WorldWideScience

Sample records for multiple checkpoint proficiency

  1. Multiple functions of the S-phase checkpoint mediator.

    Science.gov (United States)

    Tanaka, Katsunori

    2010-01-01

    There is mounting evidence that replication defects are the major source of spontaneous genomic instability in cells, and that S-phase checkpoints are the principal defense against such instability. The S-phase checkpoint mediator protein Mrc1/Claspin mediates the checkpoint response to replication stress by facilitating phosphorylation of effector kinase by a sensor kinase. In this review, the multiple functions and the regulation of the S-phase checkpoint mediator are discussed.

  2. Dpb11/TopBP1 plays distinct roles in DNA replication, checkpoint response and homologous recombination

    DEFF Research Database (Denmark)

    Germann, Susanne Manuela; Østergaard, Vibe Hallundbæk; Haas, Caroline

    2011-01-01

    DPB11/TopBP1 is an essential evolutionarily conserved gene involved in initiation of DNA replication and checkpoint signaling. Here, we show that Saccharomyces cerevisiae Dpb11 forms nuclear foci that localize to sites of DNA damage in G1, S and G2 phase, a recruitment that is conserved for its...... and Tel1, and of the checkpoint mediator Rad9. In a site-directed mutagenesis screen, we identify a separation-of-function mutant, dpb11-PF, that is sensitive to DSB-inducing agents yet remains proficient for DNA replication and the S-phase checkpoint at the permissive temperature. The dpb11-PF mutant...... homologue TopBP1 in Gallus gallus. Damage-induced Dpb11 foci are distinct from Sld3 replication initiation foci. Further, Dpb11 foci are dependent on the checkpoint proteins Mec3 (9-1-1 complex) and Rad24, and require the C-terminal domain of Dpb11. Dpb11 foci are independent of the checkpoint kinases Mec1...

  3. Detailed Modeling and Evaluation of a Scalable Multilevel Checkpointing System

    Energy Technology Data Exchange (ETDEWEB)

    Mohror, Kathryn [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Moody, Adam [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Bronevetsky, Greg [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); de Supinski, Bronis R. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2014-09-01

    High-performance computing (HPC) systems are growing more powerful by utilizing more components. As the system mean time before failure correspondingly drops, applications must checkpoint frequently to make progress. But, at scale, the cost of checkpointing becomes prohibitive. A solution to this problem is multilevel checkpointing, which employs multiple types of checkpoints in a single run. Moreover, lightweight checkpoints can handle the most common failure modes, while more expensive checkpoints can handle severe failures. We designed a multilevel checkpointing library, the Scalable Checkpoint/Restart (SCR) library, that writes lightweight checkpoints to node-local storage in addition to the parallel file system. We present probabilistic Markov models of SCR's performance. We show that on future large-scale systems, SCR can lead to a gain in machine efficiency of up to 35 percent, and reduce the load on the parallel file system by a factor of two. In addition, we predict that checkpoint scavenging, or only writing checkpoints to the parallel file system on application termination, can reduce the load on the parallel file system by 20 × on today's systems and still maintain high application efficiency.

  4. Role of the Checkpoint Clamp in DNA Damage Response

    Directory of Open Access Journals (Sweden)

    Mihoko Kai

    2013-01-01

    Full Text Available DNA damage occurs during DNA replication, spontaneous chemical reactions, and assaults by external or metabolism-derived agents. Therefore, all living cells must constantly contend with DNA damage. Cells protect themselves from these genotoxic stresses by activating the DNA damage checkpoint and DNA repair pathways. Coordination of these pathways requires tight regulation in order to prevent genomic instability. The checkpoint clamp complex consists of Rad9, Rad1 and Hus1 proteins, and is often called the 9-1-1 complex. This PCNA (proliferating cell nuclear antigen-like donut-shaped protein complex is a checkpoint sensor protein that is recruited to DNA damage sites during the early stage of the response, and is required for checkpoint activation. As PCNA is required for multiple pathways of DNA metabolism, the checkpoint clamp has also been implicated in direct roles in DNA repair, as well as in coordination of the pathways. Here we discuss roles of the checkpoint clamp in DNA damage response (DDR.

  5. Multiple Duties for Spindle Assembly Checkpoint Kinases in Meiosis

    Science.gov (United States)

    Marston, Adele L.; Wassmann, Katja

    2017-01-01

    Cell division in mitosis and meiosis is governed by evolutionary highly conserved protein kinases and phosphatases, controlling the timely execution of key events such as nuclear envelope breakdown, spindle assembly, chromosome attachment to the spindle and chromosome segregation, and cell cycle exit. In mitosis, the spindle assembly checkpoint (SAC) controls the proper attachment to and alignment of chromosomes on the spindle. The SAC detects errors and induces a cell cycle arrest in metaphase, preventing chromatid separation. Once all chromosomes are properly attached, the SAC-dependent arrest is relieved and chromatids separate evenly into daughter cells. The signaling cascade leading to checkpoint arrest depends on several protein kinases that are conserved from yeast to man. In meiosis, haploid cells containing new genetic combinations are generated from a diploid cell through two specialized cell divisions. Though apparently less robust, SAC control also exists in meiosis. Recently, it has emerged that SAC kinases have additional roles in executing accurate chromosome segregation during the meiotic divisions. Here, we summarize the main differences between mitotic and meiotic cell divisions, and explain why meiotic divisions pose special challenges for correct chromosome segregation. The less-known meiotic roles of the SAC kinases are described, with a focus on two model systems: yeast and mouse oocytes. The meiotic roles of the canonical checkpoint kinases Bub1, Mps1, the pseudokinase BubR1 (Mad3), and Aurora B and C (Ipl1) will be discussed. Insights into the molecular signaling pathways that bring about the special chromosome segregation pattern during meiosis will help us understand why human oocytes are so frequently aneuploid. PMID:29322045

  6. Multiple Duties for Spindle Assembly Checkpoint Kinases in Meiosis

    Directory of Open Access Journals (Sweden)

    Adele L. Marston

    2017-12-01

    Full Text Available Cell division in mitosis and meiosis is governed by evolutionary highly conserved protein kinases and phosphatases, controlling the timely execution of key events such as nuclear envelope breakdown, spindle assembly, chromosome attachment to the spindle and chromosome segregation, and cell cycle exit. In mitosis, the spindle assembly checkpoint (SAC controls the proper attachment to and alignment of chromosomes on the spindle. The SAC detects errors and induces a cell cycle arrest in metaphase, preventing chromatid separation. Once all chromosomes are properly attached, the SAC-dependent arrest is relieved and chromatids separate evenly into daughter cells. The signaling cascade leading to checkpoint arrest depends on several protein kinases that are conserved from yeast to man. In meiosis, haploid cells containing new genetic combinations are generated from a diploid cell through two specialized cell divisions. Though apparently less robust, SAC control also exists in meiosis. Recently, it has emerged that SAC kinases have additional roles in executing accurate chromosome segregation during the meiotic divisions. Here, we summarize the main differences between mitotic and meiotic cell divisions, and explain why meiotic divisions pose special challenges for correct chromosome segregation. The less-known meiotic roles of the SAC kinases are described, with a focus on two model systems: yeast and mouse oocytes. The meiotic roles of the canonical checkpoint kinases Bub1, Mps1, the pseudokinase BubR1 (Mad3, and Aurora B and C (Ipl1 will be discussed. Insights into the molecular signaling pathways that bring about the special chromosome segregation pattern during meiosis will help us understand why human oocytes are so frequently aneuploid.

  7. Beyond CTLA-4 and PD-1, the Generation Z of Negative Checkpoint Regulators.

    Science.gov (United States)

    Le Mercier, Isabelle; Lines, J Louise; Noelle, Randolph J

    2015-01-01

    In the last two years, clinical trials with blocking antibodies to the negative checkpoint regulators CTLA-4 and PD-1 have rekindled the hope for cancer immunotherapy. Multiple negative checkpoint regulators protect the host against autoimmune reactions but also restrict the ability of T cells to effectively attack tumors. Releasing these brakes has emerged as an exciting strategy for cancer treatment. Conversely, these pathways can be manipulated to achieve durable tolerance for treatment of autoimmune diseases and transplantation. In the future, treatment may involve combination therapy to target multiple cell types and stages of the adaptive immune responses. In this review, we describe the current knowledge on the recently discovered negative checkpoint regulators, future targets for immunotherapy.

  8. Southeast Asian Languages Proficiency Examinations.

    Science.gov (United States)

    Brown, James Dean; And Others

    The design, administration, revision, and validation of the Southeast Asian Summer Studies Institute proficiency examinations are reported. The examinations were created as parallel language proficiency tests in each of five languages: Indonesian, Khmer, Tagalog, Thai, and Vietnamese. Four tests were developed in each language: multiple-choice…

  9. Asynchronous Checkpoint Migration with MRNet in the Scalable Checkpoint / Restart Library

    Energy Technology Data Exchange (ETDEWEB)

    Mohror, K; Moody, A; de Supinski, B R

    2012-03-20

    Applications running on today's supercomputers tolerate failures by periodically saving their state in checkpoint files on stable storage, such as a parallel file system. Although this approach is simple, the overhead of writing the checkpoints can be prohibitive, especially for large-scale jobs. In this paper, we present initial results of an enhancement to our Scalable Checkpoint/Restart Library (SCR). We employ MRNet, a tree-based overlay network library, to transfer checkpoints from the compute nodes to the parallel file system asynchronously. This enhancement increases application efficiency by removing the need for an application to block while checkpoints are transferred to the parallel file system. We show that the integration of SCR with MRNet can reduce the time spent in I/O operations by as much as 15x. However, our experiments exposed new scalability issues with our initial implementation. We discuss the sources of the scalability problems and our plans to address them.

  10. Beyond CTLA-4 and PD-1, the generation Z of negative checkpoint regulators.

    Directory of Open Access Journals (Sweden)

    Isabelle eLe Mercier

    2015-08-01

    Full Text Available In the last two years, clinical trials with blocking antibodies to the negative checkpoint regulators CTLA-4 and PD-1 have rekindled the hope for cancer immunotherapy. Multiple negative checkpoint regulators protect the host against autoimmune reactions but also restrict the ability of T cells to effectively attack tumors. Releasing these brakes has emerged as an exciting strategy for cancer treatment. Conversely, these pathways can be manipulated to achieve durable tolerance for treatment of autoimmune diseases and transplantation. In the future, treatment may involve combination therapy to target multiple cell types and stages of the adaptive immune responses. In this review, we describe the current knowledge on the recently discovered negative checkpoint regulators, future targets for immunotherapy.

  11. Arabidopsis ARGONAUTE7 selects miR390 through multiple checkpoints during RISC assembly.

    Science.gov (United States)

    Endo, Yayoi; Iwakawa, Hiro-oki; Tomari, Yukihide

    2013-07-01

    Plant ARGONAUTE7 (AGO7) assembles RNA-induced silencing complex (RISC) specifically with miR390 and regulates the auxin-signalling pathway via production of TAS3 trans-acting siRNAs (tasiRNAs). However, how AGO7 discerns miR390 among other miRNAs remains unclear. Here, we show that the 5' adenosine of miR390 and the central region of miR390/miR390* duplex are critical for the specific interaction with AGO7. Furthermore, despite the existence of mismatches in the seed and central regions of the duplex, cleavage of the miR390* strand is required for maturation of AGO7-RISC. These findings suggest that AGO7 uses multiple checkpoints to select miR390, thereby circumventing promiscuous tasiRNA production.

  12. Action-oriented use of ergonomic checkpoints for healthy work design in different settings.

    Science.gov (United States)

    Kogi, Kazutaka

    2007-12-01

    Recent experiences in the action-oriented use of ergonomic checkpoints in different work settings are reviewed. The purpose is to know what features are useful for healthy work design adjusted to each local situation. Based on the review results, common features of ergonomic checkpoints used in participatory training programs for improving workplace conditions in small enterprises, construction sites, home work and agriculture in industrially developing countries in Asia are discussed. These checkpoints generally compile practical improvement options in a broad range of technical areas, such as materials handling, workstation design, physical environment and work organization. Usually, "action checklists" comprising the tiles of the checkpoints are used together. A clear focus is placed on readily applicable low-cost options. Three common features of these various checkpoints appear to be important. First, the checkpoints represent typical good practices in multiple areas. Second, each how-to section of these checkpoints presents simple improvements reflecting basic ergonomic principles. Examples of these principles include easy reach, fewer and faster transport, elbow-level work, coded displays, isolated or screened hazards and shared teamwork. Third, the illustrated checkpoints accompanied by corresponding checklists are used as group work tools in short-term training courses. Many practical improvements achieved are displayed in websites for inter-country work improvement networks. It is suggested to promote the use of locally adjusted checkpoints in various forms of participatory action-oriented training in small-scale workplaces and in agriculture particularly in industrially developing countries.

  13. Checkpoint inhibitors in advanced melanoma: effect on the field of immunotherapy.

    Science.gov (United States)

    O'reilly, Aine; Larkin, James

    2017-07-01

    The success of the immune checkpoint inhibitors in melanoma has reinvigorated the field of immunotherapy. Immune checkpoint inhibitors are now the standard of care in multiple cancer types including lung cancer, head and neck cancer, urothelial cancer and renal cell cancer. The field of immunotherapy is currently expanding rapidly and will be a focus of research and development for decades to come. Areas covered: This review covers the early development of immune checkpoint inhibitors and the changes that occurred in the drug development paradigm to facilitate the development of immunotherapy. The review will summarise the areas into which immune checkpoint inhibitors have been adopted and will review the data that supported this. Furthermore, we will discuss future developments in immunotherapy and the current landscape regarding maximising the potential of immunotherapy in clinical practice. Expert commentary: In the author's opinion, the potential of immunotherapy is vast. To date immune checkpoint inhibition has already delivered durable responses in a proportion of patients with cancer types which were previously universally lethal. The future of immunotherapy will rely upon the intelligent application of translational research to clinical practice, such that immunotherapy can be effective for a wider population and maintain its current growth.

  14. Checkpointing for a hybrid computing node

    Science.gov (United States)

    Cher, Chen-Yong

    2016-03-08

    According to an aspect, a method for checkpointing in a hybrid computing node includes executing a task in a processing accelerator of the hybrid computing node. A checkpoint is created in a local memory of the processing accelerator. The checkpoint includes state data to restart execution of the task in the processing accelerator upon a restart operation. Execution of the task is resumed in the processing accelerator after creating the checkpoint. The state data of the checkpoint are transferred from the processing accelerator to a main processor of the hybrid computing node while the processing accelerator is executing the task.

  15. Network support for system initiated checkpoints

    Science.gov (United States)

    Chen, Dong; Heidelberger, Philip

    2013-01-29

    A system, method and computer program product for supporting system initiated checkpoints in parallel computing systems. The system and method generates selective control signals to perform checkpointing of system related data in presence of messaging activity associated with a user application running at the node. The checkpointing is initiated by the system such that checkpoint data of a plurality of network nodes may be obtained even in the presence of user applications running on highly parallel computers that include ongoing user messaging activity.

  16. Immune-Checkpoint Blockade and Active Immunotherapy for Glioma

    International Nuclear Information System (INIS)

    Ahn, Brian J.; Pollack, Ian F.; Okada, Hideho

    2013-01-01

    Cancer immunotherapy has made tremendous progress, including promising results in patients with malignant gliomas. Nonetheless, the immunological microenvironment of the brain and tumors arising therein is still believed to be suboptimal for sufficient antitumor immune responses for a variety of reasons, including the operation of “immune-checkpoint” mechanisms. While these mechanisms prevent autoimmunity in physiological conditions, malignant tumors, including brain tumors, actively employ these mechanisms to evade from immunological attacks. Development of agents designed to unblock these checkpoint steps is currently one of the most active areas of cancer research. In this review, we summarize recent progresses in the field of brain tumor immunology with particular foci in the area of immune-checkpoint mechanisms and development of active immunotherapy strategies. In the last decade, a number of specific monoclonal antibodies designed to block immune-checkpoint mechanisms have been developed and show efficacy in other cancers, such as melanoma. On the other hand, active immunotherapy approaches, such as vaccines, have shown encouraging outcomes. We believe that development of effective immunotherapy approaches should ultimately integrate those checkpoint-blockade agents to enhance the efficacy of therapeutic approaches. With these agents available, it is going to be quite an exciting time in the field. The eventual success of immunotherapies for brain tumors will be dependent upon not only an in-depth understanding of immunology behind the brain and brain tumors, but also collaboration and teamwork for the development of novel trials that address multiple layers of immunological challenges in gliomas

  17. Immune-Checkpoint Blockade and Active Immunotherapy for Glioma

    Energy Technology Data Exchange (ETDEWEB)

    Ahn, Brian J. [Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Pollack, Ian F. [Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Okada, Hideho, E-mail: okadah@upmc.edu [Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States)

    2013-11-01

    Cancer immunotherapy has made tremendous progress, including promising results in patients with malignant gliomas. Nonetheless, the immunological microenvironment of the brain and tumors arising therein is still believed to be suboptimal for sufficient antitumor immune responses for a variety of reasons, including the operation of “immune-checkpoint” mechanisms. While these mechanisms prevent autoimmunity in physiological conditions, malignant tumors, including brain tumors, actively employ these mechanisms to evade from immunological attacks. Development of agents designed to unblock these checkpoint steps is currently one of the most active areas of cancer research. In this review, we summarize recent progresses in the field of brain tumor immunology with particular foci in the area of immune-checkpoint mechanisms and development of active immunotherapy strategies. In the last decade, a number of specific monoclonal antibodies designed to block immune-checkpoint mechanisms have been developed and show efficacy in other cancers, such as melanoma. On the other hand, active immunotherapy approaches, such as vaccines, have shown encouraging outcomes. We believe that development of effective immunotherapy approaches should ultimately integrate those checkpoint-blockade agents to enhance the efficacy of therapeutic approaches. With these agents available, it is going to be quite an exciting time in the field. The eventual success of immunotherapies for brain tumors will be dependent upon not only an in-depth understanding of immunology behind the brain and brain tumors, but also collaboration and teamwork for the development of novel trials that address multiple layers of immunological challenges in gliomas.

  18. Cell size checkpoint control by the retinoblastoma tumor suppressor pathway.

    Science.gov (United States)

    Fang, Su-Chiung; de los Reyes, Chris; Umen, James G

    2006-10-13

    Size control is essential for all proliferating cells, and is thought to be regulated by checkpoints that couple cell size to cell cycle progression. The aberrant cell-size phenotypes caused by mutations in the retinoblastoma (RB) tumor suppressor pathway are consistent with a role in size checkpoint control, but indirect effects on size caused by altered cell cycle kinetics are difficult to rule out. The multiple fission cell cycle of the unicellular alga Chlamydomonas reinhardtii uncouples growth from division, allowing direct assessment of the relationship between size phenotypes and checkpoint function. Mutations in the C. reinhardtii RB homolog encoded by MAT3 cause supernumerous cell divisions and small cells, suggesting a role for MAT3 in size control. We identified suppressors of an mat3 null allele that had recessive mutations in DP1 or dominant mutations in E2F1, loci encoding homologs of a heterodimeric transcription factor that is targeted by RB-related proteins. Significantly, we determined that the dp1 and e2f1 phenotypes were caused by defects in size checkpoint control and were not due to a lengthened cell cycle. Despite their cell division defects, mat3, dp1, and e2f1 mutants showed almost no changes in periodic transcription of genes induced during S phase and mitosis, many of which are conserved targets of the RB pathway. Conversely, we found that regulation of cell size was unaffected when S phase and mitotic transcription were inhibited. Our data provide direct evidence that the RB pathway mediates cell size checkpoint control and suggest that such control is not directly coupled to the magnitude of periodic cell cycle transcription.

  19. Efficient Incremental Checkpointing of Java Programs

    DEFF Research Database (Denmark)

    Lawall, Julia Laetitia; Muller, Gilles

    2000-01-01

    This paper investigates the optimization of language-level checkpointing of Java programs. First, we describe how to systematically associate incremental checkpoints with Java classes. While being safe, the genericness of this solution induces substantial execution overhead. Second, to solve...

  20. Keeping checkpoint/restart viable for exascale systems.

    Energy Technology Data Exchange (ETDEWEB)

    Riesen, Rolf E.; Bridges, Patrick G. (IBM Research, Ireland, Mulhuddart, Dublin); Stearley, Jon R.; Laros, James H., III; Oldfield, Ron A.; Arnold, Dorian (University of New Mexico, Albuquerque, NM); Pedretti, Kevin Thomas Tauke; Ferreira, Kurt Brian; Brightwell, Ronald Brian

    2011-09-01

    Next-generation exascale systems, those capable of performing a quintillion (10{sup 18}) operations per second, are expected to be delivered in the next 8-10 years. These systems, which will be 1,000 times faster than current systems, will be of unprecedented scale. As these systems continue to grow in size, faults will become increasingly common, even over the course of small calculations. Therefore, issues such as fault tolerance and reliability will limit application scalability. Current techniques to ensure progress across faults like checkpoint/restart, the dominant fault tolerance mechanism for the last 25 years, are increasingly problematic at the scales of future systems due to their excessive overheads. In this work, we evaluate a number of techniques to decrease the overhead of checkpoint/restart and keep this method viable for future exascale systems. More specifically, this work evaluates state-machine replication to dramatically increase the checkpoint interval (the time between successive checkpoint) and hash-based, probabilistic incremental checkpointing using graphics processing units to decrease the checkpoint commit time (the time to save one checkpoint). Using a combination of empirical analysis, modeling, and simulation, we study the costs and benefits of these approaches on a wide range of parameters. These results, which cover of number of high-performance computing capability workloads, different failure distributions, hardware mean time to failures, and I/O bandwidths, show the potential benefits of these techniques for meeting the reliability demands of future exascale platforms.

  1. Acquisition of Skill Proficiency Over Multiple Sessions of a Novel Rover Simulation

    Science.gov (United States)

    Dean, S. L.; DeDios,Y. E.; MacDougall, H. G.; Moore, S. T.; Wood, S. J.

    2011-01-01

    Following long-duration exploration transits, adaptive changes in sensorimotor function may impair the crew's ability to safely perform manual control tasks such as operating pressurized rovers. Postflight performance will also be influenced by the level of preflight skill proficiency they have attained. The purpose of this study was to characterize the acquisition of skills in a motion-based rover simulation over multiple sessions, and to investigate the effects of varying the simulation scenarios. METHODS: Twenty healthy subjects were tested in 5 sessions, with 1-3 days between sessions. Each session consisted of a serial presentation of 8 discrete tasks to be completed as quickly and accurately as possible. Each task consisted of 1) perspective-taking, using a map that defined a docking target, 2) navigation toward the target around a Martian outpost, and 3) docking a side hatch of the rover to a visually guided target. The simulator utilized a Stewart-type motion base (CKAS, Australia), single-seat cabin with triple scene projection covering 150 deg horizontal by 50 deg vertical, and joystick controller. Subjects were randomly assigned to a control group (tasks identical in the first 4 sessions) or a varied-practice group. The dependent variables for each task included accuracy toward the target and time to completion. RESULTS: The greatest improvements in time to completion occurred during the docking phase. The varied-practice group showed more improvement in perspective-taking accuracy. Perspective-taking accuracy was also affected by the relative orientation of the rover to the docking target. Skill acquisition was correlated with self-ratings of previous gaming experience. DISCUSSION: Varying task selection and difficulty will optimize the preflight acquisition of skills when performing novel operational tasks. Simulation of operational manual control will provide functionally relevant evidence regarding the impact of sensorimotor adaptation on early

  2. Advances of Immune Checkpoint Inhibitors in Tumor Immunotherapy

    Science.gov (United States)

    Guo, Qiao

    2018-01-01

    Immune checkpoints are cell surface molecules that can fine-tune the immune responses, they are crucial for modulating the duration and amplitude of immune reactions while maintaining self-tolerance in order to minimize autoimmune responses. Numerous studies have demonstrated that tumors cells can directly express immune-checkpoint molecules, or induce many inhibitory molecules expression in the tumor microenvironment to inhibit the anti-tumor immunity. Releasing these brakes has emerged as an exciting strategy to cure cancer. In the past few years, clinical trials with therapeutic antibodies targeting to the checkpoint molecules CTLA-4 and PD-1 have rekindled the hope for cancer immunotherapy. In contrast to the conventional treatment, checkpoint inhibitors induce broad and durable antitumor responses. In the future, treatment may involve combination therapy to target different checkpoint molecules and stages of the adaptive immune responses. In this review, we summarized the recent advances of the study and development of other checkpoint molecules in tumor immunotherapy.

  3. Checkpointing and Recovery in Distributed and Database Systems

    Science.gov (United States)

    Wu, Jiang

    2011-01-01

    A transaction-consistent global checkpoint of a database records a state of the database which reflects the effect of only completed transactions and not the results of any partially executed transactions. This thesis establishes the necessary and sufficient conditions for a checkpoint of a data item (or the checkpoints of a set of data items) to…

  4. Phosphorylation of Minichromosome Maintenance 3 (MCM3) by Checkpoint Kinase 1 (Chk1) Negatively Regulates DNA Replication and Checkpoint Activation.

    Science.gov (United States)

    Han, Xiangzi; Mayca Pozo, Franklin; Wisotsky, Jacob N; Wang, Benlian; Jacobberger, James W; Zhang, Youwei

    2015-05-08

    Mechanisms controlling DNA replication and replication checkpoint are critical for the maintenance of genome stability and the prevention or treatment of human cancers. Checkpoint kinase 1 (Chk1) is a key effector protein kinase that regulates the DNA damage response and replication checkpoint. The heterohexameric minichromosome maintenance (MCM) complex is the core component of mammalian DNA helicase and has been implicated in replication checkpoint activation. Here we report that Chk1 phosphorylates the MCM3 subunit of the MCM complex at Ser-205 under normal growth conditions. Mutating the Ser-205 of MCM3 to Ala increased the length of DNA replication track and shortened the S phase duration, indicating that Ser-205 phosphorylation negatively controls normal DNA replication. Upon replicative stress treatment, the inhibitory phosphorylation of MCM3 at Ser-205 was reduced, and this reduction was accompanied with the generation of single strand DNA, the key platform for ataxia telangiectasia mutated and Rad3-related (ATR) activation. As a result, the replication checkpoint is activated. Together, these data provide significant insights into the regulation of both normal DNA replication and replication checkpoint activation through the novel phosphorylation of MCM3 by Chk1. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  5. Verb-Noun Collocation Proficiency and Academic Years

    Directory of Open Access Journals (Sweden)

    Fatemeh Ebrahimi-Bazzaz

    2014-01-01

    Full Text Available Generally vocabulary and collocations in particular have significant roles in language proficiency. A collocation includes two words that are frequently joined concurrently in the memory of native speakers. There have been many linguistic studies trying to define, to describe, and to categorise English collocations. It contains grammatical collocations and lexical collocations which include nouns, adjectives, verbs, and adverb. In the context of a foreign language environment such as Iran, collocational proficiency can be useful because it helps the students improve their language proficiency. This paper investigates the possible relationship between verb-noun collocation proficiency among students from one academic year to the next. To reach this goal, a test of verb-noun collocations was administered to Iranian learners. The participants in the study were 212 Iranian students in an Iranian university. They were selected from the second term of freshman, sophomore, junior, and senior years. The students’ age ranged from 18 to 35.The results of ANOVA showed there was variability in the verb-noun collocations proficiency within each academic year and between the four academic years. The results of a post hoc multiple comparison tests demonstrated that the means are significantly different between the first year and the third and fourth years, and between the third and the fourth academic year; however, students require at least two years to show significant development in verb-noun collocation proficiency. These findings provided a vital implication that lexical collocations are learnt and developed through four academic years of university, but requires at least two years showing significant development in the language proficiency.

  6. Transparent checkpointing and process migration in a distributed system

    OpenAIRE

    2004-01-01

    A distributed system for creating a checkpoint for a plurality of processes running on the distributed system. The distributed system includes a plurality of compute nodes with an operating system executing on each compute node. A checkpoint library resides at the user level on each of the compute nodes, and the checkpoint library is transparent to the operating system residing on the same compute node and to the other compute nodes. Each checkpoint library uses a windowed messaging logging p...

