized N-way PLS for subset of electrodes selection in BCI experiments

    NASA Astrophysics Data System (ADS)

    Eliseyev, Andrey; Moro, Cecile; Faber, Jean; Wyss, Alexander; Torres, Napoleon; Mestais, Corinne; Benabid, Alim Louis; Aksenova, Tetiana

    2012-08-01

    Recently, the N-way partial least squares (NPLS) approach was reported as an effective tool for neuronal signal decoding and brain-computer interface (BCI) system calibration. This method simultaneously analyzes data in several domains. It combines the projection of a data tensor to a low dimensional space with linear regression. In this paper the L1-Penalized NPLS is proposed for sparse BCI system calibration, allowing uniting the projection technique with an effective selection of subset of features. The L1-Penalized NPLS was applied for the binary self-paced BCI system calibration, providing selection of electrodes subset. Our BCI system is designed for animal research, in particular for research in non-human primates.