  7. Checkpoint independence of most DNA replication origins in fission yeast.

    Science.gov (United States)

    Mickle, Katie L; Ramanathan, Sunita; Rosebrock, Adam; Oliva, Anna; Chaudari, Amna; Yompakdee, Chulee; Scott, Donna; Leatherwood, Janet; Huberman, Joel A

    2007-12-19

    In budding yeast, the replication checkpoint slows progress through S phase by inhibiting replication origin firing. In mammals, the replication checkpoint inhibits both origin firing and replication fork movement. To find out which strategy is employed in the fission yeast, Schizosaccharomyces pombe, we used microarrays to investigate the use of origins by wild-type and checkpoint-mutant strains in the presence of hydroxyurea (HU), which limits the pool of deoxyribonucleoside triphosphates (dNTPs) and activates the replication checkpoint. The checkpoint-mutant cells carried deletions either of rad3 (which encodes the fission yeast homologue of ATR) or cds1 (which encodes the fission yeast homologue of Chk2). Our microarray results proved to be largely consistent with those independently obtained and recently published by three other laboratories. However, we were able to reconcile differences between the previous studies regarding the extent to which fission yeast replication origins are affected by the replication checkpoint. We found (consistent with the three previous studies after appropriate interpretation) that, in surprising contrast to budding yeast, most fission yeast origins, including both early- and late-firing origins, are not significantly affected by checkpoint mutations during replication in the presence of HU. A few origins (approximately 3%) behaved like those in budding yeast: they replicated earlier in the checkpoint mutants than in wild type. These were located primarily in the heterochromatic subtelomeric regions of chromosomes 1 and 2. Indeed, the subtelomeric regions defined by the strongest checkpoint restraint correspond precisely to previously mapped subtelomeric heterochromatin. This observation implies that subtelomeric heterochromatin in fission yeast differs from heterochromatin at centromeres, in the mating type region, and in ribosomal DNA, since these regions replicated at least as efficiently in wild-type cells as in checkpoint

  8. Checkpoint independence of most DNA replication origins in fission yeast

    Science.gov (United States)

    Mickle, Katie L; Ramanathan, Sunita; Rosebrock, Adam; Oliva, Anna; Chaudari, Amna; Yompakdee, Chulee; Scott, Donna; Leatherwood, Janet; Huberman, Joel A

    2007-01-01

    Background In budding yeast, the replication checkpoint slows progress through S phase by inhibiting replication origin firing. In mammals, the replication checkpoint inhibits both origin firing and replication fork movement. To find out which strategy is employed in the fission yeast, Schizosaccharomyces pombe, we used microarrays to investigate the use of origins by wild-type and checkpoint-mutant strains in the presence of hydroxyurea (HU), which limits the pool of deoxyribonucleoside triphosphates (dNTPs) and activates the replication checkpoint. The checkpoint-mutant cells carried deletions either of rad3 (which encodes the fission yeast homologue of ATR) or cds1 (which encodes the fission yeast homologue of Chk2). Results Our microarray results proved to be largely consistent with those independently obtained and recently published by three other laboratories. However, we were able to reconcile differences between the previous studies regarding the extent to which fission yeast replication origins are affected by the replication checkpoint. We found (consistent with the three previous studies after appropriate interpretation) that, in surprising contrast to budding yeast, most fission yeast origins, including both early- and late-firing origins, are not significantly affected by checkpoint mutations during replication in the presence of HU. A few origins (~3%) behaved like those in budding yeast: they replicated earlier in the checkpoint mutants than in wild type. These were located primarily in the heterochromatic subtelomeric regions of chromosomes 1 and 2. Indeed, the subtelomeric regions defined by the strongest checkpoint restraint correspond precisely to previously mapped subtelomeric heterochromatin. This observation implies that subtelomeric heterochromatin in fission yeast differs from heterochromatin at centromeres, in the mating type region, and in ribosomal DNA, since these regions replicated at least as efficiently in wild-type cells as in

  9. Checkpoint independence of most DNA replication origins in fission yeast

    Directory of Open Access Journals (Sweden)

    Scott Donna

    2007-12-01

    Full Text Available Abstract Background In budding yeast, the replication checkpoint slows progress through S phase by inhibiting replication origin firing. In mammals, the replication checkpoint inhibits both origin firing and replication fork movement. To find out which strategy is employed in the fission yeast, Schizosaccharomyces pombe, we used microarrays to investigate the use of origins by wild-type and checkpoint-mutant strains in the presence of hydroxyurea (HU, which limits the pool of deoxyribonucleoside triphosphates (dNTPs and activates the replication checkpoint. The checkpoint-mutant cells carried deletions either of rad3 (which encodes the fission yeast homologue of ATR or cds1 (which encodes the fission yeast homologue of Chk2. Results Our microarray results proved to be largely consistent with those independently obtained and recently published by three other laboratories. However, we were able to reconcile differences between the previous studies regarding the extent to which fission yeast replication origins are affected by the replication checkpoint. We found (consistent with the three previous studies after appropriate interpretation that, in surprising contrast to budding yeast, most fission yeast origins, including both early- and late-firing origins, are not significantly affected by checkpoint mutations during replication in the presence of HU. A few origins (~3% behaved like those in budding yeast: they replicated earlier in the checkpoint mutants than in wild type. These were located primarily in the heterochromatic subtelomeric regions of chromosomes 1 and 2. Indeed, the subtelomeric regions defined by the strongest checkpoint restraint correspond precisely to previously mapped subtelomeric heterochromatin. This observation implies that subtelomeric heterochromatin in fission yeast differs from heterochromatin at centromeres, in the mating type region, and in ribosomal DNA, since these regions replicated at least as efficiently in wild

  10. Enhancing Immune Checkpoint Inhibitor Therapy in Kidney Cancer

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-15-1-0141 TITLE: Enhancing Immune Checkpoint Inhibitor therapy in Kidney Cancer PRINCIPAL INVESTIGATOR: Hans-Joerg Hammers...SUBTITLE Enhancing Immune Checkpoint Inhibitor therapy in Kidney Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH- 15-1-0141 5c. PROGRAM ELEMENT NUMBER...immune checkpoint inhibition in kidney cancer . The work is designed to test different strategies to induce or enhance the abscopal in a kidney cancer

  11. National radon measurement-proficiency program: Individual proficiency report

    International Nuclear Information System (INIS)

    1992-05-01

    In February 1986, the U.S. Environmental Protection Agency (EPA) established the Radon Measurement Proficiency (RMP) Program to assist the public in identifying organizations capable of providing reliable radon measurement services. In December 1991, EPA announced the new individual proficiency listing category in the RMP Program. Individuals applying for this new listing status must demonstrate knowledge of radon measurement fundamentals by passing a written proficiency examination, maintain affiliation with an RMP listed organization, and meet other program requirements. This report lists those individuals who have met the requirements of the RMP Program as of April 30, 1992. These requirements are designed to provide minimum proficiency criteria for individuals who provide radon measurement services on-site in a residential environment

  12. National Radon Contractor Proficiency Program. Proficiency report: Supplement

    International Nuclear Information System (INIS)

    1991-02-01

    The report, a supplement to the RCP Proficiency Report, will further assist governmental officials in providing advice to the public on the selection of proficient radon mitigation contractors. These reports list 1,123 contractors who have met the requirements of the RCP Program as of December 15, 1990. The Proficiency Report provides information on each contractor's name, RCP identification number, company name, address, phone number, and geographic service area. The report provides two additional tables, indexed by company name and by RCP identification number. The report is intended to help users quickly identify a proficient contractor if only the company name is known, or to verify which contractor is associated with a particular ID number

  13. Template based parallel checkpointing in a massively parallel computer system

    Science.gov (United States)

    Archer, Charles Jens [Rochester, MN; Inglett, Todd Alan [Rochester, MN

    2009-01-13

    A method and apparatus for a template based parallel checkpoint save for a massively parallel super computer system using a parallel variation of the rsync protocol, and network broadcast. In preferred embodiments, the checkpoint data for each node is compared to a template checkpoint file that resides in the storage and that was previously produced. Embodiments herein greatly decrease the amount of data that must be transmitted and stored for faster checkpointing and increased efficiency of the computer system. Embodiments are directed to a parallel computer system with nodes arranged in a cluster with a high speed interconnect that can perform broadcast communication. The checkpoint contains a set of actual small data blocks with their corresponding checksums from all nodes in the system. The data blocks may be compressed using conventional non-lossy data compression algorithms to further reduce the overall checkpoint size.

  14. Hypoxia‐induced alterations of G2 checkpoint regulators

    OpenAIRE

    Hasvold, Grete; Lund-Andersen, Christin; Lando, Malin; Patzke, Sebastian; Hauge, Sissel; Suo, ZhenHe; Lyng, Heidi; Syljuåsen, Randi G.

    2016-01-01

    Hypoxia promotes an aggressive tumor phenotype with increased genomic instability, partially due to downregulation of DNA repair pathways. However, genome stability is also surveilled by cell cycle checkpoints. An important issue is therefore whether hypoxia also can influence the DNA damage‐induced cell cycle checkpoints. Here, we show that hypoxia (24 h 0.2% O2) alters the expression of several G2 checkpoint regulators, as examined by microarray gene expression analysis and immunoblotting o...

  15. Berkeley lab checkpoint/restart (BLCR) for Linux clusters

    International Nuclear Information System (INIS)

    Hargrove, Paul H; Duell, Jason C

    2006-01-01

    This article describes the motivation, design and implementation of Berkeley Lab Checkpoint/Restart (BLCR), a system-level checkpoint/restart implementation for Linux clusters that targets the space of typical High Performance Computing applications, including MPI. Application-level solutions, including both checkpointing and fault-tolerant algorithms, are recognized as more time and space efficient than system-level checkpoints, which cannot make use of any application-specific knowledge. However, system-level checkpointing allows for preemption, making it suitable for responding to ''fault precursors'' (for instance, elevated error rates from ECC memory or network CRCs, or elevated temperature from sensors). Preemption can also increase the efficiency of batch scheduling; for instance reducing idle cycles (by allowing for shutdown without any queue draining period or reallocation of resources to eliminate idle nodes when better fitting jobs are queued), and reducing the average queued time (by limiting large jobs to running during off-peak hours, without the need to limit the length of such jobs). Each of these potential uses makes BLCR a valuable tool for efficient resource management in Linux clusters

  16. Does a peer model's task proficiency influence children's solution choice and innovation?

    Science.gov (United States)

    Wood, Lara A; Kendal, Rachel L; Flynn, Emma G

    2015-11-01

    The current study investigated whether 4- to 6-year-old children's task solution choice was influenced by the past proficiency of familiar peer models and the children's personal prior task experience. Peer past proficiency was established through behavioral assessments of interactions with novel tasks alongside peer and teacher predictions of each child's proficiency. Based on these assessments, one peer model with high past proficiency and one age-, sex-, dominance-, and popularity-matched peer model with lower past proficiency were trained to remove a capsule using alternative solutions from a three-solution artificial fruit task. Video demonstrations of the models were shown to children after they had either a personal successful interaction or no interaction with the task. In general, there was not a strong bias toward the high past-proficiency model, perhaps due to a motivation to acquire multiple methods and the salience of other transmission biases. However, there was some evidence of a model-based past-proficiency bias; when the high past-proficiency peer matched the participants' original solution, there was increased use of that solution, whereas if the high past-proficiency peer demonstrated an alternative solution, there was increased use of the alternative social solution and novel solutions. Thus, model proficiency influenced innovation. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Prevention of DNA Rereplication Through a Meiotic Recombination Checkpoint Response

    Directory of Open Access Journals (Sweden)

    Nicole A. Najor

    2016-12-01

    Full Text Available In the budding yeast Saccharomyces cerevisiae, unnatural stabilization of the cyclin-dependent kinase inhibitor Sic1 during meiosis can trigger extra rounds of DNA replication. When programmed DNA double-strand breaks (DSBs are generated but not repaired due to absence of DMC1, a pathway involving the checkpoint gene RAD17 prevents this DNA rereplication. Further genetic analysis has now revealed that prevention of DNA rereplication also requires MEC1, which encodes a protein kinase that serves as a central checkpoint regulator in several pathways including the meiotic recombination checkpoint response. Downstream of MEC1, MEK1 is required through its function to inhibit repair between sister chromatids. By contrast, meiotic recombination checkpoint effectors that regulate gene expression and cyclin-dependent kinase activity are not necessary. Phosphorylation of histone H2A, which is catalyzed by Mec1 and the related Tel1 protein kinase in response to DSBs, and can help coordinate activation of the Rad53 checkpoint protein kinase in the mitotic cell cycle, is required for the full checkpoint response. Phosphorylation sites that are targeted by Rad53 in a mitotic S phase checkpoint response are also involved, based on the behavior of cells containing mutations in the DBF4 and SLD3 DNA replication genes. However, RAD53 does not appear to be required, nor does RAD9, which encodes a mediator of Rad53, consistent with their lack of function in the recombination checkpoint pathway that prevents meiotic progression. While this response is similar to a checkpoint mechanism that inhibits initiation of DNA replication in the mitotic cell cycle, the evidence points to a new variation on DNA replication control.

  18. "Isogaba Maware": quality control of genome DNA by checkpoints.

    Science.gov (United States)

    Kitazono, A; Matsumoto, T

    1998-05-01

    Checkpoints maintain the interdependency of cell cycle events by permitting the onset of an event only after the completion of the preceding event. The DNA replication checkpoint induces a cell cycle arrest until the completion of the DNA replication. Similarly, the DNA damage checkpoint arrests cell cycle progression if DNA repair is incomplete. A number of genes that play a role in the two checkpoints have been identified through genetic studies in yeasts, and their homologues have been found in fly, mouse, and human. They form signaling cascades activated by a DNA replication block or DNA damage and subsequently generate the negative constraints on cell cycle regulators. The failure of these signaling cascades results in producing offspring that carry mutations or that lack a portion of the genome. In humans, defects in the checkpoints are often associated with cancer-prone diseases. Focusing mainly on the studies in budding and fission yeasts, we summarize the recent progress.

  19. Newly Emerging Immune Checkpoints: Promises for Future Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Robert J. Torphy

    2017-12-01

    Full Text Available Cancer immunotherapy has been a great breakthrough, with immune checkpoint inhibitors leading the way. Despite the clinical effectiveness of certain immune checkpoint inhibitors, the overall response rate remains low, and the effectiveness of immunotherapies for many tumors has been disappointing. There is substantial interest in looking for additional immune checkpoint molecules that may act as therapeutic targets for cancer. Recent advances during the last decade have identified several novel immune checkpoint targets, including lymphocyte activation gene-3 (LAG-3, B and T lymphocyte attenuator (BTLA, programmed death-1 homolog (PD-1H, T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIM-3/carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1, and the poliovirus receptor (PVR-like receptors. The investigations into these molecules have generated promising results in preclinical studies. Herein, we will summarize our current progress and understanding of these newly-characterized immune checkpoints and their potential application in cancer immunotherapy.

  20. Radiotherapy and immune checkpoint blockades: a snapshot in 2016

    Energy Technology Data Exchange (ETDEWEB)

    Koo, Tae Yool [Dept. of Radiation Oncology, Hallym University Chuncheon Sacred Heart Hospital, Chuncheon (Korea, Republic of); Kim, In Ah [Dept. of Radiation Oncology, Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2016-12-15

    Immune checkpoint blockades including monoclonal antibodies (mAbs) of cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and programmed death-ligand 1 (PD-L1) have been emerged as a promising anticancer therapy. Several immune checkpoint blockades have been approved by US Food and Drug Administration (FDA), and have shown notable success in clinical trials for patients with advanced melanoma and non-small cell lung cancer. Radiotherapy is a promising combination partner of immune checkpoint blockades due to its potent pro-immune effect. This review will cover the current issue and the future perspectives for combined with radiotherapy and immune checkpoint blockades based upon the available preclinical and clinical data.

  1. The DNA replication checkpoint directly regulates MBF-dependent G1/S transcription.

    Science.gov (United States)

    Dutta, Chaitali; Patel, Prasanta K; Rosebrock, Adam; Oliva, Anna; Leatherwood, Janet; Rhind, Nicholas

    2008-10-01

    The DNA replication checkpoint transcriptionally upregulates genes that allow cells to adapt to and survive replication stress. Our results show that, in the fission yeast Schizosaccharomyces pombe, the replication checkpoint regulates the entire G(1)/S transcriptional program by directly regulating MBF, the G(1)/S transcription factor. Instead of initiating a checkpoint-specific transcriptional program, the replication checkpoint targets MBF to maintain the normal G(1)/S transcriptional program during replication stress. We propose a mechanism for this regulation, based on in vitro phosphorylation of the Cdc10 subunit of MBF by the Cds1 replication-checkpoint kinase. Replacement of two potential phosphorylation sites with phosphomimetic amino acids suffices to promote the checkpoint transcriptional program, suggesting that Cds1 phosphorylation directly regulates MBF-dependent transcription. The conservation of MBF between fission and budding yeast, and recent results implicating MBF as a target of the budding yeast replication checkpoint, suggests that checkpoint regulation of the MBF transcription factor is a conserved strategy for coping with replication stress. Furthermore, the structural and regulatory similarity between MBF and E2F, the metazoan G(1)/S transcription factor, suggests that this checkpoint mechanism may be broadly conserved among eukaryotes.

  2. The DNA Replication Checkpoint Directly Regulates MBF-Dependent G1/S Transcription▿

    Science.gov (United States)

    Dutta, Chaitali; Patel, Prasanta K.; Rosebrock, Adam; Oliva, Anna; Leatherwood, Janet; Rhind, Nicholas

    2008-01-01

    The DNA replication checkpoint transcriptionally upregulates genes that allow cells to adapt to and survive replication stress. Our results show that, in the fission yeast Schizosaccharomyces pombe, the replication checkpoint regulates the entire G1/S transcriptional program by directly regulating MBF, the G1/S transcription factor. Instead of initiating a checkpoint-specific transcriptional program, the replication checkpoint targets MBF to maintain the normal G1/S transcriptional program during replication stress. We propose a mechanism for this regulation, based on in vitro phosphorylation of the Cdc10 subunit of MBF by the Cds1 replication-checkpoint kinase. Replacement of two potential phosphorylation sites with phosphomimetic amino acids suffices to promote the checkpoint transcriptional program, suggesting that Cds1 phosphorylation directly regulates MBF-dependent transcription. The conservation of MBF between fission and budding yeast, and recent results implicating MBF as a target of the budding yeast replication checkpoint, suggests that checkpoint regulation of the MBF transcription factor is a conserved strategy for coping with replication stress. Furthermore, the structural and regulatory similarity between MBF and E2F, the metazoan G1/S transcription factor, suggests that this checkpoint mechanism may be broadly conserved among eukaryotes. PMID:18662996

  3. Assessment of Proficiency During Simulated Rover Operations Following Long-Duration Spaceflight

    Science.gov (United States)

    Wood, S. J.; Dean, S. L.; De Dios, Y. E.; MacDougall, H. G.; Moore, S. T.

    2011-01-01

    Following long-duration space travel, pressurized rovers will enhance crew mobility to explore Mars and other planetary surfaces. Adaptive changes in sensorimotor function may limit the crew s proficiency when performing some rover operations shortly after transition to the new gravitoinertial environment. The primary goal of this investigation is to quantify postflight decrements in operational proficiency in a motion-based rover simulation after International Space Station (ISS) expeditions. Given that postflight performance will also be influenced by the level of preflight proficiency attained, a ground-based normative study was conducted to characterize the acquisition of skills over multiple sessions.

  4. Molecular Mechanisms of DNA Replication Checkpoint Activation

    Directory of Open Access Journals (Sweden)

    Bénédicte Recolin

    2014-03-01

    Full Text Available The major challenge of the cell cycle is to deliver an intact, and fully duplicated, genetic material to the daughter cells. To this end, progression of DNA synthesis is monitored by a feedback mechanism known as replication checkpoint that is untimely linked to DNA replication. This signaling pathway ensures coordination of DNA synthesis with cell cycle progression. Failure to activate this checkpoint in response to perturbation of DNA synthesis (replication stress results in forced cell division leading to chromosome fragmentation, aneuploidy, and genomic instability. In this review, we will describe current knowledge of the molecular determinants of the DNA replication checkpoint in eukaryotic cells and discuss a model of activation of this signaling pathway crucial for maintenance of genomic stability.

  5. Immune mediated neuropathy following checkpoint immunotherapy.

    Science.gov (United States)

    Gu, Yufan; Menzies, Alexander M; Long, Georgina V; Fernando, S L; Herkes, G

    2017-11-01

    Checkpoint immunotherapy has revolutionised cancer therapy and is now standard treatment for many malignancies including metastatic melanoma. Acute inflammatory neuropathies, often labelled as Guillain-Barre syndrome, are an uncommon but potentially severe complication of checkpoint immunotherapy with individual cases described but never characterised as a group. We describe a case of acute sensorimotor and autonomic neuropathy following a single dose of combination ipilimumab and nivolumab for metastatic melanoma. A literature search was performed, identifying 14 other cases of acute neuropathy following checkpoint immunotherapy, with the clinical, electrophysiological and laboratory features summarised. Most cases described an acute sensorimotor neuropathy (92%) with hyporeflexia (92%) that could occur from induction up till many weeks after the final dose of therapy. In contrast to Guillain-Barre syndrome, the cerebrospinal fluid (CSF) analysis often shows a lymphocytic picture (50%) and the electrophysiology showed an axonal pattern (55%). Treatment was variable and often in combination. 11 cases received steroid therapy with only 1 death within this group, whereas of the 4 patients who did not receive steroid therapy there were 3 deaths. In conclusion checkpoint immunotherapy - induced acute neuropathies are distinct from and progress differently to Guillain-Barre syndrome. As with other immunotherapy related adverse events corticosteroid therapy should be initiated in addition to usual therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. The DNA Replication Checkpoint Directly Regulates MBF-Dependent G1/S Transcription▿

    OpenAIRE

    Dutta, Chaitali; Patel, Prasanta K.; Rosebrock, Adam; Oliva, Anna; Leatherwood, Janet; Rhind, Nicholas

    2008-01-01

    The DNA replication checkpoint transcriptionally upregulates genes that allow cells to adapt to and survive replication stress. Our results show that, in the fission yeast Schizosaccharomyces pombe, the replication checkpoint regulates the entire G1/S transcriptional program by directly regulating MBF, the G1/S transcription factor. Instead of initiating a checkpoint-specific transcriptional program, the replication checkpoint targets MBF to maintain the normal G1/S transcriptional program du...

  7. Relationships Between English Language Proficiency, Health Literacy, and Health Outcomes in Somali Refugees.

    Science.gov (United States)

    Murphy, Jessica E; Smock, Laura; Hunter-Adams, Jo; Xuan, Ziming; Cochran, Jennifer; Paasche-Orlow, Michael K; Geltman, Paul L

    2018-06-15

    Little is known about the impacts of health literacy and English proficiency on the health status of Somali refugees. Data came from interviews in 2009-2011 of 411 adult Somali refugees recently resettled in Massachusetts. English proficiency, health literacy, and physical and mental health were measured using the Basic English Skills Test Plus, the Short Test of Health Literacy in Adults, and the Physical and Mental Component Summaries of the Short Form-12. Associations were analyzed using multiple linear regression. In adjusted analyses, higher English proficiency was associated with worse mental health in males. English proficiency was not associated with physical health. Health literacy was associated with neither physical nor mental health. Language proficiency may adversely affect the mental health of male Somali refugees, contrary to findings in other immigrant groups. Research on underlying mechanisms and opportunities to understand this relationship are needed.

  8. Orchestration of DNA Damage Checkpoint Dynamics across the Human Cell Cycle.

    Science.gov (United States)

    Chao, Hui Xiao; Poovey, Cere E; Privette, Ashley A; Grant, Gavin D; Chao, Hui Yan; Cook, Jeanette G; Purvis, Jeremy E

    2017-11-22

    Although molecular mechanisms that prompt cell-cycle arrest in response to DNA damage have been elucidated, the systems-level properties of DNA damage checkpoints are not understood. Here, using time-lapse microscopy and simulations that model the cell cycle as a series of Poisson processes, we characterize DNA damage checkpoints in individual, asynchronously proliferating cells. We demonstrate that, within early G1 and G2, checkpoints are stringent: DNA damage triggers an abrupt, all-or-none cell-cycle arrest. The duration of this arrest correlates with the severity of DNA damage. After the cell passes commitment points within G1 and G2, checkpoint stringency is relaxed. By contrast, all of S phase is comparatively insensitive to DNA damage. This checkpoint is graded: instead of halting the cell cycle, increasing DNA damage leads to slower S phase progression. In sum, we show that a cell's response to DNA damage depends on its exact cell-cycle position and that checkpoints are phase-dependent, stringent or relaxed, and graded or all-or-none. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Computer proficiency questionnaire: assessing low and high computer proficient seniors.

    Science.gov (United States)

    Boot, Walter R; Charness, Neil; Czaja, Sara J; Sharit, Joseph; Rogers, Wendy A; Fisk, Arthur D; Mitzner, Tracy; Lee, Chin Chin; Nair, Sankaran

    2015-06-01

    Computers and the Internet have the potential to enrich the lives of seniors and aid in the performance of important tasks required for independent living. A prerequisite for reaping these benefits is having the skills needed to use these systems, which is highly dependent on proper training. One prerequisite for efficient and effective training is being able to gauge current levels of proficiency. We developed a new measure (the Computer Proficiency Questionnaire, or CPQ) to measure computer proficiency in the domains of computer basics, printing, communication, Internet, calendaring software, and multimedia use. Our aim was to develop a measure appropriate for individuals with a wide range of proficiencies from noncomputer users to extremely skilled users. To assess the reliability and validity of the CPQ, a diverse sample of older adults, including 276 older adults with no or minimal computer experience, was recruited and asked to complete the CPQ. The CPQ demonstrated excellent reliability (Cronbach's α = .98), with subscale reliabilities ranging from .86 to .97. Age, computer use, and general technology use all predicted CPQ scores. Factor analysis revealed three main factors of proficiency related to Internet and e-mail use; communication and calendaring; and computer basics. Based on our findings, we also developed a short-form CPQ (CPQ-12) with similar properties but 21 fewer questions. The CPQ and CPQ-12 are useful tools to gauge computer proficiency for training and research purposes, even among low computer proficient older adults. © The Author 2013. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  10. Checkpoint independence of most DNA replication origins in fission yeast

    OpenAIRE

    Mickle, Katie L; Ramanathan, Sunita; Rosebrock, Adam; Oliva, Anna; Chaudari, Amna; Yompakdee, Chulee; Scott, Donna; Leatherwood, Janet; Huberman, Joel A

    2007-01-01

    Abstract Background In budding yeast, the replication checkpoint slows progress through S phase by inhibiting replication origin firing. In mammals, the replication checkpoint inhibits both origin firing and replication fork movement. To find out which strategy is employed in the fission yeast, Schizosaccharomyces pombe, we used microarrays to investigate the use of origins by wild-type and checkpoint-mutant strains in the presence of hydroxyurea (HU), which limits the pool of deoxyribonucleo...

  11. Checkpointing for graceful degradation in distributed embedded systems

    Science.gov (United States)

    Sababha, Belal Hussein

    Graceful degradation is an approach to developing dependable safety-critical embedded applications, where redundant active or standby resources are used to cope with faults through a system reconfiguration at run-time. Compared to traditional hardware and software redundancy, it is a promising technique that may achieve dependability with a significant reduction in cost, size, weight, and power requirements. Reconfiguration at run-time necessitates using proper checkpointing protocols to support state reservation to ensure correct task restarts after a system reconfiguration. One of the most common checkpointing protocols are communication induced checkpointing (CIC) protocols, which are well developed and understood for large parallel and information systems, but not much has been done for resource limited embedded systems. This work implements and evaluates some of the most common CIC protocols in a periodic resource constrained distributed embedded system for graceful degradation purposes. A test-bed has been developed and used for the evaluation of the various protocols. The implemented protocols are thoroughly studied and performances are contrasted. Specifically the periodicity property and how it benefits checkpointing in embedded systems is investigated. This work introduces a unique effort of CIC protocol implementation and evaluation in the field of distributed embedded systems. Other than providing a test-bed for graceful degradation support, this work shows that some checkpointing protocols that are not efficient in large information systems and supercomputers perform well in embedded systems. We show that a simple index-based CIC protocol, such as the BCS protocol, is more appropriate in embedded system applications compared to other protocols that piggyback a significant amount of information to reduce the number of forced checkpoints. Finally, this work proposes a whole graceful degradation approach to achieve fault tolerance in resource constrained

  12. Combination approaches with immune checkpoint blockade in cancer therapy

    Directory of Open Access Journals (Sweden)

    Maarten Swart

    2016-11-01

    Full Text Available In healthy individuals, immune checkpoint molecules prevent autoimmune responses and limit immune cell-mediated tissue damage. Tumors frequently exploit these molecules to evade eradication by the immune system. Over the past years, immune checkpoint blockade of cytotoxic T lymphocyte antigen-4 (CTLA-4 and programmed death-1 (PD-1 emerged as promising strategies to activate anti-tumor cytotoxic T cell responses. Although complete regression and long-term survival is achieved in some patients, not all patients respond. This review describes promising, novel combination approaches involving immune checkpoint blockade, aimed at increasing response-rates to the single treatments.

  13. Space Reclamation for Uncoordinated Checkpointing in Message-Passing Systems. Ph.D. Thesis

    Science.gov (United States)

    Wang, Yi-Min

    1993-01-01

    Checkpointing and rollback recovery are techniques that can provide efficient recovery from transient process failures. In a message-passing system, the rollback of a message sender may cause the rollback of the corresponding receiver, and the system needs to roll back to a consistent set of checkpoints called recovery line. If the processes are allowed to take uncoordinated checkpoints, the above rollback propagation may result in the domino effect which prevents recovery line progression. Traditionally, only obsolete checkpoints before the global recovery line can be discarded, and the necessary and sufficient condition for identifying all garbage checkpoints has remained an open problem. A necessary and sufficient condition for achieving optimal garbage collection is derived and it is proved that the number of useful checkpoints is bounded by N(N+1)/2, where N is the number of processes. The approach is based on the maximum-sized antichain model of consistent global checkpoints and the technique of recovery line transformation and decomposition. It is also shown that, for systems requiring message logging to record in-transit messages, the same approach can be used to achieve optimal message log reclamation. As a final topic, a unifying framework is described by considering checkpoint coordination and exploiting piecewise determinism as mechanisms for bounding rollback propagation, and the applicability of the optimal garbage collection algorithm to domino-free recovery protocols is demonstrated.

  14. Sobriety checkpoints in Thailand: a review of effectiveness and developments over time.

    Science.gov (United States)

    Ditsuwan, Vallop; Veerman, J Lennert; Bertram, Melanie; Vos, Theo

    2015-03-01

    This review describes the legal basis for and implementation of sobriety checkpoints in Thailand and identifies factors that influenced their historical development and effectiveness. The first alcohol and traffic injury control law in Thailand was implemented in 1934. The 0.05 g/100 mL blood alcohol concentration limit was set in 1994. Currently, 3 types of sobriety checkpoints are used: general police checkpoints, selective breath testing, and special event sobriety checkpoints. The authors found few reports on the strategies, frequencies, and outcomes for any of these types of checkpoints, despite Thailand having devoted many resources to their implementation. In Thailand and other low-middle income countries, it is necessary to address the country-specific barriers to successful enforcement (including political and logistical issues, lack of equipment, and absence of other supportive alcohol harm reduction measures) before sobriety checkpoints can be expected to be as effective as reported in high-income countries. © 2011 APJPH.

  15. The impact of aviation checkpoint queues on optimizing security screening effectiveness

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Adrian J., E-mail: ajlee@citeri.or [Central Illinois Technology and Education Research Institute, 2312 Connie Drive, Springfield, IL 62704-8722 (United States); Jacobson, Sheldon H., E-mail: shj@illinois.ed [Department of Computer Science, University of Illinois at Urbana-Champaign, 201 N. Goodwin Ave. M/C 258, Urbana, IL 61801-2302 (United States)

    2011-08-15

    Passenger screening at aviation security checkpoints is a critical component in protecting airports and aircraft from terrorist threats. Recent developments in screening device technology have increased the ability to detect these threats; however, the average amount of time it takes to screen a passenger still remains a concern. This paper models the queueing process for a multi-level airport checkpoint security system, where multiple security classes are formed through subsets of specialized screening devices. An optimal static assignment policy is obtained which minimizes the steady-state expected amount of time a passenger spends in the security system. Then, an optimal dynamic assignment policy is obtained through a transient analysis that balances the expected number of true alarms with the expected amount of time a passenger spends in the security system. Performance of a two-class system is compared to that of a selective security system containing primary and secondary levels of screening. The key contribution is that the resulting optimal assignment policies increase security and passenger throughput by efficiently and effectively utilizing available screening resources.

  16. The impact of aviation checkpoint queues on optimizing security screening effectiveness

    International Nuclear Information System (INIS)

    Lee, Adrian J.; Jacobson, Sheldon H.

    2011-01-01

    Passenger screening at aviation security checkpoints is a critical component in protecting airports and aircraft from terrorist threats. Recent developments in screening device technology have increased the ability to detect these threats; however, the average amount of time it takes to screen a passenger still remains a concern. This paper models the queueing process for a multi-level airport checkpoint security system, where multiple security classes are formed through subsets of specialized screening devices. An optimal static assignment policy is obtained which minimizes the steady-state expected amount of time a passenger spends in the security system. Then, an optimal dynamic assignment policy is obtained through a transient analysis that balances the expected number of true alarms with the expected amount of time a passenger spends in the security system. Performance of a two-class system is compared to that of a selective security system containing primary and secondary levels of screening. The key contribution is that the resulting optimal assignment policies increase security and passenger throughput by efficiently and effectively utilizing available screening resources.

  17. National Radon Contractor Proficiency Program. Proficiency report, October 1990

    International Nuclear Information System (INIS)

    1990-10-01

    The report lists those individual contractors in the United States who have met the requirements of the Radon Contractor Proficiency (RCP) Program as of August 18, 1990. These requirements are designed to provide minimum proficiency criteria for individuals who design and supervise the installation of radon mitigation systems in buildings. (Some States have more stringent requirements as part of their radon certification programs. The States should be consulted directly for details on their programs; see Section 5 for a list of State radon contacts). The RCP Program measures the proficiency of an individual contractor, not their company. Therefore, users of the report who select a mitigation firm should ensure that the services are provided by the listed contractor. The National RCP Program does not accredit mitigation contractors, nor does it certify, recommend, or endorse participating companies. Only the listed contractor, not their company of affilation, are deemed proficient. The inclusion of a contractor in the report should not be interpreted as a certification or accreditation of the individual or affiliated company

  18. National Radon Contractor Proficiency (RCP) Program. Proficiency report, June 1991

    International Nuclear Information System (INIS)

    1991-06-01

    The primary objective of the U.S. Environmental Protection Agency's (EPA) efforts to address the indoor radon problem is to reduce radon levels in buildings throughout the country. Achieving the objective requires a nationwide supply of capable radon mitigation contractors. In the Indoor Radon Abatement Act of 1988, Congress authorized EPA to establish a program to evaluate radon mitigation contractors and to provide the information to the public in cooperation with the States. The Radon Contractor Proficiency (RCP) Program was developed to assist States, EPA Regions, local government officials, and the public in selecting contractors who have demonstrated their proficiency in reducing indoor radon levels. The program is managed by the EPA Office of Radiation Programs' Radon Division. Under the voluntary program, radon contractors demonstrate their proficiency by meeting specific Program requirements. Individual contractors who meet these requirements are then listed in periodic RCP Proficiency Reports

  19. ATM and checkpoint responses to DNA double strand breaks

    International Nuclear Information System (INIS)

    Khanna, K.K.

    2003-01-01

    DNA damage checkpoints can be classified into G1/S, intra-S and G2/M checkpoints, so named according to the cell cycle transitions that they regulate. DNA damage incurred during the G1 or G2 phase of the cell cycle leads to growth arrest at the G1/S and G2/M phase boundaries, respectively, whereas genotoxic stress during S phase results in the transient suppression of DNA synthesis. In mammals, ATM (ataxia-telangiectasia mutated) is a protein kinase that controls all checkpoint responses to DNA damage. ATM is a versatile kinase which uses various means to regulate a given checkpoint pathway. It has been shown to act upon several proteins within the same pathway, many times controlling several different modifications of the same protein or using several different targets to arrive at the same end point. Some of the ATM targets act as adaptors by recruiting additional substrates for ATM. ATM controls two types of responses in G1. The p53-dependent responses inhibit Cyclin/Cdk activity by transcriptional induction of p21, whereas p53-independent responses inhibit CDKs through degradation of Cdc25A to maintain CdK2 inhibitory phosphorylation. In regulating p53, ATM directly phosphorylates p53 on Ser15, which likely causes p53 transcriptional activation, concurrently activating other kinases that phosphorylate p53 at other sites such as Ser20, which reduces the ability of MDM2 to bind p53, thus promoting its stability. ATM further ensures p53 stability by phosphorylating MDM2. At least six ATM targets, namely CHK2, CHK1, NBS1, BRCA1, SMC1 and FANCD2, have been implicated in the control of S-phase checkpoint. Cdc25A is the downstream effector of CHK1 and CHK2, though the underlying mechanism for control of intra S-phase checkpoint by other targets remain obscure. G2 checkpoint prevents mitotic entry solely through inhibitory phosphorylation of Cdc2/Cdk1. Several ATM targets including CHK1, CHK2, BRCA1, MDC1 and p53BP1 have been implicated in the control of G2/M

  20. Checkpoint responses to replication stalling: inducing tolerance and preventing mutagenesis

    Energy Technology Data Exchange (ETDEWEB)

    Kai, Mihoko; Wang, Teresa S.-F

    2003-11-27

    Replication mutants often exhibit a mutator phenotype characterized by point mutations, single base frameshifts, and the deletion or duplication of sequences flanked by homologous repeats. Mutation in genes encoding checkpoint proteins can significantly affect the mutator phenotype. Here, we use fission yeast (Schizosaccharomyces pombe) as a model system to discuss the checkpoint responses to replication perturbations induced by replication mutants. Checkpoint activation induced by a DNA polymerase mutant, aside from delay of mitotic entry, up-regulates the translesion polymerase DinB (Pol{kappa}). Checkpoint Rad9-Rad1-Hus1 (9-1-1) complex, which is loaded onto chromatin by the Rad17-Rfc2-5 checkpoint complex in response to replication perturbation, recruits DinB onto chromatin to generate the point mutations and single nucleotide frameshifts in the replication mutator. This chain of events reveals a novel checkpoint-induced tolerance mechanism that allows cells to cope with replication perturbation, presumably to make possible restarting stalled replication forks. Fission yeast Cds1 kinase plays an essential role in maintaining DNA replication fork stability in the face of DNA damage and replication fork stalling. Cds1 kinase is known to regulate three proteins that are implicated in maintaining replication fork stability: Mus81-Eme1, a hetero-dimeric structure-specific endonuclease complex; Rqh1, a RecQ-family helicase involved in suppressing inappropriate recombination during replication; and Rad60, a protein required for recombinational repair during replication. These Cds1-regulated proteins are thought to cooperatively prevent mutagenesis and maintain replication fork stability in cells under replication stress. These checkpoint-regulated processes allow cells to survive replication perturbation by preventing stalled replication forks from degenerating into deleterious DNA structures resulting in genomic instability and cancer development.

  1. Checkpoint responses to replication stalling: inducing tolerance and preventing mutagenesis

    International Nuclear Information System (INIS)

    Kai, Mihoko; Wang, Teresa S.-F.

    2003-01-01

    Replication mutants often exhibit a mutator phenotype characterized by point mutations, single base frameshifts, and the deletion or duplication of sequences flanked by homologous repeats. Mutation in genes encoding checkpoint proteins can significantly affect the mutator phenotype. Here, we use fission yeast (Schizosaccharomyces pombe) as a model system to discuss the checkpoint responses to replication perturbations induced by replication mutants. Checkpoint activation induced by a DNA polymerase mutant, aside from delay of mitotic entry, up-regulates the translesion polymerase DinB (Polκ). Checkpoint Rad9-Rad1-Hus1 (9-1-1) complex, which is loaded onto chromatin by the Rad17-Rfc2-5 checkpoint complex in response to replication perturbation, recruits DinB onto chromatin to generate the point mutations and single nucleotide frameshifts in the replication mutator. This chain of events reveals a novel checkpoint-induced tolerance mechanism that allows cells to cope with replication perturbation, presumably to make possible restarting stalled replication forks. Fission yeast Cds1 kinase plays an essential role in maintaining DNA replication fork stability in the face of DNA damage and replication fork stalling. Cds1 kinase is known to regulate three proteins that are implicated in maintaining replication fork stability: Mus81-Eme1, a hetero-dimeric structure-specific endonuclease complex; Rqh1, a RecQ-family helicase involved in suppressing inappropriate recombination during replication; and Rad60, a protein required for recombinational repair during replication. These Cds1-regulated proteins are thought to cooperatively prevent mutagenesis and maintain replication fork stability in cells under replication stress. These checkpoint-regulated processes allow cells to survive replication perturbation by preventing stalled replication forks from degenerating into deleterious DNA structures resulting in genomic instability and cancer development

  2. Development of cell-cycle checkpoint therapy for solid tumors.

    Science.gov (United States)

    Tamura, Kenji

    2015-12-01

    Cellular proliferation is tightly controlled by several cell-cycle checkpoint proteins. In cancer, the genes encoding these proteins are often disrupted and cause unrestrained cancer growth. The proteins are over-expressed in many malignancies; thus, they are potential targets for anti-cancer therapies. These proteins include cyclin-dependent kinase, checkpoint kinase, WEE1 kinase, aurora kinase and polo-like kinase. Cyclin-dependent kinase inhibitors are the most advanced cell-cycle checkpoint therapeutics available. For instance, palbociclib (PD0332991) is a first-in-class, oral, highly selective inhibitor of CDK4/6 and, in combination with letrozole (Phase II; PALOMA-1) or with fulvestrant (Phase III; PALOMA-3), it has significantly prolonged progression-free survival, in patients with metastatic estrogen receptor-positive, HER2-negative breast cancer, in comparison with that observed in patients using letrozole, or fulvestrant alone, respectively. In this review, we provide an overview of the current compounds available for cell-cycle checkpoint protein-directed therapy for solid tumors. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  3. A checkpoint compression study for high-performance computing systems

    Energy Technology Data Exchange (ETDEWEB)

    Ibtesham, Dewan [Univ. of New Mexico, Albuquerque, NM (United States). Dept. of Computer Science; Ferreira, Kurt B. [Sandia National Laboratories (SNL-NM), Albuquerque, NM (United States). Scalable System Software Dept.; Arnold, Dorian [Univ. of New Mexico, Albuquerque, NM (United States). Dept. of Computer Science

    2015-02-17

    As high-performance computing systems continue to increase in size and complexity, higher failure rates and increased overheads for checkpoint/restart (CR) protocols have raised concerns about the practical viability of CR protocols for future systems. Previously, compression has proven to be a viable approach for reducing checkpoint data volumes and, thereby, reducing CR protocol overhead leading to improved application performance. In this article, we further explore compression-based CR optimization by exploring its baseline performance and scaling properties, evaluating whether improved compression algorithms might lead to even better application performance and comparing checkpoint compression against and alongside other software- and hardware-based optimizations. Our results highlights are: (1) compression is a very viable CR optimization; (2) generic, text-based compression algorithms appear to perform near optimally for checkpoint data compression and faster compression algorithms will not lead to better application performance; (3) compression-based optimizations fare well against and alongside other software-based optimizations; and (4) while hardware-based optimizations outperform software-based ones, they are not as cost effective.

  4. An ATM-independent S-phase checkpoint response involves CHK1 pathway

    Science.gov (United States)

    Zhou, Xiang-Yang; Wang, Xiang; Hu, Baocheng; Guan, Jun; Iliakis, George; Wang, Ya

    2002-01-01

    After exposure to genotoxic stress, proliferating cells actively slow down the DNA replication through a S-phase checkpoint to provide time for repair. We report that in addition to the ataxia-telangiectasia mutated (ATM)-dependent pathway that controls the fast response, there is an ATM-independent pathway that controls the slow response to regulate the S-phase checkpoint after ionizing radiation in mammalian cells. The slow response of S-phase checkpoint, which is resistant to wortmannin, sensitive to caffeine and UCN-01, and related to cyclin-dependent kinase phosphorylation, is much stronger in CHK1 overexpressed cells, and it could be abolished by Chk1 antisense oligonucleotides. These results provide evidence that the ATM-independent slow response of S-phase checkpoint involves CHK1 pathway.

  5. An origin-deficient yeast artificial chromosome triggers a cell cycle checkpoint.

    Science.gov (United States)

    van Brabant, A J; Buchanan, C D; Charboneau, E; Fangman, W L; Brewer, B J

    2001-04-01

    Checkpoint controls coordinate entry into mitosis with the completion of DNA replication. Depletion of nucleotide precursors by treatment with the drug hydroxyurea triggers such a checkpoint response. However, it is not clear whether the signal for this hydroxyurea-induced checkpoint pathway is the presence of unreplicated DNA, or rather the persistence of single-stranded or damaged DNA. In a yeast artificial chromosome (YAC) we have engineered an approximately 170 kb region lacking efficient replication origins that allows us to explore the specific effects of unreplicated DNA on cell cycle progression. Replication of this YAC extends the length of S phase and causes cells to engage an S/M checkpoint. In the absence of Rad9 the YAC becomes unstable, undergoing deletions within the origin-free region.

  6. Proficiency tests, Evaluating

    NARCIS (Netherlands)

    Cofino, W.P.; Molenaar, J.; Torfs, P.J.J.F.

    2017-01-01

    Marine monitoring programs provide data that are essential for marine management. The reliability of such data is underpinned by proficiency tests. In the context of Quasimeme, a proficiency testing program for the marine environment, a statistical model has been developed in 2000 to evaluate data

  7. Anaphase onset before complete DNA replication with intact checkpoint responses

    DEFF Research Database (Denmark)

    Torres-Rosell, Jordi; De Piccoli, Giacomo; Cordon-Preciado, Violeta

    2007-01-01

    Cellular checkpoints prevent mitosis in the presence of stalled replication forks. Whether checkpoints also ensure the completion of DNA replication before mitosis is unknown. Here, we show that in yeast smc5-smc6 mutants, which are related to cohesin and condensin, replication is delayed, most...

  8. A New Adaptive Checkpointing Strategy for Mobile Computing

    Institute of Scientific and Technical Information of China (English)

    MENChaoguang; ZUODecheng; YANGXiaozong

    2005-01-01

    Adaptive checkpointing strategy is an efficient recovery scheme, which is suitable for mobile computing system. However, all existing adaptive checkpointing schemes are not correct to recover system when failure occurs in some special period. In this paper, the issues that will lead to system inconsistency are first discussed and then a new adaptive strategy that can recover system to correct consistent state is proposed. Our algorithm improves system recovery performance because only failure process needs rollback through logging.

  9. Implication of the G2 checkpoint in the maintenance of genome integrity

    International Nuclear Information System (INIS)

    Piette, J.; Munoz, P.

    2000-01-01

    Checkpoints are surveillance mechanisms that block transitions, for instance in response to DNA damage. We summarize here here recent progress in the molecular characterization of the G 2 checkpoint which controls the entry into mitosis, and review new evidence which implicates de-regulated expression of checkpoint proteins and proteins involved in DNA damage repair in cancer development. These now exists good evidence that individuals who inherited mutations in genes involved in G 2 checkpoint and DNA damage repair are predisposed to the development of various types of cancer, their cells having a strong tendency to accumulate additional mutations. However, the occurrence of mutations of most of these genes in sporadic tumors has yet to be analysed more accurately. (authors)

  10. Parallelization and checkpointing of GPU applications through program transformation

    Energy Technology Data Exchange (ETDEWEB)

    Solano-Quinde, Lizandro Damian [Iowa State Univ., Ames, IA (United States)

    2012-01-01

    GPUs have emerged as a powerful tool for accelerating general-purpose applications. The availability of programming languages that makes writing general-purpose applications for running on GPUs tractable have consolidated GPUs as an alternative for accelerating general purpose applications. Among the areas that have benefited from GPU acceleration are: signal and image processing, computational fluid dynamics, quantum chemistry, and, in general, the High Performance Computing (HPC) Industry. In order to continue to exploit higher levels of parallelism with GPUs, multi-GPU systems are gaining popularity. In this context, single-GPU applications are parallelized for running in multi-GPU systems. Furthermore, multi-GPU systems help to solve the GPU memory limitation for applications with large application memory footprint. Parallelizing single-GPU applications has been approached by libraries that distribute the workload at runtime, however, they impose execution overhead and are not portable. On the other hand, on traditional CPU systems, parallelization has been approached through application transformation at pre-compile time, which enhances the application to distribute the workload at application level and does not have the issues of library-based approaches. Hence, a parallelization scheme for GPU systems based on application transformation is needed. Like any computing engine of today, reliability is also a concern in GPUs. GPUs are vulnerable to transient and permanent failures. Current checkpoint/restart techniques are not suitable for systems with GPUs. Checkpointing for GPU systems present new and interesting challenges, primarily due to the natural differences imposed by the hardware design, the memory subsystem architecture, the massive number of threads, and the limited amount of synchronization among threads. Therefore, a checkpoint/restart technique suitable for GPU systems is needed. The goal of this work is to exploit higher levels of parallelism and

  11. Asynchronous Two-Level Checkpointing Scheme for Large-Scale Adjoints in the Spectral-Element Solver Nek5000

    Energy Technology Data Exchange (ETDEWEB)

    Schanen, Michel; Marin, Oana; Zhang, Hong; Anitescu, Mihai

    2016-01-01

    Adjoints are an important computational tool for large-scale sensitivity evaluation, uncertainty quantification, and derivative-based optimization. An essential component of their performance is the storage/recomputation balance in which efficient checkpointing methods play a key role. We introduce a novel asynchronous two-level adjoint checkpointing scheme for multistep numerical time discretizations targeted at large-scale numerical simulations. The checkpointing scheme combines bandwidth-limited disk checkpointing and binomial memory checkpointing. Based on assumptions about the target petascale systems, which we later demonstrate to be realistic on the IBM Blue Gene/Q system Mira, we create a model of the expected performance of our checkpointing approach and validate it using the highly scalable Navier-Stokes spectralelement solver Nek5000 on small to moderate subsystems of the Mira supercomputer. In turn, this allows us to predict optimal algorithmic choices when using all of Mira. We also demonstrate that two-level checkpointing is significantly superior to single-level checkpointing when adjoining a large number of time integration steps. To our knowledge, this is the first time two-level checkpointing had been designed, implemented, tuned, and demonstrated on fluid dynamics codes at large scale of 50k+ cores.

  12. Speaking in Multiple Languages: Neural Correlates of Language Proficiency in Multilingual Word Production

    Science.gov (United States)

    Videsott, Gerda; Herrnberger, Barbel; Hoenig, Klaus; Schilly, Edgar; Grothe, Jo; Wiater, Werner; Spitzer, Manfred; Kiefer, Markus

    2010-01-01

    The human brain has the fascinating ability to represent and to process several languages. Although the first and further languages activate partially different brain networks, the linguistic factors underlying these differences in language processing have to be further specified. We investigated the neural correlates of language proficiency in a…

  13. Immune checkpoint inhibitors for nonsmall cell lung cancer treatment

    Directory of Open Access Journals (Sweden)

    Yuh-Min Chen

    2017-01-01

    Full Text Available Immune checkpoint inhibition with blocking antibodies that target cytotoxic T-lymphocyte antigen-4 (CTLA-4 and the programmed cell death protein 1 (PD-1 pathway [PD-1/programmed death-ligand 1 (PD-L1] have demonstrated promise in a variety of malignancies. While ipilimumab has been approved as a CTLA-4 blocking antibody by the US Food and Drug Administration for the treatment of advanced melanoma, it is still not approved for lung cancer treatment. In contrast, nivolumab and pembrolizumab, both PD-1 blocking antibodies, have been approved for second-line treatment of nonsmall cell lung cancer in 2015 because of their high potency and long-lasting effects in some patient subgroups. Other PD-1 and PD-L1 monoclonal antibodies are also in active development phase. Treatment with such immune checkpoint inhibitors is associated with a unique pattern of immune-related adverse events or side effects. Combination approaches involving CTLA-4 and PD-1/PD-L1 blockade or checkpoint inhibitors with chemotherapy or radiotherapy are being investigated to determine whether they may enhance the efficacy of treatment. Despite many challenges ahead, immunotherapy with checkpoint inhibitors has already become a new and important treatment modality for lung cancer in the last decade following the discovery of targeted therapy.

  14. The pachytene checkpoint and its relationship to evolutionary patterns of polyploidization and hybrid sterility.

    Science.gov (United States)

    Li, X C; Barringer, B C; Barbash, D A

    2009-01-01

    Sterility is a commonly observed phenotype in interspecific hybrids. Sterility may result from chromosomal or genic incompatibilities, and much progress has been made toward understanding the genetic basis of hybrid sterility in various taxa. The underlying mechanisms causing hybrid sterility, however, are less well known. The pachytene checkpoint is a meiotic surveillance system that many organisms use to detect aberrant meiotic products, in order to prevent the production of defective gametes. We suggest that activation of the pachytene checkpoint may be an important mechanism contributing to two types of hybrid sterility. First, the pachytene checkpoint may form the mechanistic basis of some gene-based hybrid sterility phenotypes. Second, the pachytene checkpoint may be an important mechanism that mediates chromosomal-based hybrid sterility phenotypes involving gametes with non-haploid (either non-reduced or aneuploid) chromosome sets. Studies in several species suggest that the strength of the pachytene checkpoint is sexually dimorphic, observations that warrant future investigation into whether such variation may contribute to differences in patterns of sterility between male and female interspecific hybrids. In addition, plants seem to lack the pachytene checkpoint, which correlates with increased production of unreduced gametes and a higher incidence of polyploid species in plants versus animals. Although the pachytene checkpoint occurs in many animals and in fungi, at least some of the genes that execute the pachytene checkpoint are different among organisms. This finding suggests that the penetrance of the pachytene checkpoint, and even its presence or absence can evolve rapidly. The surprising degree of evolutionary flexibility in this meiotic surveillance system may contribute to the observed variation in patterns of hybrid sterility and in rates of polyploidization.

  15. Immune-checkpoint inhibitors in the era of precision medicine: What radiologists should know

    Energy Technology Data Exchange (ETDEWEB)

    Braschi-Amirfarzan, Marta; Tirumani, Sree Harsha; Hodi, Frank Stephan Jr; Nishno, Mizuki [Dept. of Radiology, Brigham and Women' s Hospital and Dana Farber Cancer Institute, Boston (United States)

    2017-01-15

    Over the past five years immune-checkpoint inhibitors have dramatically changed the therapeutic landscape of advanced solid and hematologic malignancies. The currently approved immune-checkpoint inhibitors include antibodies to cytotoxic T-lymphocyte antigen-4, programmed cell death (PD-1), and programmed cell death ligand (PD-L1 and PD-L2). Response to immune-checkpoint inhibitors is evaluated on imaging using the immune-related response criteria. Activation of immune system results in a unique toxicity profile termed immune-related adverse events. This article will review the molecular mechanism, clinical applications, imaging of immune-related response patterns and adverse events associated with immune-checkpoint inhibitors.

  16. Immune-checkpoint inhibitors in the era of precision medicine: What radiologists should know

    International Nuclear Information System (INIS)

    Braschi-Amirfarzan, Marta; Tirumani, Sree Harsha; Hodi, Frank Stephan Jr; Nishno, Mizuki

    2017-01-01

    Over the past five years immune-checkpoint inhibitors have dramatically changed the therapeutic landscape of advanced solid and hematologic malignancies. The currently approved immune-checkpoint inhibitors include antibodies to cytotoxic T-lymphocyte antigen-4, programmed cell death (PD-1), and programmed cell death ligand (PD-L1 and PD-L2). Response to immune-checkpoint inhibitors is evaluated on imaging using the immune-related response criteria. Activation of immune system results in a unique toxicity profile termed immune-related adverse events. This article will review the molecular mechanism, clinical applications, imaging of immune-related response patterns and adverse events associated with immune-checkpoint inhibitors

  17. The spindle assembly checkpoint: More than just keeping track of the spindle.

    OpenAIRE

    Lawrence, KS; Engebrecht, J

    2015-01-01

    Genome stability is essential for cell proliferation and survival. Consequently, genome integrity is monitored by two major checkpoints, the DNA damage response (DDR) and the spindle assembly checkpoint (SAC). The DDR monitors DNA lesions in G1, S, and G2 stages of the cell cycle and the SAC ensures proper chromosome segregation in M phase. There have been extensive studies characterizing the roles of these checkpoints in response to the processes for which they are named; however, emerging e...

  18. The CD47-SIRPα signaling axis as an innate immune checkpoint in cancer.

    Science.gov (United States)

    Matlung, Hanke L; Szilagyi, Katka; Barclay, Neil A; van den Berg, Timo K

    2017-03-01

    Immune checkpoint inhibitors, including those targeting CTLA-4/B7 and the PD-1/PD-L1 inhibitory pathways, are now available for clinical use in cancer patients, with other interesting checkpoint inhibitors being currently in development. Most of these have the purpose to promote adaptive T cell-mediated immunity against cancer. Here, we review another checkpoint acting to potentiate the activity of innate immune cells towards cancer. This innate immune checkpoint is composed of what has become known as the 'don't-eat me' signal CD47, which is a protein broadly expressed on normal cells and often overexpressed on cancer cells, and its counter-receptor, the myeloid inhibitory immunoreceptor SIRPα. Blocking CD47-SIRPα interactions has been shown to promote the destruction of cancer cells by phagocytes, including macrophages and neutrophils. Furthermore, there is growing evidence that targeting of the CD47-SIRPα axis may also promote antigen-presenting cell function and thereby stimulate adaptive T cell-mediated anti-cancer immunity. The development of CD47-SIRPα checkpoint inhibitors and the potential side effects that these may have are discussed. Collectively, this identifies the CD47-SIRPα axis as a promising innate immune checkpoint in cancer, and with data of the first clinical studies with CD47-SIRPα checkpoint inhibitors expected within the coming years, this is an exciting and rapidly developing field. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Top3 processes recombination intermediates and modulates checkpoint activity after DNA damage

    DEFF Research Database (Denmark)

    Mankouri, Hocine W; Hickson, Ian D

    2006-01-01

    Mutation of TOP3 in Saccharomyces cerevisiae causes poor growth, hyperrecombination, and a failure to fully activate DNA damage checkpoints in S phase. Here, we report that overexpression of a dominant-negative allele of TOP3, TOP3(Y356F), which lacks the catalytic (decatenation) activity of Top3......, the catalytic activity of Top3 is not required for DNA damage checkpoint activation, but it is required for normal S-phase progression after DNA damage. We also present evidence that the checkpoint-mediated cell cycle delay and persistence of X-shaped DNA molecules resulting from overexpression of TOP3(Y356F......) are downstream of Rad51 function. We propose that Top3 functions in S phase to both process homologous recombination intermediates and modulate checkpoint activity....

  20. Myasthenia triggered by immune checkpoint inhibitors: New case and literature review.

    Science.gov (United States)

    Gonzalez, Natalia L; Puwanant, Araya; Lu, Angela; Marks, Stanley M; Živković, Saša A

    2017-03-01

    Immune checkpoint molecules are potent regulators of immunologic homeostasis that prevent the development of autoimmunity while maintaining self-tolerance. Inhibitors of immune checkpoint molecules are used as immunotherapy in the treatment of melanoma and different types of refractory cancer, and can trigger various autoimmune complications including myositis and myasthenia gravis. We describe a case of generalized myasthenia gravis induced by pembrolizumab and review 11 other cases. Five patients also had elevated serum CK levels ranging from 1200 to 8729 IU/L, and biopsy showed myositis in one. Severity was highly variable as symptoms normalized spontaneously in one patient, but three others developed myasthenic crisis (including two with fatal outcomes). Steroids have been recommended as a preferred treatment of autoimmune complications of immune-checkpoint inhibitors. Myasthenia gravis should be considered when weakness, diplopia or bulbar symptoms are seen after treatment with immune checkpoint inhibitors, and additional studies are needed to characterize association with hyperCKemia. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. A New Tool for Assessing Mobile Device Proficiency in Older Adults: The Mobile Device Proficiency Questionnaire.

    Science.gov (United States)

    Roque, Nelson A; Boot, Walter R

    2018-02-01

    Mobile device proficiency is increasingly required to participate in society. Unfortunately, there still exists a digital divide between younger and older adults, especially with respect to mobile devices (i.e., tablet computers and smartphones). Training is an important goal to ensure that older adults can reap the benefits of these devices. However, efficient/effective training depends on the ability to gauge current proficiency levels. We developed a new scale to accurately assess the mobile device proficiency of older adults: the Mobile Device Proficiency Questionnaire (MDPQ). We present and validate the MDPQ and a short 16-question version of the MDPQ (MDPQ-16). The MDPQ, its subscales, and the MDPQ-16 were found to be highly reliable and valid measures of mobile device proficiency in a large sample. We conclude that the MDPQ and MDPQ-16 may serve as useful tools for facilitating mobile device training of older adults and measuring mobile device proficiency for research purposes.

  2. Rituximab does not reset defective early B cell tolerance checkpoints

    Science.gov (United States)

    Chamberlain, Nicolas; Massad, Christopher; Oe, Tyler; Cantaert, Tineke; Herold, Kevan C.; Meffre, Eric

    2015-01-01

    Type 1 diabetes (T1D) patients show abnormalities in early B cell tolerance checkpoints, resulting in the accumulation of large numbers of autoreactive B cells in their blood. Treatment with rituximab, an anti-CD20 mAb that depletes B cells, has been shown to preserve β cell function in T1D patients and improve other autoimmune diseases, including rheumatoid arthritis and multiple sclerosis. However, it remains largely unknown how anti–B cell therapy thwarts autoimmunity in these pathologies. Here, we analyzed the reactivity of Abs expressed by single, mature naive B cells from 4 patients with T1D before and 52 weeks after treatment to determine whether rituximab resets early B cell tolerance checkpoints. We found that anti–B cell therapy did not alter the frequencies of autoreactive and polyreactive B cells, which remained elevated in the blood of all patients after rituximab treatment. Moreover, the limited proliferative history of autoreactive B cells after treatment revealed that these clones were newly generated B cells and not self-reactive B cells that had escaped depletion and repopulated the periphery through homeostatic expansion. We conclude that anti–B cell therapy may provide a temporary dampening of autoimmune processes through B cell depletion. However, repletion with autoreactive B cells may explain the relapse that occurs in many autoimmune patients after anti–B cell therapy. PMID:26642366

  3. Immune checkpoint inhibitors for metastatic bladder cancer.

    Science.gov (United States)

    Massari, Francesco; Di Nunno, Vincenzo; Cubelli, Marta; Santoni, Matteo; Fiorentino, Michelangelo; Montironi, Rodolfo; Cheng, Liang; Lopez-Beltran, Anto; Battelli, Nicola; Ardizzoni, Andrea

    2018-03-01

    Chemotherapy has represented the standard therapy for unresectable or metastatic urothelial carcinoma for more than 20 years. The growing knowledge of the interaction between tumour and immune system has led to the advent of new classes of drugs, the immune-checkpoints inhibitors, which are intended to change the current scenario. To date, immunotherapy is able to improve the overall responses and survival. Moreover, thanks to its safety profile immune-checkpoint inhibitors could be proposed also to patients unfit for standard chemotherapy. No doubts that these agents have started a revolution expected for years, but despite this encouraging results it appears clear that not all subjects respond to these agents and requiring the development of reliable predictive response factors able to isolate patients who can more benefit from these treatments as well as new strategies aimed to improve immunotherapy clinical outcome. In this review we describe the active or ongoing clinical trials involving Programmed Death Ligand 1 (PD-L1), Programmed Death receptor 1 (PD-1) and Cytotoxic-T Lymphocyte Antigen 4 (CTLA 4) inhibitors in urothelial carcinoma focusing our attention on the developing new immune-agents and combination strategies with immune-checkpoint inhibitors. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Checkpoint inhibitors in endometrial cancer: preclinical rationale and clinical activity.

    Science.gov (United States)

    Mittica, Gloria; Ghisoni, Eleonora; Giannone, Gaia; Aglietta, Massimo; Genta, Sofia; Valabrega, Giorgio

    2017-10-27

    Treatment of advanced and recurrent endometrial cancer (EC) is still an unmet need for oncologists and gynecologic oncologists. The Cancer Genome Atlas Research Network (TCGA) recently provided a new genomic classification, dividing EC in four subgroups. Two types of EC, the polymerase epsilon (POLE)-ultra-mutated and the microsatellite instability-hyper-mutated (MSI-H), are characterized by a high mutation rate providing the rationale for a potential activity of checkpoint inhibitors. We analyzed all available evidence supporting the role of tumor microenvironment (TME) in EC development and the therapeutic implications offered by immune checkpoint inhibitors in this setting. We performed a review on Pubmed with Mesh keywords 'endometrial cancer' and the name of each checkpoint inhibitor discussed in the article. The same search was operated on clinicaltrial.gov to identify ongoing clinical trials exploring PD-1/PD-L1 and CTLA-4 axis in EC, particularly focusing on POLE-ultra-muted and MSI-H cancer types. POLE-ultra-mutated and MSI-H ECs showed an active TME expressing high number of neo-antigens and an elevated amount of tumor infiltrating lymphocytes (TILs). Preliminary results from a phase-1 clinical trial (KEYNOTE-028) demonstrated antitumor activity of Pembrolizumab in EC. Moreover, both Pembrolizumab and Nivolumab reported durable clinical responses in POLE-ultra-mutated patients. Immune checkpoint inhibitors are an attractive option in POLE-ultra-mutated and MSI-H ECs. Future investigations in these subgroups include combinations of checkpoints inhibitors with chemotherapy and small tyrosine kinase inhibitors (TKIs) to enhance a more robust intra-tumoral immune response.

  5. National Radon Contractor Proficiency (RCP) program. Proficiency report, September 1991

    International Nuclear Information System (INIS)

    1991-09-01

    The primary objective of the U.S. Environmental Protection Agency's (EPA) efforts to address the indoor radon problem is to reduce radon levels in buildings throughout the country. Achieving this objective requires a nationwide supply of capable radon mitigation contractors. In the Indoor Radon Abatement Act of 1988, Congress authorized EPA to establish a program to evaluate radon mitigation contractors and to provide this information to the public in cooperation with the States. The Radon Contractor Proficiency (RCP) Program was developed to assist States, EPA Regions, local government officials, and the public in selecting contractors who have demonstrated their proficiency in reducing indoor radon levels. The program is managed by the EPA Office of Radiation Programs' Radon Division. Under this voluntary program, radon contractors demonstrate their proficiency by meeting specific Program requirements. Individual contractors who meet these requirements are then listed in the Report

  6. National Radon Contractor Proficiency (RCP) Program. Proficiency report, January 1992

    International Nuclear Information System (INIS)

    1992-01-01

    The primary objective of the U.S. Environmental Protection Agency's (EPA) efforts to address the indoor radon problem is to reduce radon levels in buildings throughout the country. Achieving the objective requires a nationwide supply of capable radon mitigation contractors. In the Indoor Radon Abatement Act of 1988, Congress authorized EPA to establish a program to evaluate radon mitigation contractors and to provide the information to the public in cooperation with the States. The Radon Contractor Proficiency (RCP) Program was developed to assist States, EPA Regions, local government officials, and the public in selecting contractors who have demonstrated their proficiency in reducing indoor radon levels. The program is managed by the EPA Office of Radiation Programs' Radon Division. Under the voluntary program, radon contractors demonstrate their proficiency by meeting specific Program requirements. Individual contractors who meet these requirements are then listed in the Report

  7. The point of no return: The poly(A)-associated elongation checkpoint.

    Science.gov (United States)

    Tellier, Michael; Ferrer-Vicens, Ivan; Murphy, Shona

    2016-01-01

    Cyclin-dependent kinases play critical roles in transcription by RNA polymerase II (pol II) and processing of the transcripts. For example, CDK9 regulates transcription of protein-coding genes, splicing, and 3' end formation of the transcripts. Accordingly, CDK9 inhibitors have a drastic effect on the production of mRNA in human cells. Recent analyses indicate that CDK9 regulates transcription at the early-elongation checkpoint of the vast majority of pol II-transcribed genes. Our recent discovery of an additional CDK9-regulated elongation checkpoint close to poly(A) sites adds a new layer to the control of transcription by this critical cellular kinase. This novel poly(A)-associated checkpoint has the potential to powerfully regulate gene expression just before a functional polyadenylated mRNA is produced: the point of no return. However, many questions remain to be answered before the role of this checkpoint becomes clear. Here we speculate on the possible biological significance of this novel mechanism of gene regulation and the players that may be involved.

  8. The point of no return: The poly(A)-associated elongation checkpoint

    Science.gov (United States)

    Tellier, Michael; Ferrer-Vicens, Ivan; Murphy, Shona

    2016-01-01

    abstract Cyclin-dependent kinases play critical roles in transcription by RNA polymerase II (pol II) and processing of the transcripts. For example, CDK9 regulates transcription of protein-coding genes, splicing, and 3′ end formation of the transcripts. Accordingly, CDK9 inhibitors have a drastic effect on the production of mRNA in human cells. Recent analyses indicate that CDK9 regulates transcription at the early-elongation checkpoint of the vast majority of pol II-transcribed genes. Our recent discovery of an additional CDK9-regulated elongation checkpoint close to poly(A) sites adds a new layer to the control of transcription by this critical cellular kinase. This novel poly(A)-associated checkpoint has the potential to powerfully regulate gene expression just before a functional polyadenylated mRNA is produced: the point of no return. However, many questions remain to be answered before the role of this checkpoint becomes clear. Here we speculate on the possible biological significance of this novel mechanism of gene regulation and the players that may be involved. PMID:26853452

  9. A genetic screen identifies BRCA2 and PALB2 as key regulators of G2 checkpoint maintenance

    DEFF Research Database (Denmark)

    Menzel, Tobias; Nähse-Kumpf, Viola; Kousholt, Arne Nedergaard

    2011-01-01

    To identify key connections between DNA-damage repair and checkpoint pathways, we performed RNA interference screens for regulators of the ionizing radiation-induced G2 checkpoint, and we identified the breast cancer gene BRCA2. The checkpoint was also abrogated following depletion of PALB2......, an interaction partner of BRCA2. BRCA2 and PALB2 depletion led to premature checkpoint abrogation and earlier activation of the AURORA A-PLK1 checkpoint-recovery pathway. These results indicate that the breast cancer tumour suppressors and homologous recombination repair proteins BRCA2 and PALB2 are main...

  10. More Proficient vs. Less Proficient EFL Learners’ Perceptions of Teachers ‘Motivation Raising Strategies

    Directory of Open Access Journals (Sweden)

    Nasrin Yousefi

    2022-09-01

    Full Text Available Motivation raising strategies are frequently used in English as a Foreign Language (EFL classes; nevertheless, learners’ perceptions of such strategies used by language teachers have not sufficiently been explored. Also, there are not enough studies on differences and similarities between more and less proficient EFL learners regarding this issue. To scrutinize this topic, a groups of more (No=50 and less proficient EFL learners (No=50 participated in this study by completing to a validated, researcher-made questionnaire with a five-point Likert type format. Non-parametric Mann-Whiteny U test was run in the SPSS ver. 23 to check the differences between the two groups. The results of the study verified that, regardless of each individual scale in the utilized questionnaire, overall, the more proficient ones manifested significantly less perceptions on teachers’ motivation raising strategies based on the total estimated mean ranks compared with the less proficient learners.  However, within the surveyed scales, only in the classroom atmosphere scale, the results showed that the less proficient learners were more mindful of teacher strategies for motivation raising. The findings from this study have implications for motivation raising strategy instructions for a language classroom.

  11. The Dynamical Mechanisms of the Cell Cycle Size Checkpoint

    International Nuclear Information System (INIS)

    Feng Shi-Fu; Yang Ling; Yan Jie; Liu Zeng-Rong

    2012-01-01

    Cell division must be tightly coupled to cell growth in order to maintain cell size, whereas the mechanisms of how initialization of mitosis is regulated by cell size remain to be elucidated. We develop a mathematical model of the cell cycle, which incorporates cell growth to investigate the dynamical properties of the size checkpoint in embryos of Xenopus laevis. We show that the size checkpoint is naturally raised from a saddle-node bifurcation, and in a mutant case, the cell loses its size control ability due to the loss of this saddle-node point

  12. Assessment of Preschoolers' Gross Motor Proficiency: Revisiting Bruininks-Oseretsky Test of Motor Proficiency

    Science.gov (United States)

    Lam, Hazel Mei Yung

    2011-01-01

    Literature reveals that there are very few validated motor proficiency tests for young children. According to Gallahue and Ozmun, the Bruininks-Oseretsky Test of Motor Proficiency is a valid test. However, manipulative skills, which are classified as gross motor skills by most motor development specialists, are only tested in the Upper Limb…

  13. Bir1 Deletion Causes Malfunction of the Spindle Assembly Checkpoint and Apoptosis in Yeast

    International Nuclear Information System (INIS)

    Ren, Qun; Liou, Liang-Chun; Gao, Qiuqiang; Bao, Xiaoming; Zhang, Zhaojie

    2012-01-01

    Cell division in yeast is a highly regulated and well studied event. Various checkpoints are placed throughout the cell cycle to ensure faithful segregation of sister chromatids. Unexpected events, such as DNA damage or oxidative stress, cause the activation of checkpoint(s) and cell cycle arrest. Malfunction of the checkpoints may induce cell death. We previously showed that under oxidative stress, the budding yeast cohesin Mcd1, a homolog of human Rad21, was cleaved by the caspase-like protease Esp1. The cleaved Mcd1 C-terminal fragment was then translocated to mitochondria, causing apoptotic cell death. In the present study, we demonstrated that Bir1 plays an important role in spindle assembly checkpoint and cell death. Similar to H 2 O 2 treatment, deletion of BIR1 using a BIR1-degron strain caused degradation of the securin Pds1, which binds and inactivates Esp1 until metaphase-anaphase transition in a normal cell cycle. BIR1 deletion caused an increase level of ROS and mis-location of Bub1, a major protein for spindle assembly checkpoint. In wild type, Bub1 was located at the kinetochores, but was primarily in the cytoplasm in bir1 deletion strain. When BIR1 was deleted, addition of nocodazole was unable to retain the Bub1 localization on kinetochores, further suggesting that Bir1 is required to activate and maintain the spindle assembly checkpoint. Our study suggests that the BIR1 function in cell cycle regulation works in concert with its anti-apoptosis function.

  14. BET Bromodomain Inhibition Synergizes with PARP Inhibitor in Epithelial Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Sergey Karakashev

    2017-12-01

    Full Text Available PARP inhibition is known to be an effective clinical strategy in BRCA mutant cancers, but PARP inhibition has not been applied to BRCA-proficient tumors. Here, we show the synergy of BET bromodomain inhibition with PARP inhibition in BRCA-proficient ovarian cancers due to mitotic catastrophe. Treatment of BRCA-proficient ovarian cancer cells with the BET inhibitor JQ1 downregulated the G2-M cell-cycle checkpoint regulator WEE1 and the DNA-damage response factor TOPBP1. Combining PARP inhibitor Olaparib with the BET inhibitor, we observed a synergistic increase in DNA damage and checkpoint defects, which allowed cells to enter mitosis despite the accumulation of DNA damage, ultimately causing mitotic catastrophe. Moreover, JQ1 and Olaparib showed synergistic suppression of growth of BRCA-proficient cancer in vivo in a xenograft ovarian cancer mouse model. Our findings indicate that a combination of BET inhibitor and PARP inhibitor represents a potential therapeutic strategy for BRCA-proficient cancers.

  15. CHECKPOINT INHIBITOR IMMUNE THERAPY: Systemic Indications and Ophthalmic Side Effects.

    Science.gov (United States)

    Dalvin, Lauren A; Shields, Carol L; Orloff, Marlana; Sato, Takami; Shields, Jerry A

    2018-06-01

    To review immune checkpoint inhibitor indications and ophthalmic side effects. A literature review was performed using a PubMed search for publications between 1990 and 2017. Immune checkpoint inhibitors are designed to treat system malignancies by targeting one of three ligands, leading to T-cell activation for attack against malignant cells. These ligands (and targeted drug) include cytotoxic T-lymphocyte antigen-4 (CTLA-4, ipilimumab), programmed death protein 1 (PD-1, pembrolizumab, nivolumab), and programmed death ligand-1 (PD-L1, atezolizumab, avelumab, durvalumab). These medications upregulate the immune system and cause autoimmune-like side effects. Ophthalmic side effects most frequently manifest as uveitis (1%) and dry eye (1-24%). Other side effects include myasthenia gravis (n = 19 reports), inflammatory orbitopathy (n = 11), keratitis (n = 3), cranial nerve palsy (n = 3), optic neuropathy (n = 2), serous retinal detachment (n = 2), extraocular muscle myopathy (n = 1), atypical chorioretinal lesions (n = 1), immune retinopathy (n = 1), and neuroretinitis (n = 1). Most inflammatory side effects are managed with topical or periocular corticosteroids, but advanced cases require systemic corticosteroids and cessation of checkpoint inhibitor therapy. Checkpoint inhibitors enhance the immune system by releasing inhibition on T cells, with risk of autoimmune-like side effects. Ophthalmologists should include immune-related adverse events in their differential when examining cancer patients with new ocular symptoms.

  16. Developmental checkpoints and feedback circuits time insect maturation

    DEFF Research Database (Denmark)

    Rewitz, Kim Furbo; Yamanaka, Naoki; O'Connor, Michael B.

    2013-01-01

    as external cues, to time production and release of ecdysone. Based on results discussed here, we suggest that developmental progression to adulthood is controlled by checkpoints that regulate the genetic timing program enabling it to adapt to different environmental conditions. These checkpoints utilize...... a number of signaling pathways to modulate ecdysone production in the prothoracic gland. Release of ecdysone activates an autonomous cascade of both feedforward and feedback signals that determine the duration of the ecdysone pulse at each developmental transitions. Conservation of the genetic mechanisms...... that coordinate the juvenile-adult transition suggests that insights from the fruit fly Drosophila will provide a framework for future investigation of developmental timing in metazoans....

  17. Fundamental movement skills proficiency in children with developmental coordination disorder: does physical self-concept matter?

    Science.gov (United States)

    Yu, Jie; Sit, Cindy H P; Capio, Catherine M; Burnett, Angus; Ha, Amy S C; Huang, Wendy Y J

    2016-01-01

    The purpose of this study was to (1) examine differences in fundamental movement skills (FMS) proficiency, physical self-concept, and physical activity in children with and without developmental coordination disorder (DCD), and (2) determine the association of FMS proficiency with physical self-concept while considering key confounding factors. Participants included 43 children with DCD and 87 age-matched typically developing (TD) children. FMS proficiency was assessed using the Test of Gross Motor Development - second edition. Physical self-concept and physical activity were assessed using self-report questionnaires. A two-way (group by gender) ANCOVA was used to determine whether between-group differences existed in FMS proficiency, physical self-concept, and physical activity after controlling for age and BMI. Partial correlations and hierarchical multiple regression models were used to examine the relationship between FMS proficiency and physical self-concept. Compared with their TD peers, children with DCD displayed less proficiency in various components of FMS and viewed themselves as being less competent in physical coordination, sporting ability, and physical health. Physical coordination was a significant predictor of ability in object control skills. DCD status and gender were significant predictors of FMS proficiency. Future FMS interventions should target children with DCD and girls, and should emphasize improving object control skills proficiency and physical coordination. Children with DCD tend to have not only lower FMS proficiency than age-matched typically developing children but also lower physical self-concept. Self-perceptions of physical coordination by children with DCD are likely to be valuable contributors to development of object control skills. This may then help to develop their confidence in performing motor skills. Children with DCD need supportive programs that facilitate the development of object control skills. Efficacy of training

  18. Conformation-specific anti-Mad2 monoclonal antibodies for the dissection of checkpoint signaling

    DEFF Research Database (Denmark)

    Sedgwick, Garry G; Larsen, Marie Sofie Yoo; Lischetti, Tiziana

    2016-01-01

    The spindle assembly checkpoint (SAC) ensures accurate chromosome segregation during mitosis by delaying the activation of the anaphase-promoting complex/cyclosome (APC/C) in response to unattached kinetochores. The Mad2 protein is essential for a functional checkpoint because it binds directly t...

  19. Maintenance proficiency evaluation test bank

    International Nuclear Information System (INIS)

    Maier, Loran

    2003-01-01

    The Maintenance Proficiency Evaluation Test Bank (MPETB) is an Electric Power Research Institute- (EPRJ-) operated, utility-sponsored means of developing, maintaining, and disseminating secure, high-quality written and performance maintenance proficiency tests. EPRTs charter is to ensure that all tests and test items that go into the Test Bank have been validated, screened for reliability, and evaluated to high standards of psychometric excellence. Proficiency tests of maintenance personnel.(mechanics, electricians, and instrumentation and control [I and C] technicians) are most often used to determine if an experienced employee is capable of performing maintenance tasks without further training. Such tests provide objective evidence for decisions to exempt an employee from what, for the employee, is unnecessary training. This leads to considerable savings in training costs and increased productivity because supervisors can assign personnel to tasks at which their competence is proven. The ultimate objective of proficiency evaluation is to ensure that qualified maintenance personnel are available to meet the maintenance requirements of the plant Numerous task-specific MPE tests (both written and performance) have been developed and validated using the EPRI MPE methodology by the utilities participating in the MPETB project A task-specific MPE consists of a multiple-choice written examination and a multi-step performance evaluation that can be used to assess an individual's present knowledge and skill level for a given maintenance task. The MPETB contains MPEs and test items for the mechanical, electrical, and I and C classifications that are readily available to participating utilities. Presently, utilities are placing emphasis on developing MPEs to evaluate outage-related maintenance tasks that demonstrate the competency and qualifications of plant and contractor personnel before the start of outage work. Utilities are also using the MPE methodology and process to

  20. Immigration, language proficiency, and autobiographical memories: Lifespan distribution and second-language access.

    Science.gov (United States)

    Esposito, Alena G; Baker-Ward, Lynne

    2016-08-01

    This investigation examined two controversies in the autobiographical literature: how cross-language immigration affects the distribution of autobiographical memories across the lifespan and under what circumstances language-dependent recall is observed. Both Spanish/English bilingual immigrants and English monolingual non-immigrants participated in a cue word study, with the bilingual sample taking part in a within-subject language manipulation. The expected bump in the number of memories from early life was observed for non-immigrants but not immigrants, who reported more memories for events surrounding immigration. Aspects of the methodology addressed possible reasons for past discrepant findings. Language-dependent recall was influenced by second-language proficiency. Results were interpreted as evidence that bilinguals with high second-language proficiency, in contrast to those with lower second-language proficiency, access a single conceptual store through either language. The final multi-level model predicting language-dependent recall, including second-language proficiency, age of immigration, internal language, and cue word language, explained ¾ of the between-person variance and (1)/5 of the within-person variance. We arrive at two conclusions. First, major life transitions influence the distribution of memories. Second, concept representation across multiple languages follows a developmental model. In addition, the results underscore the importance of considering language experience in research involving memory reports.

  1. The amount of DNA damage needed to activate the radiation-induced G2 checkpoint varies between single cells

    International Nuclear Information System (INIS)

    Tkacz-Stachowska, Kinga; Lund-Andersen, Christin; Velissarou, Angeliki; Myklebust, June H.; Stokke, Trond; Syljuåsen, Randi G.

    2011-01-01

    Background and purpose: The radiation-induced G2 checkpoint helps facilitate DNA repair before cell division. However, recent work has revealed that human cells often escape the G2 checkpoint with unrepaired DNA breaks. The purpose was to explore whether G2 checkpoint activation occurs according to a threshold level of DNA damage. Materials and methods: G2 checkpoint activation was assayed at 75–90 min and 24–48 h after X-ray irradiation of BJ diploid fibroblasts and U2OS osteosarcoma cells. Multiparameter flow cytometry with pacific blue barcoding, and flow cytometry-based sorting of phospho-H3 positive cells to microscope slides, were used to examine the DNA damage marker γ-H2AX in individual mitotic cells that had escaped the G2 checkpoint. Results: For all radiation doses and times tested, the number of γ-H2AX foci varied between individual mitotic cells. At 75 min the median levels of γ-H2AX in mitotic cells increased with higher radiation doses. At 24–48 h, following a prolonged G2 checkpoint, cells were more resistant to checkpoint re-activation by a second dose of radiation. Conclusion: Our results suggest that different amounts of DNA damage are needed to activate the G2 checkpoint in individual cells. Such single cell variation in checkpoint activation may potentially contribute to radiation-induced genomic instability.

  2. Checkpoint kinase 1-induced phosphorylation of O-linked β-N-acetylglucosamine transferase regulates the intermediate filament network during cytokinesis.

    Science.gov (United States)

    Li, Zhe; Li, Xueyan; Nai, Shanshan; Geng, Qizhi; Liao, Ji; Xu, Xingzhi; Li, Jing

    2017-12-01

    Checkpoint kinase 1 (Chk1) is a kinase instrumental for orchestrating DNA replication, DNA damage checkpoints, the spindle assembly checkpoint, and cytokinesis. Despite Chk1's pivotal role in multiple cellular processes, many of its substrates remain elusive. Here, we identified O- linked β- N -acetylglucosamine ( O -GlcNAc)-transferase (OGT) as one of Chk1's substrates. We found that Chk1 interacts with and phosphorylates OGT at Ser-20, which not only stabilizes OGT, but also is required for cytokinesis. Phospho-specific antibodies of OGT-pSer-20 exhibited specific signals at the midbody of the cell, consistent with midbody localization of OGT as reported previously. Moreover, phospho-deficient OGT (S20A) cells attenuated cellular O -GlcNAcylation levels and also reduced phosphorylation of Ser-71 in the cytoskeletal protein vimentin, a modification critical for severing vimentin filament during cytokinesis. Consequently, elongated vimentin bridges were observed in cells depleted of OGT via an si OGT- based approach. Lastly, expression of plasmids resistant to si OGT efficiently rescued the vimentin bridge phenotype, but the OGT-S20A rescue plasmids did not. Our results suggest a Chk1-OGT-vimentin pathway that regulates the intermediate filament network during cytokinesis. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. Association between pediatric asthma care quality and morbidity and English language proficiency in Ohio.

    Science.gov (United States)

    Montgomery, Martha P; Allen, Elizabeth D; Thomas, Olivia; Robinson, Byron F; Clark, Donnie; Connelly, Ann; Mott, Joshua A; Conrey, Elizabeth

    2018-05-08

    Limited English proficiency can be a barrier to asthma care and is associated with poor outcomes. This study examines whether pediatric patients in Ohio with limited English proficiency experience lower asthma care quality or higher morbidity. We used electronic health records for asthma patients aged 2-17 years from a regional, urban, children's hospital in Ohio during 2011-2015. Community-level demographics were included from U.S. Census data. By using chi-square and t-tests, patients with limited English proficiency and bilingual English-speaking patients were compared with English-only patients. Five asthma outcomes-two quality and three morbidity measures-were modeled using generalized estimating equations. The study included 15 352 (84%) English-only patients, 1744 (10%) patients with limited English proficiency, and 1147 (6%) bilingual patients. Pulmonary function testing (quality measure) and multiple exacerbation visits (morbidity measure) did not differ by language group. Compared with English-only patients, bilingual patients had higher odds of ever having an exacerbation visit (morbidity measure) (adjusted odds ratio [aOR], 1.4; 95% confidence interval [CI], 1.2-1.6) but lower odds of admission to intensive care (morbidity measure) (aOR, 0.3; 95% CI, 0.2-0.7), while patients with limited English proficiency did not differ on either factor. Recommended follow-up after exacerbation (quality measure) was higher for limited English proficiency (aOR, 1.8; 95% CI, 1.4-2.3) and bilingual (aOR, 1.6; 95% CI, 1.3-2.1), compared with English-only patients. In this urban, pediatric population with reliable interpreter services, limited English proficiency was not associated with worse asthma care quality or morbidity.

  4. Targeting the Checkpoint to Kill Cancer Cells

    Czech Academy of Sciences Publication Activity Database

    Benada, Jan; Macůrek, Libor

    2015-01-01

    Roč. 6, č. 3 (2015), s. 1912-1937 ISSN 2218-273X R&D Projects: GA ČR(CZ) GA14-34264S Institutional support: RVO:68378050 Keywords : checkpoint * DNA damage response * cancer Subject RIV: EB - Genetics ; Molecular Biology

  5. Clinical Wisdom among Proficient Nurses

    DEFF Research Database (Denmark)

    Uhrenfeldt, Lisbeth; Hall, Elisabeth

    2007-01-01

    This paperexamines clinical wisdom which has emerged from a broader study anout nurse managers´influence on proficient registered nurse turnover and retention. The purpose of the study was to increase understanding of proficient nurses´experience and clinical practice by giving voice to the nurses...

  6. Emodnet Med Sea Check-Point - Indicators for decision- maker

    Science.gov (United States)

    Besnard, Sophie; Claverie, Vincent; Blanc, Frédérique

    2015-04-01

    The Emodnet Checkpoint projects aim is to assess the cost-effectiveness, reliability and utility of the existing monitoring at the sea basin level. This involves the development of monitoring system indicators and a GIS Platform to perform the assessment and make it available. Assessment or production of Check-Point information is made by developing targeted products based on the monitoring data and determining whether the products are meeting the needs of industry and public authorities. Check-point users are the research community, the 'institutional' policy makers for IMP and MSFD implementation, the 'intermediate users', i.e., users capable to understand basic raw data but that benefit from seeing the Checkpoint targeted products and the assessment of the fitness for purpose. We define assessment criteria aimed to characterize/depict the input datasets in terms of 3 territories capable to show performance and gaps of the present monitoring system, appropriateness, availability and fitness for purpose. • Appropriateness: What is made available to users? What motivate/decide them to select this observation rather than this one. • Availability: How this is made available to the user? Place to understand the readiness and service performance of the EU infrastructure • Fitness for use / fitness for purpose: Ability for non-expert user to appreciate the data exploitability (feedback on efficiency & reliability of marine data) For each territory (appropriateness, Availability and Fitness for purpose / for use), we define several indicators. For example, for Availability we define Visibility, Accessibility and Performance. And Visibility is itself defined by "Easily found" and "EU service". So these indicators can be classified according to their territory and sub-territory as seen above, but also according to the complexity to build them. Indicators are built from raw descriptors in 3 stages:  Stage 1: to give a neutral and basic status directly computed from

  7. 34 CFR 300.27 - Limited English proficient.

    Science.gov (United States)

    2010-07-01

    ... 34 Education 2 2010-07-01 2010-07-01 false Limited English proficient. 300.27 Section 300.27... CHILDREN WITH DISABILITIES General Definitions Used in This Part § 300.27 Limited English proficient. Limited English proficient has the meaning given the term in section 9101(25) of the ESEA. (Authority: 20...

  8. Spindle assembly checkpoint acquisition at the mid-blastula transition.

    Directory of Open Access Journals (Sweden)

    Maomao Zhang

    Full Text Available The spindle assembly checkpoint (SAC maintains the fidelity of chromosome segregation during mitosis. Nonpathogenic cells lacking the SAC are typically only found in cleavage stage metazoan embryos, which do not acquire functional checkpoints until the mid-blastula transition (MBT. It is unclear how proper SAC function is acquired at the MBT, though several models exist. First, SAC acquisition could rely on transcriptional activity, which increases dramatically at the MBT. Embryogenesis prior to the MBT relies primarily on maternally loaded transcripts, and if SAC signaling components are not maternally supplied, the SAC would depend on zygotic transcription at the MBT. Second, checkpoint acquisition could depend on the Chk1 kinase, which is activated at the MBT to elongate cell cycles and is required for the SAC in somatic cells. Third, SAC function could depend on a threshold nuclear to cytoplasmic (N:C ratio, which increases during pre-MBT cleavage cycles and dictates several MBT events like zygotic transcription and cell cycle remodeling. Finally, the SAC could by regulated by a timer mechanism that coincides with other MBT events but is independent of them. Using zebrafish embryos we show that SAC acquisition at the MBT is independent of zygotic transcription, indicating that the checkpoint program is maternally supplied. Additionally, by precociously lengthening cleavage cycles with exogenous Chk1 activity, we show that cell cycle lengthening and Chk1 activity are not sufficient for SAC acquisition. Furthermore, we find that SAC acquisition can be uncoupled from the N:C ratio. Together, our findings indicate that SAC acquisition is regulated by a maternally programmed developmental timer.

  9. Analysis of Drug Development Paradigms for Immune Checkpoint Inhibitors.

    Science.gov (United States)

    Jardim, Denis L; de Melo Gagliato, Débora; Giles, Francis J; Kurzrock, Razelle

    2018-04-15

    Immune checkpoint inhibitors have unique toxicities and response kinetics compared with cytotoxic and gene-targeted anticancer agents. We investigated the impact of innovative/accelerated immunotherapy drug development/approval models on the accuracy of safety and efficacy assessments by searching the FDA website. Initial phase I trials for each agent were reviewed and safety and efficacy data compared with that found in later trials leading to regulatory approvals of the same agents. As of June 2017, the FDA approved six checkpoint inhibitors for a variety of cancer types. All checkpoint inhibitors received a priority review status and access to at least two additional FDA special access programs, more often breakthrough therapy designation and accelerated approval. Median clinical development time (investigational new drug application to approval) was 60.77 months [avelumab had the shortest timeline (52.33 months)]. Response rates during early phase I trials (median = 16%) are higher than for phase I trials of other agents (with the exception of gene-targeted agents tested with a biomarker). Doses approved were usually not identical to doses recommended on phase I trials. Approximately 50% of types of immune-related and 43% of types of clinically relevant toxicities from later trials were identified in early-phase trials. Even so, treatment-related mortality remains exceedingly low in later studies (0.33% of patients). In conclusion, efficacy and safety of immune checkpoint inhibitors appear to be reasonably predicted from the dose-finding portion of phase I trials, indicating that the fast-track development of these agents is safe and justified. Clin Cancer Res; 24(8); 1785-94. ©2017 AACR . ©2017 American Association for Cancer Research.

  10. Smurf2 as a novel mitotic regulator: From the spindle assembly checkpoint to tumorigenesis

    Directory of Open Access Journals (Sweden)

    Moore Finola E

    2009-07-01

    Full Text Available Abstract The execution of the mitotic program with high fidelity is dependent upon precise spatiotemporal regulation of posttranslational protein modifications. For example, the timely polyubiquitination of critical mitotic regulators by Anaphase Promoting Complex/Cyclosome (APC/C is essential for the metaphase to anaphase transition and mitotic exit. The spindle assembly checkpoint prevents unscheduled activity of APC/C-Cdc20 in early mitosis, allowing bipolar attachment of kinetochores to mitotic spindle and facilitating equal segregation of sister chromatids. The critical effector of the spindle checkpoint, Mitotic arrest deficient 2 (Mad2, is recruited to unattached kinetochores forming a complex with other regulatory proteins to efficiently and cooperatively inhibit APC/C-Cdc20. A weakened and/or dysfunctional spindle checkpoint has been linked to the development of genomic instability in both cell culture and animal models, and evidence suggests that aberrant regulation of the spindle checkpoint plays a critical role in human carcinogenesis. Recent studies have illuminated a network of both degradative and non-degradative ubiquitination events that regulate the metaphase to anaphase transition and mitotic exit. Within this context, our recent work showed that the HECT (Homologous to E6-AP C-terminus-family E3 ligase Smurf2 (Smad specific ubiquitin regulatory factor 2, known as a negative regulator of transforming growth factor-beta (TGF-β signaling, is required for a functional spindle checkpoint by promoting the functional localization and stability of Mad2. Here we discuss putative models explaining the role of Smurf2 as a new regulator in the spindle checkpoint. The dynamic mitotic localization of Smurf2 to the centrosome and other critical mitotic structures provides implications about mitotic checkpoint control dependent on various ubiquitination events. Finally, deregulated Smurf2 activity may contribute to carcinogenesis by

  11. Nucleotide Selectivity at a Preinsertion Checkpoint of T7 RNA Polymerase Transcription Elongation.

    Science.gov (United States)

    E, Chao; Duan, Baogen; Yu, Jin

    2017-04-20

    Nucleotide selection is crucial for transcription fidelity control, in particular, for viral T7 RNA polymerase (RNAP) lack of proofreading activity. It has been recognized that multiple kinetic checkpoints exist prior to full nucleotide incorporation. In this work, we implemented intensive atomistic molecular dynamics (MD) simulations to quantify how strong the nucleotide selection is at the initial checkpoint of an elongation cycle of T7 RNAP. The incoming nucleotides bind into a preinsertion site where a critical tyrosine residue locates nearby to assist the nucleotide selection. We calculated the relative binding free energy between a noncognate nucleotide and a cognate one at a preinsertion configuration via alchemical simulations, showing that a small selection free energy or the binding free energy difference (∼3 k B T) exists between the two nucleotides. Indeed, another preinsertion configuration favored by the noncognate nucleotides was identified, which appears to be off path for further nucleotide insertion and additionally assists the nucleotide selection. By chemical master equation (CME) approach, we show that the small selection free energy at the preinsertion site along with the off-path noncognate nucleotide filtering can help substantially to reduce the error rate and to maintain the elongation rate high in the T7 RNAP transcription.

  12. Unique Contributions of Maternal Reading Proficiency to Predicting Children's Preschool Receptive Vocabulary and Reading Proficiency

    Science.gov (United States)

    Phillips, Linda M.; Norris, Stephen P.; Hayward, Denyse V.; Lovell, Meridith A.

    2017-01-01

    This study investigated whether mothers' measured reading proficiency and their educational level predict, over and above each other, their children's receptive vocabulary and reading proficiency when confounding factors of speaking a minority language, ethnicity, number of children in the family, and marital and employment status are controlled.…

  13. Localization of spindle checkpoint proteins in cells undergoing mitosis with unreplicated genomes.

    Science.gov (United States)

    Johnson, Mary Kathrine; Cooksey, Amanda M; Wise, Dwayne A

    2008-11-01

    CHO cells can be arrested with hydoxyurea at the beginning of the DNA synthesis phase of the cell cycle. Subsequent treatment with the xanthine, caffeine, induces cells to bypass the S-phase checkpoint and enter unscheduled mitosis [Schlegel and Pardee,1986, Science 232:1264-1266]. These treated cells build a normal spindle and distribute kinetochores, unattached to chromosomes, to their daughter cells [Brinkley et al.,1988, Nature 336:251-254; Zinkowski et al.,1991, J Cell Biol 113:1091-1110; Wise and Brinkley,1997, Cell Motil Cytoskeleton 36:291-302; Balczon et al.,2003, Chromosoma 112:96-102]. To investigate how these cells distribute kinetochores to daughter cells, we analyzed the spindle checkpoint components, Mad2, CENP-E, and the 3F3 phosphoepitope, using immunofluorescence and digital microscopy. Even though the kinetochores were unpaired and DNA was fragmented, the tension, alignment, and motor components of the checkpoint were found to be present and localized as predicted in prometaphase and metaphase. This unusual mitosis proves that a cell can successfully localize checkpoint proteins and divide even when kinetochores are unpaired and fragmented. (c) 2008 Wiley-Liss, Inc.

  14. Measuring receptive collocational competence across proficiency levels

    Directory of Open Access Journals (Sweden)

    Déogratias Nizonkiza

    2015-12-01

    Full Text Available The present study investigates, (i English as Foreign Language (EFL learners’ receptive collocational knowledge growth in relation to their linguistic proficiency level; (ii how much receptive collocational knowledge is acquired as proficiency develops; and (iii the extent to which receptive knowledge of collocations of EFL learners varies across word frequency bands. A proficiency measure and a collocation test were administered to English majors at the University of Burundi. Results of the study suggest that receptive collocational competence develops alongside EFL learners’ linguistic proficiency; which lends empirical support to Gyllstad (2007, 2009 and Author (2011 among others, who reported similar findings. Furthermore, EFL learners’ collocations growth seems to be quantifiable wherein both linguistic proficiency level and word frequency occupy a crucial role. While more gains in terms of collocations that EFL learners could potentially add as a result of change in proficiency are found at lower levels of proficiency; collocations of words from more frequent word bands seem to be mastered first, and more gains are found at more frequent word bands. These results confirm earlier findings on the non-linearity nature of vocabulary growth (cf. Meara 1996 and the fundamental role played by frequency in word knowledge for vocabulary in general (Nation 1983, 1990, Nation and Beglar 2007, which are extended here to collocations knowledge.

  15. The anaphase inhibitor of Saccharomyces cerevisiae Pds1p is a target of the DNA damage checkpoint pathway

    International Nuclear Information System (INIS)

    Cohen-Fix, O.; Koshland, D.

    1997-01-01

    Inhibition of DNA replication and physical DNA damage induce checkpoint responses that arrest cell cycle progression at two different stages. In Saccharomyces cerevisiae, the execution of both checkpoint responses requires the Mec1 and Rad53 proteins. This observation led to the suggestion that these checkpoint responses are mediated through a common signal transduction pathway. However, because the checkpoint-induced arrests occur at different cell cycle stages, the downstream effectors mediating these arrests are likely to be distinct. We have previously shown that the S. cerevisiae protein Pds1p is an anaphase inhibitor and is essential for cell cycle arrest in mitosis in the presence DNA damage. Herein we show that DNA damage, but not inhibition of DNA replication, induces the phosphorylation of Pds1p. Analyses of Pds1p phosphorylation in different checkpoint mutants reveal that in the presence of DNA damage, Pds1p is phosphorylated in a Mec1p- and Rad9p-dependent hut Rad53p-independent manner. Our data place Pds1p and Rad53p on parallel branches of the DNA damage checkpoint pathway. We suggest that Pds1p is a downstream target of the DNA damage checkpoint pathway and that it is involved in implementing the DNA damage checkpoint arrest specifically in mitosis

  16. Immune Checkpoint Inhibitors in the Treatment of Patients with Neuroendocrine Neoplasia.

    Science.gov (United States)

    Weber, Matthias M; Fottner, Christian

    2018-01-01

    Well-differentiated neuroendocrine neoplasms (NENs) are usually controlled by antiproliferative, local ablative and/or radionuclide therapies, whereas poorly differentiated NENs generally require cytotoxic chemotherapy. However, treatment options for patients with advanced/metastatic high-grade NENs remain limited. Review of the literature and international congress abstracts on the efficacy and safety of immunotherapy by checkpoint inhibition in advanced/metastatic NENs. Evidence points to an important role of immune phenomena in the pathogenesis and treatment of neuroendocrine tumors (NETs). Programmed cell death 1 (PD-1) protein and its ligand are mainly expressed in poorly differentiated NENs. Microsatellite instability and high mutational load are more pronounced in high-grade NENs and may predict response to immunotherapy. Clinical experience of immune checkpoint blockade mainly exists for Merkel cell carcinoma, a high-grade cutaneous neuroendocrine carcinoma (NEC), which has led to approval of the anti-PD-1 antibody avelumab. In addition, there is anecdotal evidence for the efficacy of checkpoint inhibitors in large-cell lung NECs, ovarian NECs and others, including gastroenteropancreatic NENs. Currently, phase II studies investigate PDR001, pembrolizumab, combined durvalumab and tremelimumab, and avelumab treatment in patients with advanced/metastatic NENs. Immune checkpoint inhibitors are a promising therapeutic option, especially in progressive NECs or high-grade NETs with high tumor burden, microsatellite instability, and/or mutational load. © 2018 S. Karger GmbH, Freiburg.

  17. An Iterative Maximum a Posteriori Estimation of Proficiency Level to Detect Multiple Local Likelihood Maxima

    Science.gov (United States)

    Magis, David; Raiche, Gilles

    2010-01-01

    In this article the authors focus on the issue of the nonuniqueness of the maximum likelihood (ML) estimator of proficiency level in item response theory (with special attention to logistic models). The usual maximum a posteriori (MAP) method offers a good alternative within that framework; however, this article highlights some drawbacks of its…

  18. RNA interference regulates the cell cycle checkpoint through the RNA export factor, Ptr1, in fission yeast

    Energy Technology Data Exchange (ETDEWEB)

    Iida, Tetsushi, E-mail: tiida@nig.ac.jp [Division of Cytogenetics, National Institute of Genetics, Mishima, 1111 Yata, Mishima 411-8540 (Japan); The Graduate University for Advanced Studies, Sokendai, Mishima, 1111 Yata, Mishima 411-8540 (Japan); Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), 4-1-8, Honcho, Kawaguchi-shi, Saitama 332-0012 (Japan); Iida, Naoko [Division of Mutagenesis, National Institute of Genetics, Mishima, 1111 Yata, Mishima 411-8540 (Japan); Tsutsui, Yasuhiro [Department of Life Science, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Nagatsuda-cho, Midori-ku, Yokohama 226-8501 (Japan); Yamao, Fumiaki [Division of Mutagenesis, National Institute of Genetics, Mishima, 1111 Yata, Mishima 411-8540 (Japan); The Graduate University for Advanced Studies, Sokendai, Mishima, 1111 Yata, Mishima 411-8540 (Japan); Kobayashi, Takehiko [Division of Cytogenetics, National Institute of Genetics, Mishima, 1111 Yata, Mishima 411-8540 (Japan); The Graduate University for Advanced Studies, Sokendai, Mishima, 1111 Yata, Mishima 411-8540 (Japan)

    2012-10-12

    Highlights: Black-Right-Pointing-Pointer RNAi is linked to the cell cycle checkpoint in fission yeast. Black-Right-Pointing-Pointer Ptr1 co-purifies with Ago1. Black-Right-Pointing-Pointer The ptr1-1 mutation impairs the checkpoint but does not affect gene silencing. Black-Right-Pointing-Pointer ago1{sup +} and ptr1{sup +} regulate the cell cycle checkpoint via the same pathway. Black-Right-Pointing-Pointer Mutations in ago1{sup +} and ptr1{sup +} lead to the nuclear accumulation of poly(A){sup +} RNAs. -- Abstract: Ago1, an effector protein of RNA interference (RNAi), regulates heterochromatin silencing and cell cycle arrest in fission yeast. However, the mechanism by which Ago1 controls cell cycle checkpoint following hydroxyurea (HU) treatment has not been elucidated. In this study, we show that Ago1 and other RNAi factors control cell cycle checkpoint following HU treatment via a mechanism independent of silencing. While silencing requires dcr1{sup +}, the overexpression of ago1{sup +} alleviated the cell cycle defect in dcr1{Delta}. Ago1 interacted with the mRNA export factor, Ptr1. The ptr1-1 mutation impaired cell cycle checkpoint but gene silencing was unaffected. Genetic analysis revealed that the regulation of cell cycle checkpoint by ago1{sup +} is dependent on ptr1{sup +}. Nuclear accumulation of poly(A){sup +} RNAs was detected in mutants of ago1{sup +} and ptr1{sup +}, suggesting there is a functional link between the cell cycle checkpoint and RNAi-mediated RNA quality control.

  19. Blocking CHK1 Expression Induces Apoptosis and Abrogates the G2 Checkpoint Mechanism

    Directory of Open Access Journals (Sweden)

    Yan Luo

    2001-01-01

    Full Text Available Checkpoint kinase 1 (Chki is a checkpoint gene that is activated after DNA damage. It phosphorylates and inactivates the Cdc2 activating phosphatase Cdc25C. This in turn inactivates Cdc2, which leads to G2/M arrest. We report that blocking Chki expression by antisense or ribozymes in mammalian cells induces apoptosis and interferes with the G2/M arrest induced by adriamycin. The Chki inhibitor UCN-01 also blocks the G2 arrest after DNA damage and renders cells more susceptible to adriamycin. These results indicate that Chki is an essential gene for the checkpoint mechanism during normal cell proliferation as well as in the DNA damage response.

  20. Extending the Binomial Checkpointing Technique for Resilience

    Energy Technology Data Exchange (ETDEWEB)

    Walther, Andrea; Narayanan, Sri Hari Krishna

    2016-10-10

    In terms of computing time, adjoint methods offer a very attractive alternative to compute gradient information, re- quired, e.g., for optimization purposes. However, together with this very favorable temporal complexity result comes a memory requirement that is in essence proportional with the operation count of the underlying function, e.g., if algo- rithmic differentiation is used to provide the adjoints. For this reason, checkpointing approaches in many variants have become popular. This paper analyzes an extension of the so-called binomial approach to cover also possible failures of the computing systems. Such a measure of precaution is of special interest for massive parallel simulations and adjoint calculations where the mean time between failure of the large scale computing system is smaller than the time needed to complete the calculation of the adjoint information. We de- scribe the extensions of standard checkpointing approaches required for such resilience, provide a corresponding imple- mentation and discuss numerical results.

  1. PD-1 Checkpoint Inhibitor Associated Autoimmune Encephalitis

    Directory of Open Access Journals (Sweden)

    Stephanie Schneider

    2017-05-01

    Full Text Available Objective: To report first-hand narrative experience of autoimmune encephalitis and to briefly review currently available evidence of autoimmune encephalitis in cancer patients treated with immune checkpoint inhibitors. Setting: A case study is presented on the management of a patient who developed autoimmune encephalitis during nivolumab monotherapy occurring after 28 weeks on anti-PD-1 monotherapy (nivolumab 3 mg/kg every 2 weeks for non-small cell lung cancer. Results: No substantial improvement was observed by antiepileptic treatment. After administration of 80 mg methylprednisolone, neurologic symptoms disappeared within 24 h and the patient fully recovered. Conclusions: Immune checkpoint inhibitor treatment can lead to autoimmune encephalitis. Clinical trial data indicate a frequency of autoimmune encephalitis of ≥0.1 to <1% with a higher probability during combined or sequential anti-CTLA-4/anti-PD-1 therapy than during anti-PD-1 or anti-PD-L1 monotherapy. Further collection of evidence and translational research is warranted.

  2. Knowledge Management and Organizational Proficiency with NPP

    International Nuclear Information System (INIS)

    Marler, M.

    2016-01-01

    Full text: The pace of new NPP construction, startup, and operation is straining the supply of proficient operators, technicians, and engineers. This technical brief explains an approach implemented by a US nuclear utility to capture and transfer knowledge possessed by proficient workers to new workers using the VISION learning content management system. This approach could also be used to accelerate worker proficiency in new NPP organizations. (author

  3. The Rating of Direct and Semi-Direct Oral Proficiency Interviews: Comparing Performance at Lower Proficiency Levels.

    Science.gov (United States)

    Kenyon, Dorry M.; Tschirner, Erwin

    2000-01-01

    Reports on a study comparing student performances and test reliabilities for the German Speaking Test, a semi-direct tape-mediated oral proficiency test (GST) developed by the Center for Applied Linguistics, and the American Council on the Teaching of Foreign Languages Oral Proficiency Interviews. (Author/VWL)

  4. Language proficiency and nursing registration.

    Science.gov (United States)

    Müller, Amanda

    2016-02-01

    This discussion paper focuses on English proficiency standards for nursing registration in Australia, how Australia has dealt with the issue of language proficiency, and the factors which have led to the establishment of the current language standards. Also, this paper will provide a comparison of the two language tests that are currently accepted in Australia (OET and IELTS), including the appropriateness of these tests and the minimum standards used. The paper will also examine the use of educational background as an indicator of language proficiency. Finally, communication-based complaints in the post-registration environment will be explored, and some discussion will be provided about why pre-registration measures might have failed to prevent such problematic situations from occurring. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. NEK11: linking CHK1 and CDC25A in DNA damage checkpoint signaling

    DEFF Research Database (Denmark)

    Sørensen, Claus Storgaard; Melixetian, Marina; Klein, Ditte Kjaersgaard

    2010-01-01

    The DNA damage induced G(2)/M checkpoint is an important guardian of the genome that prevents cell division when DNA lesions are present. The checkpoint prevents cells from entering mitosis by degrading CDC25A, a key CDK activator. CDC25A proteolysis is controlled by direct phosphorylation events...... is required for beta-TrCP mediated CDC25A polyubiquitylation and degradation. The activity of NEK11 is in turn controlled by CHK1 that activates NEK11 via phosphorylation on serine 273. Since inhibition of NEK11 activity forces checkpoint-arrested cells into mitosis and cell death, NEK11 is, like CHK1...

  6. Measuring receptive collocational competence across proficiency ...

    African Journals Online (AJOL)

    The present study investigates (i) English as Foreign Language (EFL) learners' receptive collocational knowledge growth in relation to their linguistic proficiency level; (ii) how much receptive collocational knowledge is acquired as linguistic proficiency develops; and (iii) the extent to which receptive knowledge of ...

  7. Proficiency study for quinolones in egg

    NARCIS (Netherlands)

    Berendsen, B.J.A.; Stolker, A.A.M.

    2008-01-01

    The aim of this proficiency study was to give laboratories the possibility to evaluate or demonstrate their competence for the analysis of quinolones in egg. Furthermore the specificity of the applied methods is evaluated by including possibly interfering compounds in the proficiency study. This

  8. Clinical characteristics of patient selection and imaging predictors of outcome in solid tumors treated with checkpoint-inhibitors

    International Nuclear Information System (INIS)

    Rossi, Sabrina; Toschi, Luca; Castello, Angelo; Grizzi, Fabio; Mansi, Luigi; Lopci, Egesta

    2017-01-01

    The rapidly evolving knowledge on tumor immunology and the continuous implementation of immunotherapy in cancer have recently led to the FDA and EMA approval of several checkpoint inhibitors as immunotherapic agents in clinical practice. Anti-CTLA-4, anti-PD-1, and anti-PDL-1 antibodies are becoming standard of care in advanced melanoma, as well as in relapsed or metastatic lung and kidney cancer, demonstrating higher and longer response compared to standard chemotherapy. These encouraging results have fostered the evaluation of these antibodies either alone or in combination with other therapies in several dozen clinical trials for the treatment of multiple tumor types. However, not all patients respond to immune checkpoint inhibitors, hence, specific biomarkers are necessary to guide and monitor therapy. The utility of PD-L1 expression as a biomarker has varied in different clinical trials, but, to date, no consensus has been reached on whether PD-L1 expression is an ideal marker for response and patient selection; approximately 20-25% of patients will respond to immunotherapy with checkpoint inhibitors despite a negative PD-L1 staining. On the other hand, major issues concern the evaluation of objective response in patients treated with immunotherapy. Pure morphological criteria as commonly used in solid tumors (i.e. RECIST) are not sufficient because change in size is not an early and reliable marker of tumor response to biological therapies. Thus, the scientific community has required a continuous adaptation of immune-related response criteria (irRC) to overcome the problem. In this context, metabolic information and antibody-based imaging with positron emission tomography (PET) have been investigated, providing a powerful approach for an optimal stratification of patients at staging and during the evaluation of the response to therapy. In the present review we provide an overview on the clinical characteristics of patient selection when using imaging

  9. Clinical characteristics of patient selection and imaging predictors of outcome in solid tumors treated with checkpoint-inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Rossi, Sabrina; Toschi, Luca [Humanitas Clinical and Research Hospital, Medical Oncology, Rozzano (Italy); Castello, Angelo [Humanitas Clinical and Research Hospital, Nuclear Medicine, Rozzano (Italy); Grizzi, Fabio [Humanitas Clinical and Research Hospital, Immunology and Inflammation, Rozzano (Italy); Mansi, Luigi [Seconda Universita di Napoli, Nuclear Medicine, Naples (Italy); Lopci, Egesta [Humanitas Clinical and Research Hospital, Nuclear Medicine, Rozzano (Italy); Humanitas Cancer Center, Humanitas Clinical and Research Hospital, Nuclear Medicine, Rozzano, MI (Italy)

    2017-12-15

    The rapidly evolving knowledge on tumor immunology and the continuous implementation of immunotherapy in cancer have recently led to the FDA and EMA approval of several checkpoint inhibitors as immunotherapic agents in clinical practice. Anti-CTLA-4, anti-PD-1, and anti-PDL-1 antibodies are becoming standard of care in advanced melanoma, as well as in relapsed or metastatic lung and kidney cancer, demonstrating higher and longer response compared to standard chemotherapy. These encouraging results have fostered the evaluation of these antibodies either alone or in combination with other therapies in several dozen clinical trials for the treatment of multiple tumor types. However, not all patients respond to immune checkpoint inhibitors, hence, specific biomarkers are necessary to guide and monitor therapy. The utility of PD-L1 expression as a biomarker has varied in different clinical trials, but, to date, no consensus has been reached on whether PD-L1 expression is an ideal marker for response and patient selection; approximately 20-25% of patients will respond to immunotherapy with checkpoint inhibitors despite a negative PD-L1 staining. On the other hand, major issues concern the evaluation of objective response in patients treated with immunotherapy. Pure morphological criteria as commonly used in solid tumors (i.e. RECIST) are not sufficient because change in size is not an early and reliable marker of tumor response to biological therapies. Thus, the scientific community has required a continuous adaptation of immune-related response criteria (irRC) to overcome the problem. In this context, metabolic information and antibody-based imaging with positron emission tomography (PET) have been investigated, providing a powerful approach for an optimal stratification of patients at staging and during the evaluation of the response to therapy. In the present review we provide an overview on the clinical characteristics of patient selection when using imaging

  10. Proficiency Testing in Nondestructive Testing (NDT)

    International Nuclear Information System (INIS)

    Amry Amin Abbas; Suhairy Sani; Mohamad Pauzi Ismail; Abd Nassir Ibrahim

    2014-01-01

    Department of Standard Malaysia (DSM) launched myPTP programme on 31 December 2013 in accordance to ISO/IC 17043. The standard states the requirements for Proficiency Testing. The provider of these services is called Proficiency Testing Provider (PTP). The role of PTP is to compare the proficiency level between inspection bodies or laboratories. With the assistance of expert panel, the PTP will determine the assigned value as reference to be compared to the values obtained from the inspection bodies or laboratories. Quality wise, this services is important as participation will improve wuality of the inspection quality continuously and increase confidence level of client and improve safety level. Requirement of PT in NDT is mentioned in SC1.5- Specific Criteria for Accreditation of Mechanical Testing and Non-Destructive Testing (NDT) for MS ISO/IEC17025 and MTR2- MIBAS Technical Requirements for Accreditation of NDT. This paper explains and discusses the result of this proficiency test done on a number of NDT companies that participated. (author)

  11. The emerging role of immune checkpoint based approaches in AML and MDS.

    Science.gov (United States)

    Boddu, Prajwal; Kantarjian, Hagop; Garcia-Manero, Guillermo; Allison, James; Sharma, Padmanee; Daver, Naval

    2018-04-01

    The development of immune checkpoint inhibitors represents a major breakthrough in the field of cancer therapeutics. Pursuant to their success in melanoma and numerous solid tumor malignancies, these agents are being investigated in hematological malignancies including acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS). Although AML/MDS have traditionally been considered to be less immunogenic than solid tumor malignancies, recent pre-clinical models suggest a therapeutic role for immune checkpoint inhibition in these diseases. CTLA-4 inhibition may be especially effective in treating late post-allogeneic stem cell transplant relapse of AML in patients with limited or no graft versus host disease. Immune checkpoint inhibition, specifically PD-1 inhibition, demonstrated limited single agent efficacy in patients with relapsed AML and with MDS post-hypomethylating therapy. Rationally designed combinations of PD-1 inhibitors with standard anti-leukemic therapy are needed. Hypomethylating agents such as azacitidine, up-regulate PD-1, PD-L1, and PD-L2 in patients with AML/MDS and up-regulation of these genes was associated with the emergence of resistance. The combination of azacitidine and PD-1/PD-L1 inhibition may be a potential mechanism to prevent or overcome resistance to 5-azacitidine. A number of such combinations are being evaluated in clinical trials with early encouraging results. Immune checkpoint inhibition is also an attractive option to improve relapse-free survival or eliminate minimal residual disease post induction and consolidation by enhancing T-cell surveillance in patients with high-risk AML. The ongoing clinical trials with checkpoint inhibitors in AML/MDS will improve our understanding of the immunobiology of these diseases and guide us to the most appropriate application of these agents in the therapy of AML/MDS.

  12. A novel ATM-dependent checkpoint defect distinct from loss of function mutation promotes genomic instability in melanoma.

    Science.gov (United States)

    Spoerri, Loredana; Brooks, Kelly; Chia, KeeMing; Grossman, Gavriel; Ellis, Jonathan J; Dahmer-Heath, Mareike; Škalamera, Dubravka; Pavey, Sandra; Burmeister, Bryan; Gabrielli, Brian

    2016-05-01

    Melanomas have high levels of genomic instability that can contribute to poor disease prognosis. Here, we report a novel defect of the ATM-dependent cell cycle checkpoint in melanoma cell lines that promotes genomic instability. In defective cells, ATM signalling to CHK2 is intact, but the cells are unable to maintain the cell cycle arrest due to elevated PLK1 driving recovery from the arrest. Reducing PLK1 activity recovered the ATM-dependent checkpoint arrest, and over-expressing PLK1 was sufficient to overcome the checkpoint arrest and increase genomic instability. Loss of the ATM-dependent checkpoint did not affect sensitivity to ionizing radiation demonstrating that this defect is distinct from ATM loss of function mutations. The checkpoint defective melanoma cell lines over-express PLK1, and a significant proportion of melanomas have high levels of PLK1 over-expression suggesting this defect is a common feature of melanomas. The inability of ATM to impose a cell cycle arrest in response to DNA damage increases genomic instability. This work also suggests that the ATM-dependent checkpoint arrest is likely to be defective in a higher proportion of cancers than previously expected. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Relationship between phonological awareness and spelling proficiency in first-grade students

    Directory of Open Access Journals (Sweden)

    Nasibe Soltaninejad

    2014-12-01

    Full Text Available Background and Aim: Phonological awareness (consisting of phoneme, syllable and intra-syllable awareness is an important part of receptive and expressive language; it facilitates reading and writing skills through phonological re-coding. Multiple studies in several languages have studied the relationship between phonological awareness and dictation. This research is based on a study of the relationship between phonological skill and spelling score in first-grade Persian students.Methods: Four hundred first-grade students participated in the study, including 209 girls and 191 boys. A phonological awareness test was individually administered for each student and then a spelling exam was administered in groups. The correlation between the two tests was studied using a simple regression model. The comparison of mean scores of girls and boys was evaluated employing an independent t-test.Results: A correlation coefficient of 0.82 was obtained between phonological awareness and spelling proficiency (p<0.001. Phonological skill sub-tests also showed a significant correlation with spelling proficiency (highest for phoneme awareness r=0.34 and lowest for rhyme awareness r=0.12. The mean scores of girls and boys differed significantly (p<0.05.Conclusion: There is a strong positive association between phonological awareness and spelling proficiency. Therefore, if phonological skill is improved, spelling score can be enhanced.

  14. READING COMPREHENSION EXERCISES ONLINE: THE EFFECTS OF FEEDBACK, PROFICIENCY AND INTERACTION

    Directory of Open Access Journals (Sweden)

    Philip Murphy

    2007-02-01

    Full Text Available This paper describes an ongoing project to create an online version of a reading programme, a custom-designed English language proficiency course at a university in Japan. Following an interactionist view of second language acquisition, it was hypothesised that comprehension of a reading passage could be enhanced by online materials promoting interaction between students as they completed a multiple-choice reading comprehension exercise. Interaction was promoted: (a through pair work at a single computer and (b by providing Elaborative feedback in the form of hints about incorrect answers as a means of stimulating discussion about corrections. Students were randomly selected from upper and lower levels of English proficiency, as determined by the Kanda English Proficiency Test (Bonk & Ockey, 2003, to receive either Elaborative feedback or Knowledge of Correct Response feedback (which supplies the correct answers. Within these groups, some students worked in pairs and some alone. Quantitative results show that the interaction between Type of feedback and Manner of study (individual or pair work was statistically significant; students performed best on a follow-up comprehension exercise when in pairs and having been provided with Elaborative feedback. Furthermore, qualitative analysis of transcribed interactions also shows that Elaborative feedback was conducive to quality interaction.

  15. Discrepancies between perceptions of English proficiency and ...

    African Journals Online (AJOL)

    multilingual awareness pedagogy” embedded in Dörnyei's (2009) L2 Motivational Self System theory. Key words: self-reported perceptions, language proficiency, English proficiency, multilingualism, pedagogy, resilience, L2 Motivational Self System ...

  16. Checkpoint blockade in combination with cancer vaccines.

    Science.gov (United States)

    Morse, Michael A; Lyerly, H Kim

    2015-12-16

    Checkpoint blockade, prevention of inhibitory signaling that limits activation or function of tumor antigen-specific T cells responses, is revolutionizing the treatment of many poor prognosis malignancies. Indeed monoclonal antibodies that modulate signaling through the inhibitory molecules CTLA-4 and PD-1 are now clinically available; however, many tumors, demonstrate minimal response suggesting the need for combinations with other therapeutic strategies. Because an inadequate frequency of activated tumor antigen-specific T cells in the tumor environment, the so-called non-inflamed phenotype, is observed in some malignancies, other rationale partners are modalities that lead to enhanced T cell activation (vaccines, cytokines, toll-like receptor agonists, and other anticancer therapies such as chemo-, radio- or targeted therapies that lead to release of antigen from tumors). This review will focus on preclinical and clinical data supporting the use of cancer vaccines with anti-CTLA-4 and anti-PD-1/PD-L1 antibodies. Preliminary preclinical data demonstrate enhanced antitumor activity although the results in human studies are less clear. Broader combinations of multiple immune modulators are now under study. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. PD-1 checkpoint inhibition: Toxicities and management.

    Science.gov (United States)

    Hahn, Andrew W; Gill, David M; Agarwal, Neeraj; Maughan, Benjamin L

    2017-12-01

    With the recent approval of 5 PD-1/PD-L1 inhibitors for a number of malignancies, PD-1 axis inhibition is drastically changing the treatment landscape of immunotherapy in cancer. As PD-1/PD-L1 are involved in peripheral immune tolerance, inhibition of this immune checkpoint has led to novel immune-related adverse events including colitis, hepatitis, pneumonitis, rash, and endocrinopathies among many others. In this seminar, we will analyze the incidence of immune-related adverse events for nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab. Then, we will discuss the specific management of the most common immune-mediated adverse events including colitis, hepatitis, pneumonitis, rash, endocrinopathies, nephritis, and neurologic toxicities. Immune-related adverse events are frequently treated with immunosuppressive medication such as steroids and mycofenolate mofetil. There are specific immune-related adverse events which are frequently seen by the treating oncologist from checkpoint inhibitors. It is essential to understand the recommended treatment options to minimize toxicity and mortality from this important class of anti-neoplastic therapies. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Language proficiency: Current strategies, future remedies ...

    African Journals Online (AJOL)

    Language proficiency among young South Africans is low. This is true not only of mother tongue speakers of English and Afrikaans, but also, and especially, of non-mother tongue speakers of English, among whom language proficiency levels raise serious concern. Some examples are given to illustrate the importance of ...

  19. Continuing global improvement in human papillomavirus DNA genotyping services: The 2013 and 2014 HPV LabNet international proficiency studies.

    Science.gov (United States)

    Eklund, Carina; Forslund, Ola; Wallin, Keng-Ling; Dillner, Joakim

    2018-04-01

    Accurate and internationally comparable human papillomavirus (HPV) DNA detection and typing services are essential for HPV vaccine research and surveillance. This study assessed the proficiency of different HPV typing services offered routinely in laboratories worldwide. The HPV Laboratory Network (LabNet) has designed international proficiency panels that can be regularly issued. The HPV genotyping proficiency panels of 2013 and 2014 contained 43 and 41 coded samples, respectively, composed of purified plasmids of sixteen HPV types (HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68a and 68b) and 3 extraction controls. Proficient typing was defined as detection in both single and multiple infections of 50 International Units of HPV 16 and HPV 18 and 500 genome equivalents for the other 14 HPV types, with at least 97% specificity. Ninety-six laboratories submitted 136 datasets in 2013 and 121 laboratories submitted 148 datasets in 2014. Thirty-four different HPV genotyping assays were used, notably Linear Array, HPV Direct Flow-chip, GenoFlow HPV array, Anyplex HPV 28, Inno-LiPa, and PGMY-CHUV assays. A trend towards increased sensitivity and specificity was observed. In 2013, 59 data sets (44%) were 100% proficient compared to 86 data sets (59%) in 2014. This is a definite improvement compared to the first proficiency panel, issued in 2008, when only 19 data sets (26%) were fully proficient. The regularly issued global proficiency program has documented an ongoing worldwide improvement in comparability and reliability of HPV genotyping services. Copyright © 2018 Elsevier B.V. All rights reserved.

  20. Silencing of poly(ADP-ribose) glycohydrolase sensitizes lung cancer cells to radiation through the abrogation of DNA damage checkpoint

    Energy Technology Data Exchange (ETDEWEB)

    Nakadate, Yusuke [Shien-Lab, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 (Japan); Department of Bioengineering, Graduate School of Engineering, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585 (Japan); Kodera, Yasuo; Kitamura, Yuka [Shien-Lab, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 (Japan); Tachibana, Taro [Department of Bioengineering, Graduate School of Engineering, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585 (Japan); Tamura, Tomohide [Division of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 (Japan); Koizumi, Fumiaki, E-mail: fkoizumi@ncc.go.jp [Division of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 (Japan)

    2013-11-29

    Highlights: •Radiosensitization by PARG silencing was observed in multiple lung cancer cells. •PAR accumulation was enhanced by PARG silencing after DNA damage. •Radiation-induced G2/M arrest and checkpoint activation were impaired by PARG siRNA. -- Abstract: Poly(ADP-ribose) glycohydrolase (PARG) is a major enzyme that plays a role in the degradation of poly(ADP-ribose) (PAR). PARG deficiency reportedly sensitizes cells to the effects of radiation. In lung cancer, however, it has not been fully elucidated. Here, we investigated whether PARG siRNA contributes to an increased radiosensitivity using 8 lung cancer cell lines. Among them, the silencing of PARG induced a radiosensitizing effect in 5 cell lines. Radiation-induced G2/M arrest was largely suppressed by PARG siRNA in PC-14 and A427 cells, which exhibited significantly enhanced radiosensitivity in response to PARG knockdown. On the other hand, a similar effect was not observed in H520 cells, which did not exhibit a radiosensitizing effect. Consistent with a cell cycle analysis, radiation-induced checkpoint signals were not well activated in the PC-14 and A427 cells when treated with PARG siRNA. These results suggest that the increased sensitivity to radiation induced by PARG knockdown occurs through the abrogation of radiation-induced G2/M arrest and checkpoint activation in lung cancer cells. Our findings indicate that PARG could be a potential target for lung cancer treatments when used in combination with radiotherapy.

  1. Covering Resilience: A Recent Development for Binomial Checkpointing

    Energy Technology Data Exchange (ETDEWEB)

    Walther, Andrea; Narayanan, Sri Hari Krishna

    2016-09-12

    In terms of computing time, adjoint methods offer a very attractive alternative to compute gradient information, required, e.g., for optimization purposes. However, together with this very favorable temporal complexity result comes a memory requirement that is in essence proportional with the operation count of the underlying function, e.g., if algorithmic differentiation is used to provide the adjoints. For this reason, checkpointing approaches in many variants have become popular. This paper analyzes an extension of the so-called binomial approach to cover also possible failures of the computing systems. Such a measure of precaution is of special interest for massive parallel simulations and adjoint calculations where the mean time between failure of the large scale computing system is smaller than the time needed to complete the calculation of the adjoint information. We describe the extensions of standard checkpointing approaches required for such resilience, provide a corresponding implementation and discuss first numerical results.

  2. Lyn tyrosine kinase promotes silencing of ATM-dependent checkpoint signaling during recovery from DNA double-strand breaks

    International Nuclear Information System (INIS)

    Fukumoto, Yasunori; Kuki, Kazumasa; Morii, Mariko; Miura, Takahito; Honda, Takuya; Ishibashi, Kenichi; Hasegawa, Hitomi; Kubota, Sho; Ide, Yudai; Yamaguchi, Noritaka; Nakayama, Yuji; Yamaguchi, Naoto

    2014-01-01

    Highlights: • Inhibition of Src family kinases decreased γ-H2AX signal. • Inhibition of Src family increased ATM-dependent phosphorylation of Chk2 and Kap1. • shRNA-mediated knockdown of Lyn increased phosphorylation of Kap1 by ATM. • Ectopic expression of Src family kinase suppressed ATM-mediated Kap1 phosphorylation. • Src is involved in upstream signaling for inactivation of ATM signaling. - Abstract: DNA damage activates the DNA damage checkpoint and the DNA repair machinery. After initial activation of DNA damage responses, cells recover to their original states through completion of DNA repair and termination of checkpoint signaling. Currently, little is known about the process by which cells recover from the DNA damage checkpoint, a process called checkpoint recovery. Here, we show that Src family kinases promote inactivation of ataxia telangiectasia mutated (ATM)-dependent checkpoint signaling during recovery from DNA double-strand breaks. Inhibition of Src activity increased ATM-dependent phosphorylation of Chk2 and Kap1. Src inhibition increased ATM signaling both in G2 phase and during asynchronous growth. shRNA knockdown of Lyn increased ATM signaling. Src-dependent nuclear tyrosine phosphorylation suppressed ATM-mediated Kap1 phosphorylation. These results suggest that Src family kinases are involved in upstream signaling that leads to inactivation of the ATM-dependent DNA damage checkpoint

  3. Gender impacts on motor skill proficiency-physical activity relationship in children

    Directory of Open Access Journals (Sweden)

    Diana Samara

    2015-12-01

    Full Text Available BACKGROUND Physical activity is the greatest contributor to achievement of adequate physical activity. Children performing adequate daily physical activity will get positive benefits from their activity. Several studies indicate a difference in motor skills between boys and girls. To understand the development of motor skill proficiency and physical activity in boys and girls, a study was conducted to determine the role of gender on motor skill proficiency and physical activity in children aged 6-12 years. METHODS A cross-sectional observational study was conducted and a total of 162 children were included at a primary school in the Grogol area, West Jakarta. Data collection was by questionnaire-based interviews, covering age, gender, and physical activity (watching TV, playing games, and outdoor play. Assessment of motor skills was performed using the Bruininks-Oseretsky Test–Second Edition (BOT-2. Data analysis was performed using SPSS for Windows release 17.0 and level of significance was set at 0.05. RESULTS Multiple linear regression results showed that in boys the strength subset was the most influential factor on TV watching activity, with the higher scores for strength indicating a lower TV watching activity (â=-0.125;p=0.021. Age was the most influential factor on outdoor playing activity in girls, with older girls having lower outdoor playing activity (â=-0.375;p=0.016. CONCLUSIONS This study revealed that gender difference impacts on motor skills and physical activity in children. Higher motor proficiency increases outdoor playing activity only in boys. Primary school pupils should be given opportunities for performing outdoor playing activities to improve their motor proficiency.

  4. Gender impacts on motor skill proficiency-physical activity relationship in children

    Directory of Open Access Journals (Sweden)

    Diana Samara

    2012-12-01

    Full Text Available Background Physical activity is the greatest contributor to achievement of adequate physical activity. Children performing adequate daily physical activity will get positive benefits from their activity. Several studies indicate a difference in motor skills between boys and girls. To understand the development of motor skill proficiency and physical activity in boys and girls, a study was conducted to determine the role of gender on motor skill proficiency and physical activity in children aged 6-12 years. Methods A cross-sectional observational study was conducted and a total of 162 children were included at a primary school in the Grogol area, West Jakarta. Data collection was by questionnaire-based interviews, covering age, gender, and physical activity (watching TV, playing games, and outdoor play. Assessment of motor skills was performed using the Bruininks-Oseretsky Test–Second Edition (BOT-2. Data analysis was performed using SPSS for Windows release 17.0 and level of significance was set at 0.05. Results Multiple linear regression results showed that in boys the strength subset was the most influential factor on TV watching activity, with the higher scores for strength indicating a lower TV watching activity (â=-0.125;p=0.021. Age was the most influential factor on outdoor playing activity in girls, with older girls having lower outdoor playing activity (â=-0.375;p=0.016. Conclusions This study revealed that gender difference impacts on motor skills and physical activity in children. Higher motor proficiency increases outdoor playing activity only in boys. Primary school pupils should be given opportunities for performing outdoor playing activities to improve their motor proficiency.

  5. Participation of SRM5/CDC28, SRM8/NET1 and SRM12/HF11 genes in activation of checkpoints of Yeast Saccharomyces Cerevisiae

    International Nuclear Information System (INIS)

    Kadyshevskaya, E.Yu.; Koltovaya, N.A.

    2007-01-01

    It is known that there are about twenty checkpoint genes in yeast Saccharomyces cerevisiae. We study participation of SRM genes selected as genes affecting genetic stability and radiosensitivity. It has been shown that srm5/cdc28-srm, srm8/net1-srm, srm12/hfil-srm mutations prevent checkpoint activation by DNA damage, particularly G0/S-checkpoint (srm5, srm8), G1/S-checkpoint (srm5, srm8, srm12), S-checkpoint (srm5, srm12) and G2-checkpoint (srm5). These data indicate, at least in budding yeast, CDC28/SRM5, HF11/ADA1/SRM12 and NET1/SRM8 genes mediate cellular response induced by DNA damage including checkpoint control

  6. Casein kinase II is required for the spindle assembly checkpoint by regulating Mad2p in fission yeast

    Energy Technology Data Exchange (ETDEWEB)

    Shimada, Midori [Department of Biochemistry and Cell Biology, Graduate School of Medicine, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Yamamoto, Ayumu [Department of Chemistry, Shizuoka University, 836 Ohya, Suruga-ku, Sizuoka 422-8529 (Japan); Murakami-Tonami, Yuko; Nakanishi, Makoto; Yoshida, Takashi [Department of Biochemistry and Cell Biology, Graduate School of Medicine, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Aiba, Hirofumi [Laboratory of Molecular Microbiology, School of Agriculture, Nagoya University, Chikusa-ku, Nagoya 464-8601 (Japan); Murakami, Hiroshi, E-mail: hmura@med.nagoya-cu.ac.jp [Department of Biochemistry and Cell Biology, Graduate School of Medicine, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan)

    2009-10-23

    The spindle checkpoint is a surveillance mechanism that ensures the fidelity of chromosome segregation in mitosis. Here we show that fission yeast casein kinase II (CK2) is required for this checkpoint function. In the CK2 mutants mitosis occurs in the presence of a spindle defect, and the spindle checkpoint protein Mad2p fails to localize to unattached kinetochores. The CK2 mutants are sensitive to the microtubule depolymerising drug thiabendazole, which is counteracted by ectopic expression of mad2{sup +}. The level of Mad2p is low in the CK2 mutants. These results suggest that CK2 has a role in the spindle checkpoint by regulating Mad2p.

  7. Casein kinase II is required for the spindle assembly checkpoint by regulating Mad2p in fission yeast

    International Nuclear Information System (INIS)

    Shimada, Midori; Yamamoto, Ayumu; Murakami-Tonami, Yuko; Nakanishi, Makoto; Yoshida, Takashi; Aiba, Hirofumi; Murakami, Hiroshi

    2009-01-01

    The spindle checkpoint is a surveillance mechanism that ensures the fidelity of chromosome segregation in mitosis. Here we show that fission yeast casein kinase II (CK2) is required for this checkpoint function. In the CK2 mutants mitosis occurs in the presence of a spindle defect, and the spindle checkpoint protein Mad2p fails to localize to unattached kinetochores. The CK2 mutants are sensitive to the microtubule depolymerising drug thiabendazole, which is counteracted by ectopic expression of mad2 + . The level of Mad2p is low in the CK2 mutants. These results suggest that CK2 has a role in the spindle checkpoint by regulating Mad2p.

  8. NDR1 modulates the UV-induced DNA-damage checkpoint and nucleotide excision repair

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jeong-Min; Choi, Ji Ye [Department of Biological Science, Dong-A University, Busan (Korea, Republic of); Yi, Joo Mi [Research Center, Dongnam Institute of Radiological & Medical Sciences, Busan (Korea, Republic of); Chung, Jin Woong; Leem, Sun-Hee; Koh, Sang Seok [Department of Biological Science, Dong-A University, Busan (Korea, Republic of); Kang, Tae-Hong, E-mail: thkang@dau.ac.kr [Department of Biological Science, Dong-A University, Busan (Korea, Republic of)

    2015-06-05

    Nucleotide excision repair (NER) is the sole mechanism of UV-induced DNA lesion repair in mammals. A single round of NER requires multiple components including seven core NER factors, xeroderma pigmentosum A–G (XPA–XPG), and many auxiliary effector proteins including ATR serine/threonine kinase. The XPA protein helps to verify DNA damage and thus plays a rate-limiting role in NER. Hence, the regulation of XPA is important for the entire NER kinetic. We found that NDR1, a novel XPA-interacting protein, modulates NER by modulating the UV-induced DNA-damage checkpoint. In quiescent cells, NDR1 localized mainly in the cytoplasm. After UV irradiation, NDR1 accumulated in the nucleus. The siRNA knockdown of NDR1 delayed the repair of UV-induced cyclobutane pyrimidine dimers in both normal cells and cancer cells. It did not, however, alter the expression levels or the chromatin association levels of the core NER factors following UV irradiation. Instead, the NDR1-depleted cells displayed reduced activity of ATR for some set of its substrates including CHK1 and p53, suggesting that NDR1 modulates NER indirectly via the ATR pathway. - Highlights: • NDR1 is a novel XPA-interacting protein. • NDR1 accumulates in the nucleus in response to UV irradiation. • NDR1 modulates NER (nucleotide excision repair) by modulating the UV-induced DNA-damage checkpoint response.

  9. Trainee-Associated Factors and Proficiency at Percutaneous Nephrolithotomy

    Directory of Open Access Journals (Sweden)

    Seyed Mohammad Kazem Aghamir

    2017-09-01

    Full Text Available Percutaneous nephrolithotomy (PNL is a complicated procedure for urology trainees. This study was designed to investigate the effect of trainees’ ages and previous experience, as well as the number of operated cases, on proficiency at PNL by using patient outcomes. A cross sectional observational study was designed during a five-year period. Trainees in PNL fellowship programs were included. At the end of the program, the trainees’ performance in PNL was assessed regarding five competencies and scored 1-5. If the overall score was 4 or above, the trainee was considered as proficient. The trainees’ age at the beginning of the program and the years passed from their residency graduation were asked and recorded. Also, the number of PNL cases operated by each trainee was obtained via their logbooks. The age, years passed from graduation, and number of operated cases were compared between two groups of proficient and non-proficient trainees. Univariate and multivariate binary logistic regression analysis was applied to estimate the effect of aforementioned variables on the occurrence of the proficiency. Forty-two trainees were included in the study. The mean and standard deviation for the overall score were 3.40 (out of 5 and 0.67, respectively. Eleven trainees (26.2% recognized as proficient in performing PNL. Univariate regression analysis indicated that each of three variables (age, years passed from graduation and number of operated cases had statistically significant effect on proficiency. However, the multivariate regression analysis revealed that just the number of cases had significant effect on achieving proficiency. Although it might be assumed that trainees’ age negatively correlates with their scores, in fact, it is their amount of practice that makes a difference. A certain number of cases is required to be operated by a trainee in order to reach the desired competency in PNL.

  10. Trainee-Associated Factors and Proficiency at Percutaneous Nephrolithotomy.

    Science.gov (United States)

    Aghamir, Seyed Mohammad Kazem; Behtash, Negar; Hamidi, Morteza; Farahmand, Hasan; Salavati, Alborz; Mortaz Hejri, Sara

    2017-07-01

    Percutaneous nephrolithotomy (PNL) is a complicated procedure for urology trainees. This study was designed to investigate the effect of trainees' ages and previous experience, as well as the number of operated cases, on proficiency at PNL by using patient outcomes. A cross sectional observational study was designed during a five-year period. Trainees in PNL fellowship programs were included. At the end of the program, the trainees' performance in PNL was assessed regarding five competencies and scored 1-5. If the overall score was 4 or above, the trainee was considered as proficient. The trainees' age at the beginning of the program and the years passed from their residency graduation were asked and recorded. Also, the number of PNL cases operated by each trainee was obtained via their logbooks. The age, years passed from graduation, and number of operated cases were compared between two groups of proficient and non-proficient trainees. Univariate and multivariate binary logistic regression analysis was applied to estimate the effect of aforementioned variables on the occurrence of the proficiency. Forty-two trainees were included in the study. The mean and standard deviation for the overall score were 3.40 (out of 5) and 0.67, respectively. Eleven trainees (26.2%) recognized as proficient in performing PNL. Univariate regression analysis indicated that each of three variables (age, years passed from graduation and number of operated cases) had statistically significant effect on proficiency. However, the multivariate regression analysis revealed that just the number of cases had significant effect on achieving proficiency. Although it might be assumed that trainees' age negatively correlates with their scores, in fact, it is their amount of practice that makes a difference. A certain number of cases is required to be operated by a trainee in order to reach the desired competency in PNL.

  11. Nek2A destruction marks APC/C activation at the prophase-to-prometaphase transition by spindle-checkpoint-restricted Cdc20.

    Science.gov (United States)

    Boekhout, Michiel; Wolthuis, Rob

    2015-04-15

    Nek2 isoform A (Nek2A) is a presumed substrate of the anaphase-promoting complex/cyclosome containing Cdc20 (APC/C(Cdc20)). Nek2A, like cyclin A, is degraded in mitosis while the spindle checkpoint is active. Cyclin A prevents spindle checkpoint proteins from binding to Cdc20 and is recruited to the APC/C in prometaphase. We found that Nek2A and cyclin A avoid being stabilized by the spindle checkpoint in different ways. First, enhancing mitotic checkpoint complex (MCC) formation by nocodazole treatment inhibited the degradation of geminin and cyclin A, whereas Nek2A disappeared at a normal rate. Second, depleting Cdc20 effectively stabilized cyclin A but not Nek2A. Nevertheless, Nek2A destruction crucially depended on Cdc20 binding to the APC/C. Third, in contrast to cyclin A, Nek2A was recruited to the APC/C before the start of mitosis. Interestingly, the spindle checkpoint very effectively stabilized an APC/C-binding mutant of Nek2A, which required the Nek2A KEN box. Apparently, in cells, the spindle checkpoint primarily prevents Cdc20 from binding destruction motifs. Nek2A disappearance marks the prophase-to-prometaphase transition, when Cdc20, regardless of the spindle checkpoint, activates the APC/C. However, Mad2 depletion accelerated Nek2A destruction, showing that spindle checkpoint release further increases APC/C(Cdc20) catalytic activity. © 2015. Published by The Company of Biologists Ltd.

  12. Cyclin F suppresses B-Myb activity to promote cell cycle checkpoint control

    DEFF Research Database (Denmark)

    Klein, Ditte Kjærsgaard; Hoffmann, Saskia; Ahlskog, Johanna K

    2015-01-01

    an important role in checkpoint control following ionizing radiation. Cyclin F-depleted cells initiate checkpoint signalling after ionizing radiation, but fail to maintain G2 phase arrest and progress into mitosis prematurely. Importantly, cyclin F suppresses the B-Myb-driven transcriptional programme...... that promotes accumulation of crucial mitosis-promoting proteins. Cyclin F interacts with B-Myb via the cyclin box domain. This interaction is important to suppress cyclin A-mediated phosphorylation of B-Myb, a key step in B-Myb activation. In summary, we uncover a regulatory mechanism linking the F-box protein...

  13. Immune checkpoint blockade therapy: The 2014 Tang prize in biopharmaceutical science

    Directory of Open Access Journals (Sweden)

    Ya-Shan Chen

    2015-02-01

    Full Text Available The first Tang Prize for Biopharmaceutical Science has been awarded to Prof. James P. Allison and Prof. Tasuku Honjo for their contributions leading to an entirely new way to treat cancer by blocking the molecules cytotoxic T lymphocyte-associated antigen 4 (CTLA-4 and programmed cell death protein 1 (PD-1 that turn off immune response. The treatment, called "immune checkpoint blockade therapy," has opened a new therapeutic era. Here the discoveries of the immune checkpoints and how they contribute to the maintenance of self-tolerance, as well as how to protect tissues from the excess immune responses causing damage are reviewed. The efforts made by Prof. Allison and Prof. Honjo for developing the most promising approaches to activate therapeutic antitumor immunity are also summarized. Since these certain immune checkpoint pathways appear to be one of the major mechanisms resulting in immune escape of tumors, the presence of anti-CTLA-4 and/or anti-PD-1 should contribute to removal of the inhibition signals for T cell activation. Subsequently, it will enhance specific T cell activation and, therefore, strengthen antitumor immunity.

  14. [Effects of Korean proficiency and parent-child cohesion on self-esteem and acculturation among children from multicultural families].

    Science.gov (United States)

    Kim, Mi Ye; Lim, Ji Young; Chung, Grace H

    2012-12-01

    There is evidence that parent-child cohesion is a potentially influential factor in children's self-esteem and acculturation. However, no research to date has examined cohesion with parents as a potential pathway between Korean proficiency and self-esteem or acculturation among children from multicultural families. This study was done to address these limitations by examining whether and to what extent cohesion with parents mediated the effect of Korean proficiency on self-esteem and acculturation among children from multicultural families. Data were collected from a sample of 138 mothers and their children living in Seoul, Daegu, Kyungi province, and Kyungpook province. Multiple regression analysis was used to examine the relationships between the variables of interest. Mediation effects of cohesion with parents were tested by following the procedure recommended by Baron and Kenny (1986). Cohesion with parents partially mediated the relationship between Korean proficiency and self-esteem. For children's acculturation, the effect of Korean proficiency was partially mediated through father-child cohesion. Mother-child cohesion completely mediated the relationship between Korean proficiency and acculturation. These findings suggest that to help children from multicultural families experiencing difficulties with self-esteem or acculturation, it might be useful to develop programs that are aimed at strengthen cohesion with parents.

  15. What Is Lexical Proficiency? Some Answers from Computational Models of Speech Data

    Science.gov (United States)

    Crossley, Scott A.; Salsbury, Tom; McNamara, Danielle S.; Jarvis, Scott

    2011-01-01

    Lexical proficiency, as a cognitive construct, is poorly understood. However, lexical proficiency is an important element of language proficiency and fluency, especially for second language (L2) learners. Lexical proficiency is also an important attribute of L2 academic achievement. Generally speaking, lexical proficiency comprises breadth of…

  16. Observed hierarchy of student proficiency with period, frequency, and angular frequency

    Directory of Open Access Journals (Sweden)

    Nicholas T. Young

    2018-01-01

    Full Text Available In the context of a generic harmonic oscillator, we investigated students’ accuracy in determining the period, frequency, and angular frequency from mathematical and graphical representations. In a series of studies including interviews, free response tests, and multiple choice tests developed in an iterative process, we assessed students in both algebra-based and calculus-based, traditionally instructed university-level introductory physics courses. Using the results, we categorized nine skills necessary for proficiency in determining period, frequency, and angular frequency. Overall results reveal that, postinstruction, proficiency is quite low: only about 20%–40% of students mastered most of the nine skills. Next, we used a semiquantitative, intuitive method to investigate the hierarchical structure of the nine skills. We also employed the more formal item tree analysis method to verify this structure and found that the skills form a multilevel, nonlinear hierarchy, with mastery of some skills being prerequisite for mastery in other skills. Finally, we implemented a targeted, 30-min group-work activity to improve proficiency in these skills and found a 1 standard deviation gain in accuracy. Overall, the results suggest that many students currently lack these essential skills, targeted practice may lead to required mastery, and that the observed hierarchical structure in the skills suggests that instruction should especially attend to the skills lower in the hierarchy.

  17. Dynein Light Intermediate Chain 2 Facilitates the Metaphase to Anaphase Transition by Inactivating the Spindle Assembly Checkpoint.

    Directory of Open Access Journals (Sweden)

    Sagar P Mahale

    Full Text Available The multi-functional molecular motor cytoplasmic dynein performs diverse essential roles during mitosis. The mechanistic importance of the dynein Light Intermediate Chain homologs, LIC1 and LIC2 is unappreciated, especially in the context of mitosis. LIC1 and LIC2 are believed to exist in distinct cytoplasmic dynein complexes as obligate subunits. LIC1 had earlier been reported to be required for metaphase to anaphase progression by inactivating the kinetochore-microtubule attachment-sensing arm of the spindle assembly checkpoint (SAC. However, the functional importance of LIC2 during mitosis remains elusive. Here we report prominent novel roles for the LIC2 subunit of cytoplasmic dynein in regulating the spindle assembly checkpoint. LIC2 depletion in mammalian cells led to prolonged metaphase arrest in the presence of an active SAC and also to stretched kinetochores, thus implicating it in SAC inactivation. Quantitative fluorescence microscopy of SAC components revealed accumulation of both attachment- and tension-sensing checkpoint proteins at metaphase kinetochores upon LIC2 depletion. These observations support a stronger and more diverse role in checkpoint inactivation for LIC2 in comparison to its close homolog LIC1. Our study uncovers a novel functional hierarchy during mitotic checkpoint inactivation between the closely related but homologous LIC subunits of cytoplasmic dynein. These subtle functional distinctions between dynein subpopulations could be exploited to study specific aspects of the spindle assembly checkpoint, which is a key mediator of fidelity in eukaryotic cell division.

  18. Immunogenic Chemotherapy Sensitizes Renal Cancer to Immune Checkpoint Blockade Therapy in Preclinical Models.

    Science.gov (United States)

    Cui, Shujin

    2017-07-11

    BACKGROUND Renal cell carcinoma (RCC) is among the most common malignant cancers of males worldwide. For advanced RCC patients, there still is no effective therapy. Immune checkpoint blockade therapies have shown benefits for many cancers, but previous clinical trials of immune checkpoint blockade therapies in RCC patients achieved only modest results. MATERIAL AND METHODS We explored the effects of combining chemotherapy with immune checkpoint blockade therapy in RCC xenograft mouse models. We also studied the potential mechanisms by which chemotherapy might enhance the efficacy of immune checkpoint blockade therapy, both in vitro and in vivo. RESULTS Our results showed that many commonly used chemotherapy agents can induce immunogenic marker release in RCC cell lines. Importantly, the RCC xenograft mouse model mice who received the combination treatment of 5-fluorouracil (5-FU) and anti-programmed cell death-ligand 1 (PD-L1) antibodies (Abs) had longer survival times compared to those who received 5-FU or anti-PD-L1 Abs alone. Also, increased key cytokines that promote tumor immunity, such as IL-2, IFN-γ, and TNF-α, as well as tumor-infiltrating cytotoxic T cells, were also increased after the combination treatment. CONCLUSIONS We conclude that 5-FU can sensitize RCC to anti-PD-L1 treatment by releasing the immune suppression in the tumor microenvironment.

  19. Modeling the language learning strategies and English language proficiency of pre-university students in UMS: A case study

    Science.gov (United States)

    Kiram, J. J.; Sulaiman, J.; Swanto, S.; Din, W. A.

    2015-10-01

    This study aims to construct a mathematical model of the relationship between a student's Language Learning Strategy usage and English Language proficiency. Fifty-six pre-university students of University Malaysia Sabah participated in this study. A self-report questionnaire called the Strategy Inventory for Language Learning was administered to them to measure their language learning strategy preferences before they sat for the Malaysian University English Test (MUET), the results of which were utilised to measure their English language proficiency. We attempted the model assessment specific to Multiple Linear Regression Analysis subject to variable selection using Stepwise regression. We conducted various assessments to the model obtained, including the Global F-test, Root Mean Square Error and R-squared. The model obtained suggests that not all language learning strategies should be included in the model in an attempt to predict Language Proficiency.

  20. Proficiency test for aflatoxin in pig feed

    NARCIS (Netherlands)

    Elbers, I.J.W.; Nijs, de W.C.M.

    2015-01-01

    Proficiency testing is conducted to provide laboratories with a powerful tool to evaluate and demonstrate the reliability of the data that are produced. Next to validation and accreditation, proficiency testing is an important requirement of the EU Additional Measures Directive 93/99/EEC [1] and is

  1. Proficiency test for allergens in food 2014

    NARCIS (Netherlands)

    Bremer, M.G.E.G.; Alamenou, P.; Elbers, I.J.W.

    2015-01-01

    In the autumn of 2014 a proficiency test for allergens in baby cereal was organized by RIKILT, Wageningen UR. This PT-test enabled laboratories to evaluate their competence for the analysis of allergens in baby cereal. Both quantitative and qualitative methods were accepted. The proficiency test was

  2. SPARC: Demonstrate burst-buffer-based checkpoint/restart on ATS-1.

    Energy Technology Data Exchange (ETDEWEB)

    Oldfield, Ron A. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Ulmer, Craig D. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Widener, Patrick [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Ward, H. Lee [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

    2018-01-01

    Recent high-performance computing (HPC) platforms such as the Trinity Advanced Technology System (ATS-1) feature burst buffer resources that can have a dramatic impact on an application’s I/O performance. While these non-volatile memory (NVM) resources provide a new tier in the storage hierarchy, developers must find the right way to incorporate the technology into their applications in order to reap the benefits. Similar to other laboratories, Sandia is actively investigating ways in which these resources can be incorporated into our existing libraries and workflows without burdening our application developers with excessive, platform-specific details. This FY18Q1 milestone summaries our progress in adapting the Sandia Parallel Aerodynamics and Reentry Code (SPARC) in Sandia’s ATDM program to leverage Trinity’s burst buffers for checkpoint/restart operations. We investigated four different approaches with varying tradeoffs in this work: (1) simply updating job script to use stage-in/stage out burst buffer directives, (2) modifying SPARC to use LANL’s hierarchical I/O (HIO) library to store/retrieve checkpoints, (3) updating Sandia’s IOSS library to incorporate the burst buffer in all meshing I/O operations, and (4) modifying SPARC to use our Kelpie distributed memory library to store/retrieve checkpoints. Team members were successful in generating initial implementation for all four approaches, but were unable to obtain performance numbers in time for this report (reasons: initial problem sizes were not large enough to stress I/O, and SPARC refactor will require changes to our code). When we presented our work to the SPARC team, they expressed the most interest in the second and third approaches. The HIO work was favored because it is lightweight, unobtrusive, and should be portable to ATS-2. The IOSS work is seen as a long-term solution, and is favored because all I/O work (including checkpoints) can be deferred to a single library.

  3. The Pch2 AAA+ ATPase promotes phosphorylation of the Hop1 meiotic checkpoint adaptor in response to synaptonemal complex defects.

    Science.gov (United States)

    Herruzo, Esther; Ontoso, David; González-Arranz, Sara; Cavero, Santiago; Lechuga, Ana; San-Segundo, Pedro A

    2016-09-19

    Meiotic cells possess surveillance mechanisms that monitor critical events such as recombination and chromosome synapsis. Meiotic defects resulting from the absence of the synaptonemal complex component Zip1 activate a meiosis-specific checkpoint network resulting in delayed or arrested meiotic progression. Pch2 is an evolutionarily conserved AAA+ ATPase required for the checkpoint-induced meiotic block in the zip1 mutant, where Pch2 is only detectable at the ribosomal DNA array (nucleolus). We describe here that high levels of the Hop1 protein, a checkpoint adaptor that localizes to chromosome axes, suppress the checkpoint defect of a zip1 pch2 mutant restoring Mek1 activity and meiotic cell cycle delay. We demonstrate that the critical role of Pch2 in this synapsis checkpoint is to sustain Mec1-dependent phosphorylation of Hop1 at threonine 318. We also show that the ATPase activity of Pch2 is essential for its checkpoint function and that ATP binding to Pch2 is required for its localization. Previous work has shown that Pch2 negatively regulates Hop1 chromosome abundance during unchallenged meiosis. Based on our results, we propose that, under checkpoint-inducing conditions, Pch2 also possesses a positive action on Hop1 promoting its phosphorylation and its proper distribution on unsynapsed chromosome axes. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

  4. The final checkpoint. Cancer as an adaptive evolutionary mechanism

    Directory of Open Access Journals (Sweden)

    Rumena Petkova

    2016-05-01

    Full Text Available The mechanisms for identification of DNA damage and repair usually manage DNA damage very efficiently. If damaged cells manage to bypass the checkpoints where the integrity of the genome is assessed and the decisions whether to proceed with the cell cycle are made, they may evade the imperative to stop dividing and to die. As a result, cancer may develop. Warding off the potential sequence-altering effects of DNA damage during the life of the individual or the existence span of the species is controlled by a set of larger checkpoints acting on a progressively increasing scale, from systematic removal of damaged cells from the proliferative pool by means of repair of DNA damage/programmed cell death through ageing to, finally, cancer. They serve different purposes and act at different levels of the life cycle, safeguarding the integrity of the genetic backup of the individual, the genetic diversity of the population, and, finally, the survival of the species and of life on Earth. In the light of the theory that cancer is the final checkpoint or the nature's manner to prevent complex organisms from living forever at the expense of genetic stagnation, the eventual failure of modern anti-cancer treatments is only to be expected. Nevertheless, the medicine of today and the near future has enough potential to slow down the progression to terminal cancer so that the life expectancy and the quality of life of cancer-affected individuals may be comparable to those of healthy aged individuals.

  5. Caffeine stabilizes Cdc25 independently of Rad3 in S chizosaccharomyces pombe contributing to checkpoint override

    Science.gov (United States)

    Alao, John P; Sjölander, Johanna J; Baar, Juliane; Özbaki-Yagan, Nejla; Kakoschky, Bianca; Sunnerhagen, Per

    2014-01-01

    Cdc25 is required for Cdc2 dephosphorylation and is thus essential for cell cycle progression. Checkpoint activation requires dual inhibition of Cdc25 and Cdc2 in a Rad3-dependent manner. Caffeine is believed to override activation of the replication and DNA damage checkpoints by inhibiting Rad3-related proteins in both S chizosaccharomyces pombe and mammalian cells. In this study, we have investigated the impact of caffeine on Cdc25 stability, cell cycle progression and checkpoint override. Caffeine induced Cdc25 accumulation in S . pombe independently of Rad3. Caffeine delayed cell cycle progression under normal conditions but advanced mitosis in cells treated with replication inhibitors and DNA-damaging agents. In the absence of Cdc25, caffeine inhibited cell cycle progression even in the presence of hydroxyurea or phleomycin. Caffeine induces Cdc25 accumulation in S . pombe by suppressing its degradation independently of Rad3. The induction of Cdc25 accumulation was not associated with accelerated progression through mitosis, but rather with delayed progression through cytokinesis. Caffeine-induced Cdc25 accumulation appears to underlie its ability to override cell cycle checkpoints. The impact of Cdc25 accumulation on cell cycle progression is attenuated by Srk1 and Mad2. Together our findings suggest that caffeine overrides checkpoint enforcement by inducing the inappropriate nuclear localization of Cdc25. PMID:24666325

  6. Cenp-meta is required for sustained spindle checkpoint

    Directory of Open Access Journals (Sweden)

    Thomas Rubin

    2014-05-01

    Full Text Available Cenp-E is a kinesin-like motor protein required for efficient end-on attachment of kinetochores to the spindle microtubules. Cenp-E immunodepletion in Xenopus mitotic extracts results in the loss of mitotic arrest and massive chromosome missegregation, whereas its depletion in mammalian cells leads to chromosome segregation defects despite the presence of a functional spindle assembly checkpoint (SAC. Cenp-meta has previously been reported to be the Drosophila homolog of vertebrate Cenp-E. In this study, we show that cenp-metaΔ mutant neuroblasts arrest in mitosis when treated with colchicine. cenp-metaΔ mutant cells display a mitotic delay. Yet, despite the persistence of the two checkpoint proteins Mad2 and BubR1 on unattached kinetochores, these cells eventually enter anaphase and give rise to highly aneuploid daughter cells. Indeed, we find that cenp-metaΔ mutant cells display a slow but continuous degradation of cyclin B, which eventually triggers the mitotic exit observed. Thus, our data provide evidence for a role of Cenp-meta in sustaining the SAC response.

  7. Proficiency and sentence constraint effects on second language word learning.

    Science.gov (United States)

    Ma, Tengfei; Chen, Baoguo; Lu, Chunming; Dunlap, Susan

    2015-07-01

    This paper presents an experiment that investigated the effects of L2 proficiency and sentence constraint on semantic processing of unknown L2 words (pseudowords). All participants were Chinese native speakers who learned English as a second language. In the experiment, we used a whole sentence presentation paradigm with a delayed semantic relatedness judgment task. Both higher and lower-proficiency L2 learners could make use of the high-constraint sentence context to judge the meaning of novel pseudowords, and higher-proficiency L2 learners outperformed lower-proficiency L2 learners in all conditions. These results demonstrate that both L2 proficiency and sentence constraint affect subsequent word learning among second language learners. We extended L2 word learning into a sentence context, replicated the sentence constraint effects previously found among native speakers, and found proficiency effects in L2 word learning. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. The modulatory role of second language proficiency on performance monitoring: evidence from a saccadic countermanding task in high and low proficient bilinguals.

    Science.gov (United States)

    Singh, Niharika; Mishra, Ramesh K

    2014-01-01

    We compared Hindi-English bilinguals differing in their L2 proficiency on a saccadic countermanding task which taps inhibitory control as well as monitoring. We particularly explored whether response inhibition and performance monitoring within the oculomotor domain are affected by language proficiency in bilinguals. There were two different oculomotor redirect tasks: Visually Guided Redirect (VGR) task (Experiment1) and Memory Guided Redirect (MGR) task (Experiment 2). In the redirect task, typically a target is presented and the subject is required to make a saccade (no-step trials), unless a new target appears on a different location after some delay from the first target onset (step trials). On such trials participants are required to inhibit and cancel the saccade to the first target and programme a saccade to the new target. Using trial switch reaction time (TSRT), the time taken to inhibit the initiated saccade to the first target as a measure of response inhibition and post-step slowing as a measure of performance monitoring. The results showed the high proficient bilinguals displayed more post-step slowing on the no-step trials as compared to the low proficient bilinguals for both VGR and MGR versions of the task. Secondly, both the high and low proficient bilinguals exhibited comparable TSRT in both VGR and MGR task, showing no modulatory effects of language proficiency on the response inhibition. These results suggest that language proficiency may have an effect on performance monitoring, but not the inhibitory control per se. Thus, we infer that higher proficiency may lead to superior cognitive flexibility and an ability to adjust behavior that facilitates the attainment of the cognitive goal. These findings are in consonance with other current studies that suggest a top-down effect of bilingualism on action control systems.

  9. Proverb Comprehension as a Function of Reading Proficiency in Preadolescents.

    Science.gov (United States)

    Nippold, Marilyn A.; Allen, Melissa M.; Kirsch, Dixon I.

    2001-01-01

    Proverb comprehension through reading was examined in 42 preadolescent students, 24 of whom were identified as "proficient readers," and 18 as "less proficient readers." Comprehension on both unfamiliar concrete and abstract proverbs was associated with reading proficiency, word knowledge, and analogical reasoning. (Contains references.)…

  10. A Contextualized Approach to Describing Oral Proficiency.

    Science.gov (United States)

    Chalhoub-Deville, Micheline

    1995-01-01

    Studies learners' second-language (L2) oral proficiency, incorporating an interview, a narration, and a read-aloud. Results show that the nature of the L2 oral construct is not constant. The article concludes that proficiency researchers should use dimensions empirically derived according to the specific elicitation task and audience. (53…

  11. Language Learning Strategy Use across Proficiency Levels

    Science.gov (United States)

    Zarei, Abbas, Ali; Baharestani, Nooshin

    2014-01-01

    To investigate the use of language learning strategies (LLS) by Iranian EFL learners across proficiency levels, a total of 180 Iranian adult female EFL learners were selected and divided into three different proficiency level groups. To collect data, Oxford's (1990) Strategy Inventory for Language Learning (SILL) was used. One-way ANOVA procedures…

  12. Beyond English Proficiency: Rethinking Immigrant Integration

    Science.gov (United States)

    Akresh, Ilana Redstone; Massey, Douglas S.; Frank, Reanne

    2014-01-01

    We develop and test a conceptual model of English language acquisition and the strength of the latter in predicting social and cultural assimilation. We present evidence that the path to English proficiency begins with exposure to English in the home country and on prior U.S. trips. English proficiency, then, has direct links to the intermediate migration outcomes of occupational status in the U.S., the amount of time in the U.S. since the most recent trip, and the co-ethnic residential context in the U.S. In turn, pre-migration characteristics and the intermediate characteristics work in tandem with English proficiency to determine social assimilation in the U.S., while cultural assimilation is primarily determined by pre-migration habits. A shift in focus to English use is desirable in studies of immigrant integration. PMID:24576636

  13. A Validation Study of the Student Oral Proficiency Assessment (SOPA).

    Science.gov (United States)

    Thompson, Lynn E.; Kenyon, Dorry M.; Rhodes, Nancy C.

    This study validated the Student Oral Proficiency Assessment (SOPA), an oral proficiency instrument designed for students in elementary foreign language programs. Elementary students who were tested with the SOPA were also administered other instruments designed to measure proficiency. These instruments included the Stanford Foreign Language Oral…

  14. Caenorhabditis elegans histone methyltransferase MET-2 shields the male X chromosome from checkpoint machinery and mediates meiotic sex chromosome inactivation.

    Directory of Open Access Journals (Sweden)

    Paula M Checchi

    2011-09-01

    Full Text Available Meiosis is a specialized form of cellular division that results in the precise halving of the genome to produce gametes for sexual reproduction. Checkpoints function during meiosis to detect errors and subsequently to activate a signaling cascade that prevents the formation of aneuploid gametes. Indeed, asynapsis of a homologous chromosome pair elicits a checkpoint response that can in turn trigger germline apoptosis. In a heterogametic germ line, however, sex chromosomes proceed through meiosis with unsynapsed regions and are not recognized by checkpoint machinery. We conducted a directed RNAi screen in Caenorhabditis elegans to identify regulatory factors that prevent recognition of heteromorphic sex chromosomes as unpaired and uncovered a role for the SET domain histone H3 lysine 9 histone methyltransferase (HMTase MET-2 and two additional HMTases in shielding the male X from checkpoint machinery. We found that MET-2 also mediates the transcriptional silencing program of meiotic sex chromosome inactivation (MSCI but not meiotic silencing of unsynapsed chromatin (MSUC, suggesting that these processes are distinct. Further, MSCI and checkpoint shielding can be uncoupled, as double-strand breaks targeted to an unpaired, transcriptionally silenced extra-chromosomal array induce checkpoint activation in germ lines depleted for met-2. In summary, our data uncover a mechanism by which repressive chromatin architecture enables checkpoint proteins to distinguish between the partnerless male X chromosome and asynapsed chromosomes thereby shielding the lone X from inappropriate activation of an apoptotic program.

  15. CDC28, NETI, and HFII are required for checkpoints in Saccharomyces cerevisiae

    International Nuclear Information System (INIS)

    Koltovaya, N.A.; Kadyshevskaya, E.Yu.; Roshina, M.P.; Devin, A.B.

    2009-01-01

    The involvement of SRM genes selected as genes affecting genetic stability and radiosensitivity in a cell cycle arrest under the action of damaging agents was studied. It was shown that the srm5/cdc28-srm, srm8/netI-srm, and srmI2/hfiI-srm mutations prevent checkpoint activation by DNA damage, particularly the G 0 /S (srm5, srm8), G 1 /S (srm5, srm8, srm12), S (srm8, srm12) and S/G 2 (srm5) checkpoints. It seems that in budding yeast the CDC28, HFII/ADAI, and NETI genes mediate cellular response induced by DNA damage with checkpoint control. The well-known checkpoint-genes RAD9, RAD17, RAD24, and RAD53, and the genes CDC28, and NETI have been found to belong to one epistasis group named RAD9-group as regards cell sensitivity to γ radiation. An analysis of the radiosensitivity of double mutants has revealed that the mutation cdc-28-srm is hypostatic to each of mutations rad9Δ, and rad24Δ, and additive to rad17Δ. The mutation netI-srm is hypostatic to the mutations rad9Δ but additive to rad17Δ, rad24Δ, and rad53. The mutation hfiI-srm has an additive effect in compound with the mutations rad24Δ and rad9Δ. So, investigations of epistatic interactions have demonstrated a branched RAD9-dependent pathway. The analyzed genes can also participate in a minor mechanism involved in determining cell radiation sensitivity independently of the mentioned RAD9-dependent pathway

  16. Differential impact of diverse anticancer chemotherapeutics on the Cdc25A-degradation checkpoint pathway

    International Nuclear Information System (INIS)

    Agner, Jeppe; Falck, Jacob; Lukas, Jiri; Bartek, Jiri

    2005-01-01

    When exposed to DNA-damaging insults such as ionizing radiation (IR) or ultraviolet light (UV), mammalian cells activate checkpoint pathways to halt cell cycle progression or induce cell death. Here we examined the ability of five commonly used anticancer drugs with different mechanisms of action to activate the Chk1/Chk2-Cdc25A-CDK2/cyclin E cell cycle checkpoint pathway, previously shown to be induced by IR or UV. Whereas exposure of human cells to topoisomerase inhibitors camptothecin, etoposide, or adriamycin resulted in rapid (within 1 h) activation of the pathway including degradation of the Cdc25A phosphatase and inhibition of cyclin E/CDK2 kinase activity, taxol failed to activate this checkpoint even after a prolonged treatment. Unexpectedly, although the alkylating agent cisplatin also induced degradation of Cdc25A (albeit delayed, after 8-12 h), cyclin E/CDK2 activity was elevated and DNA synthesis continued, a phenomena that correlated with increased E2F1 protein levels and consequently enhanced expression of cyclin E. These results reveal a differential impact of various classes of anticancer chemotherapeutics on the Cdc25A-degradation pathway, and indicate that the kinetics of checkpoint induction, and the relative balance of key components within the DNA damage response network may dictate whether the treated cells arrest their cell cycle progression

  17. Immuno-oncologic Approaches: CAR-T Cells and Checkpoint Inhibitors.

    Science.gov (United States)

    Gay, Francesca; D'Agostino, Mattia; Giaccone, Luisa; Genuardi, Mariella; Festuccia, Moreno; Boccadoro, Mario; Bruno, Benedetto

    2017-08-01

    Advances in understanding myeloma biology have shown that disease progression is not only the consequence of intrinsic tumor changes but also of interactions between the tumor and the microenvironment in which the cancer grows. The immune system is an important component of the tumor microenvironment in myeloma, and acting on the immune system is an appealing new treatment strategy. There are 2 ways to act toward immune cells and boost antitumor immunity: (1) to increase antitumor activity (acting on T and NK cytotoxic cells), and (2) to reduce immunosuppression (acting on myeloid-derived stem cells and T regulatory cells). Checkpoint inhibitors and adoptive cell therapy (ACT) are 2 of the main actors, together with monoclonal antibodies and immunomodulatory agents, in the immune-oncologic approach. The aim of checkpoint inhibitors is to release the brakes that block the action of the immune system against the tumor. Anti-programmed death-1 (PD-1) and PD-1-Ligand, as well as anti-CTLA4 and KIR are currently under evaluation, as single agents or in combination, with the best results achieved so far with combination of anti-PD-1 and immunomodulatory agents. The aim of ACT is to create an immune effector specific against the tumor. Preliminary results on chimeric antigen receptor (CAR) T cells, first against CD19, and more recently against B-cell maturation antigen, have shown to induce durable responses in heavily pretreated patients. This review focuses on the most recent clinical results available on the use of checkpoint inhibitors and CAR-T cells in myeloma, in the context of the new immune-oncologic approach. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Learning Strategies in Proficient and Less Proficient Readers in Medicine

    Science.gov (United States)

    Nemati, Majid; Nodoushan, Mohammad Ali Salmani; Ashrafzadeh, Anis

    2010-01-01

    The current study aimed to diagnose the probable significant differences in the use of language learning strategies among medical-text readers of opposite sex from different levels of proficiency. 120 (N = 120) participants were randomly selected from Azad Medical University of Mashhad: 60 medical students (age range 23-25; 30 = male and 30 =…

  19. The Aurora B kinase in chromosome biorientation and spindle checkpoint signalling

    Directory of Open Access Journals (Sweden)

    Veronica eKrenn

    2015-10-01

    Full Text Available Aurora B, a member of the Aurora family of serine/threonine protein kinases, is a key player in chromosome segregation. As part of a macromolecular complex known as the chromosome passenger complex, Aurora B concentrates early during mitosis in the proximity of centromeres and kinetochores, the sites of attachment of chromosomes to spindle microtubules. There, it contributes to a number of processes that impart fidelity to cell division, including kinetochore stabilization, kinetochore-microtubule attachment, and the regulation of a surveillance mechanism named the spindle assembly checkpoint. In the regulation of these processes, Aurora B is the fulcrum of a remarkably complex network of interactions that feed back on its localization and activation state. In this review we discuss the multiple roles of Aurora B during mitosis, focusing in particular on its role at centromeres and kinetochores. Many details of the network of interactions at these locations remain poorly understood, and we focus here on several crucial outstanding questions.

  20. Measures to detect and control radioactive contaminated metallurgical scrap at border checkpoints in Poland

    International Nuclear Information System (INIS)

    Smagala, G.

    1999-01-01

    The issue of radioactive contaminated metallurgical scrap has never received a high priority in Poland and in the international community. Since the dissolution of the former Soviet Union a higher attention has been given to the problem. Poland which is located between the West and East Europe has the obligation to develop and implement an effective prevention and detection system. The reasons to increase national control and detection system at the border checkpoints in Poland are to avoid the following risks: post Chernobyl contamination transports of commodities; transport of contaminated metal scrap; transfer of radioactive waste for their disposal or utilization; high risk of becoming a transit country of illicit trafficking of nuclear materials and radioactive sources. In order to avoid the above-mentioned risks, Poland initiated in 1990, a deployment of the portable radiation devices at the border checkpoints and, as of 1998, the number of installed instruments exceeded a hundred. This paper presents Poland's activities to detect contaminated scrap at its border checkpoints. (author)

  1. A tumor suppressor role of the Bub3 spindle checkpoint protein after apoptosis inhibition

    Science.gov (United States)

    Moutinho-Santos, Tatiana

    2013-01-01

    Most solid tumors contain aneuploid cells, indicating that the mitotic checkpoint is permissive to the proliferation of chromosomally aberrant cells. However, mutated or altered expression of mitotic checkpoint genes accounts for a minor proportion of human tumors. We describe a Drosophila melanogaster tumorigenesis model derived from knocking down spindle assembly checkpoint (SAC) genes and preventing apoptosis in wing imaginal discs. Bub3-deficient tumors that were also deficient in apoptosis displayed neoplastic growth, chromosomal aneuploidy, and high proliferative potential after transplantation into adult flies. Inducing aneuploidy by knocking down CENP-E and preventing apoptosis does not induce tumorigenesis, indicating that aneuploidy is not sufficient for hyperplasia. In this system, the aneuploidy caused by a deficient SAC is not driving tumorigenesis because preventing Bub3 from binding to the kinetochore does not cause hyperproliferation. Our data suggest that Bub3 has a nonkinetochore-dependent function that is consistent with its role as a tumor suppressor. PMID:23609535

  2. Genetic Control of the Trigger for the G2/M Checkpoint

    Energy Technology Data Exchange (ETDEWEB)

    Hall, Eric J. [Columbia University; Smilenov, Lubomir B. [Columbia University; Young, Erik F. [Columbia University

    2013-10-01

    The work undertaken in this project addressed two seminal areas of low dose radiation biology that are poorly understood and controversial. These areas are the challenge to the linear-no-threshold (LNT) paradigm at low doses of radiation and, the fundamental elements of radiation bystander effect biology Genetic contributions to low dose checkpoint engagement: The LNT paradigm is an extrapolation of known, measured cancer induction endpoints. Importantly, data for lower doses is often not available. Debatably, radiation protection standards have been introduced which are prudently contingent on the adherence of cancer risk to the established trend seen at higher doses. Intriguing findings from other labs have hinted at separate DNA damage response programs that engage at low or high levels of radiation. Individual radiation sensitivity commensurate with hemizygosity for a radiation sensitivity gene has been estimated at 1-2% in the U.S.. Careful interrogation of the DNA damage response at low doses of radiation became important and served as the basis for this grant. Several genes were tested in combinations to determine if combined haploinsufficiency for multiple radiosensitizing genes could render a cell more sensitive to lower levels of acute radiation exposure. We measured a classical radiation response endpoint, cell cycle arrest prior to mitosis. Mouse embryo fibroblasts were used and provided a uniform, rapidly dividing and genetically manipulable population of study. Our system did not report checkpoint engagement at acute doses of gamma rays below 100 mGy. The system did report checkpoint engagement reproducibly at 500 mGy establishing a threshold for activation between 100 and 500 mGy. Engagement of the checkpoint was ablated in cells nullizygous for ATM but was otherwise unperturbed in cells combinatorially haploinsufficient for ATM and Rad9, ATM and PTEN or PTEN and Rad9. Taken together, these experiments tell us that, in a sensitive fibroblast culture

  3. Cells bearing chromosome aberrations lacking one telomere are selectively blocked at the G2/M checkpoint

    Energy Technology Data Exchange (ETDEWEB)

    Rodriguez, Pilar [Unitat de Biologia Cel.lular, Departament de Biologia Cel.lular, Fisiologia i Immunologia, Universitat Autonoma de Barcelona, 08193 Bellaterra (Spain); Barquinero, Joan Francesc [Unitat d' Antropologia Biologica, Departament de Biologia Animal, Biologia Vegetal i Ecologia, Universitat Autonoma de Barcelona, 08193 Bellaterra (Spain); Duran, Assumpta [Unitat de Biologia Cel.lular, Departament de Biologia Cel.lular, Fisiologia i Immunologia, Universitat Autonoma de Barcelona, 08193 Bellaterra (Spain); Caballin, Maria Rosa [Unitat d' Antropologia Biologica, Departament de Biologia Animal, Biologia Vegetal i Ecologia, Universitat Autonoma de Barcelona, 08193 Bellaterra (Spain); Ribas, Montserrat [Servei de Radiofisica i Radioproteccio de l' Hospital de la Santa Creu i Sant Pau, 08025 Barcelona (Spain); Barrios, Leonardo, E-mail: Lleonard.Barrios@uab.cat [Unitat de Biologia Cel.lular, Departament de Biologia Cel.lular, Fisiologia i Immunologia, Universitat Autonoma de Barcelona, 08193 Bellaterra (Spain)

    2009-11-02

    Cell cycle checkpoints are part of the cellular mechanisms to maintain genomic integrity. After ionizing radiation exposure, the cells can show delay or arrest in their progression through the cell cycle, as well as an activation of the DNA repair machinery in order to reduce the damage. The G2/M checkpoint prevents G2 cells entering mitosis until the DNA damage has been reduced. The present study evaluates which G0 radiation-induced chromosome aberrations are negatively selected in the G2/M checkpoint. For this purpose, peripheral blood samples were irradiated at 1 and 3 Gy of {gamma}-rays, and lymphocytes were cultured for 48 h. Calyculin-A and Colcemid were used to analyze, in the same slide, cells in G2 and M. Chromosome spreads were consecutively analyzed by solid stain, pancentromeric and pantelomeric FISH and mFISH. The results show that the frequency of incomplete chromosome elements, those lacking a telomeric signal at one end, decreases abruptly from G2 to M. This indicates that cells with incomplete chromosome elements can progress from G0 to G2, but at the G2/M checkpoint suffer a strong negative selection.

  4. Cells bearing chromosome aberrations lacking one telomere are selectively blocked at the G2/M checkpoint

    International Nuclear Information System (INIS)

    Rodriguez, Pilar; Barquinero, Joan Francesc; Duran, Assumpta; Caballin, Maria Rosa; Ribas, Montserrat; Barrios, Leonardo

    2009-01-01

    Cell cycle checkpoints are part of the cellular mechanisms to maintain genomic integrity. After ionizing radiation exposure, the cells can show delay or arrest in their progression through the cell cycle, as well as an activation of the DNA repair machinery in order to reduce the damage. The G2/M checkpoint prevents G2 cells entering mitosis until the DNA damage has been reduced. The present study evaluates which G0 radiation-induced chromosome aberrations are negatively selected in the G2/M checkpoint. For this purpose, peripheral blood samples were irradiated at 1 and 3 Gy of γ-rays, and lymphocytes were cultured for 48 h. Calyculin-A and Colcemid were used to analyze, in the same slide, cells in G2 and M. Chromosome spreads were consecutively analyzed by solid stain, pancentromeric and pantelomeric FISH and mFISH. The results show that the frequency of incomplete chromosome elements, those lacking a telomeric signal at one end, decreases abruptly from G2 to M. This indicates that cells with incomplete chromosome elements can progress from G0 to G2, but at the G2/M checkpoint suffer a strong negative selection.

  5. 5 CFR 9901.364 - Foreign language proficiency pay.

    Science.gov (United States)

    2010-01-01

    ... 5 Administrative Personnel 3 2010-01-01 2010-01-01 false Foreign language proficiency pay. 9901... NATIONAL SECURITY PERSONNEL SYSTEM (NSPS) Pay and Pay Administration Premium Pay § 9901.364 Foreign language proficiency pay. (a) General provisions. (1) This section applies to employees who may be paid...

  6. Use of common time base for checkpointing and rollback recovery in a distributed system

    Science.gov (United States)

    Ramanathan, Parameswaran; Shin, Kang G.

    1993-01-01

    An approach to checkpointing and rollback recovery in a distributed computing system using a common time base is proposed. A common time base is established in the system using a hardware clock synchronization algorithm. This common time base is coupled with the idea of pseudo-recovery points to develop a checkpointing algorithm that has the following advantages: reduced wait for commitment for establishing recovery lines, fewer messages to be exchanged, and less memory requirement. These advantages are assessed quantitatively by developing a probabilistic model.

  7. Synthesis of Fault-Tolerant Embedded Systems with Checkpointing and Replication

    DEFF Research Database (Denmark)

    Izosimov, Viacheslav; Pop, Paul; Eles, Petru

    2006-01-01

    We present an approach to the synthesis of fault-tolerant hard real-time systems for safety-critical applications. We use checkpointing with rollback recovery and active replication for tolerating transient faults. Processes are statically scheduled and communications are performed using the time...

  8. Cell cycle checkpoints: reversible when possible, irreversible when needed

    NARCIS (Netherlands)

    Krenning, L.

    2015-01-01

    Cell cycle checkpoints are reversible in nature, and can prevent progression into the next cell cycle phase if needed. In the case of DNA damage, cells can prevent progression from G1 into S phase, and from G2 into mitosis in the presence of DNA double strand breaks. Following DNA repair, these

  9. Comparing Examinee Attitudes Toward Computer-Assisted and Other Oral Proficiency Assessments.

    Science.gov (United States)

    Kenyon, Dorry M.; Malabonga, Valerie

    2001-01-01

    Examined attitudes toward taking different formats of oral proficiency assessments across three languages: Spanish, Arabic, and Chinese. Students were administered both the tape-mediated Simulated Oral Proficiency Interview (SOPI) and a new Computerized Oral Proficiency Instrument (COPI). Questionnaire responses showed examinees, particularly…

  10. Implementing forward recovery using checkpointing in distributed systems

    Science.gov (United States)

    Long, Junsheng; Fuchs, W. K.; Abraham, Jacob A.

    1991-01-01

    The paper describes the implementation of a forward recovery scheme using checkpoints and replicated tasks. The implementation is based on the concept of lookahead execution and rollback validation. In the experiment, two tasks are selected for the normal execution and one for rollback validation. It is shown that the recovery strategy has nearly error-free execution time and an average redundancy lower than TMR.

  11. Proficiency test for heavy metals in compound feed

    NARCIS (Netherlands)

    Pereboom, D.P.K.H.; Elbers, I.J.W.; Jong, de J.; Lee, van der M.K.; Nijs, de W.C.M.

    2016-01-01

    The here described proficiency test for heavy metals in compound feed was organised by RIKILT, Wageningen UR in accordance with ISO 17043. RIKILT Wageningen UR has an ISO/IEC 17043 accreditation for proficiency tests of residues in products of animal origin. However, this specific test is not part

  12. Checkpoint inhibitors in breast cancer

    DEFF Research Database (Denmark)

    Polk, Anne; Svane, Inge-Marie; Andersson, Michael

    2018-01-01

    INTRODUCTION: An increasing number of compounds directed against immune checkpoints are currently under clinical development. In this review we summarize current research in breast cancer. MATERIAL AND METHODS: A computer-based literature search was carried out using PubMed and EMBASE; data...... reported at international meetings and clinicaltrials.gov were included as well. RESULTS: The obtained overall response rate of PD-1/PD-L1 monotherapy varied from 5 to 30% in heavily pretreated triple negative breast cancer (TNBC). The median duration of progression free survival and overall survival were...... and induce long standing anti-tumor immunity in a subgroup of breast cancer patients. However, the identification of predictive biomarkers is crucial for further development of this treatment modality....

  13. The correlation between motor proficiency and physical activity in ...

    African Journals Online (AJOL)

    Lizl-Louise van Niekerk

    eOseretsky Test of Motor Proficiency 2 (BOT-2) for motor proficiency, and the International. Physical Activity ... Pienaar, 2007; Malina, 2012). ..... sults of Hardy, Reinten-Reynolds, Espinel, Zask, and Okely .... Journal of Psychiatric and Mental.

  14. [Sea urchin embryo, DNA-damaged cell cycle checkpoint and the mechanisms initiating cancer development].

    Science.gov (United States)

    Bellé, Robert; Le Bouffant, Ronan; Morales, Julia; Cosson, Bertrand; Cormier, Patrick; Mulner-Lorillon, Odile

    2007-01-01

    Cell division is an essential process for heredity, maintenance and evolution of the whole living kingdom. Sea urchin early development represents an excellent experimental model for the analysis of cell cycle checkpoint mechanisms since embryonic cells contain a functional DNA-damage checkpoint and since the whole sea urchin genome is sequenced. The DNA-damaged checkpoint is responsible for an arrest in the cell cycle when DNA is damaged or incorrectly replicated, for activation of the DNA repair mechanism, and for commitment to cell death by apoptosis in the case of failure to repair. New insights in cancer biology lead to two fundamental concepts about the very first origin of cancerogenesis. Cancers result from dysfunction of DNA-damaged checkpoints and cancers appear as a result of normal stem cell (NCS) transformation into a cancer stem cell (CSC). The second aspect suggests a new definition of "cancer", since CSC can be detected well before any clinical evidence. Since early development starts from the zygote, which is a primary stem cell, sea urchin early development allows analysis of the early steps of the cancerization process. Although sea urchins do not develop cancers, the model is alternative and complementary to stem cells which are not easy to isolate, do not divide in a short time and do not divide synchronously. In the field of toxicology and incidence on human health, the sea urchin experimental model allows assessment of cancer risk from single or combined molecules long before any epidemiologic evidence is available. Sea urchin embryos were used to test the worldwide used pesticide Roundup that contains glyphosate as the active herbicide agent; it was shown to activate the DNA-damage checkpoint of the first cell cycle of development. The model therefore allows considerable increase in risk evaluation of new products in the field of cancer and offers a tool for the discovery of molecular markers for early diagnostic in cancer biology

  15. Cdk2 is required for p53-independent G2/M checkpoint control.

    Directory of Open Access Journals (Sweden)

    Jon H Chung

    2010-02-01

    Full Text Available The activation of phase-specific cyclin-dependent kinases (Cdks is associated with ordered cell cycle transitions. Among the mammalian Cdks, only Cdk1 is essential for somatic cell proliferation. Cdk1 can apparently substitute for Cdk2, Cdk4, and Cdk6, which are individually dispensable in mice. It is unclear if all functions of non-essential Cdks are fully redundant with Cdk1. Using a genetic approach, we show that Cdk2, the S-phase Cdk, uniquely controls the G(2/M checkpoint that prevents cells with damaged DNA from initiating mitosis. CDK2-nullizygous human cells exposed to ionizing radiation failed to exclude Cdk1 from the nucleus and exhibited a marked defect in G(2/M arrest that was unmasked by the disruption of P53. The DNA replication licensing protein Cdc6, which is normally stabilized by Cdk2, was physically associated with the checkpoint regulator ATR and was required for efficient ATR-Chk1-Cdc25A signaling. These findings demonstrate that Cdk2 maintains a balance of S-phase regulatory proteins and thereby coordinates subsequent p53-independent G(2/M checkpoint activation.

  16. The proficiency testing of determination of dioxins in food

    Energy Technology Data Exchange (ETDEWEB)

    Matsuda, R.; Tsutsumi, T.; Maitani, T. [National Institute of Health Sciences, Tokyo (Japan); Toyoda, M. [Jissen Womens Univ., Hino (Japan)

    2004-09-15

    Food intake is the main route of human dioxin exposure, making the determination of dioxins in food indispensable for risk assessment and risk management of dioxins. The uncertainty of analytical results, however, can be very great because of the low concentration of the analytes and complicated cleanup procedures. The risk assessment of dioxins based on analytical results also suffers from a similar degree of uncertainty. The Ministry of Health, Labor and Welfare of Japan has published ''Guideline for the Determination of Dioxins in Food'' to standardize the analytical procedures. The guideline contains the quality assurance procedures to obtain reliable analytical results and recommends participation in the relevant proficiency testing scheme. The proficiency testing provides the fair evaluation of the analytical results. The central science laboratory in England and the food and drug safety center in Japan offer the proficiency testing on food. The National Institute of Health Sciences of Japan (NIHS) also has carried out proficiency testing of dioxins in food since 1998 to assure the quality of analytical results for dioxins. In this presentation we will show the results of 5 rounds of proficiency testing.

  17. THE BANGLADESHI EMPLOYMENT SECTOR: EMPLOYER PERSPECTIVES CONCERNING ENGLISH PROFICIENCY

    Directory of Open Access Journals (Sweden)

    Rubina Khan

    2012-07-01

    Full Text Available Abstract: This paper presents a brief summary of a study which was carried out to investigate how employers representing major employment sectors in the Bangladeshi Industry view the skills and English proficiency level of the current employees. Opinions were also solicited on what skills are required for fresh recruits. Semi-structured interviews were conducted with 30 employers representing the major employment sectors in Bangladeshi Industry. Results revealed the importance of English as an indispensible means of communication in the Bangladeshi corporate sector and showed that the business enterprises use extensive amounts of English. It also highlighted that the existent English proficiency of the employees was far below the required proficiency level. Recommendations were made to address the gap and prepare the youth to meet the demands of the global market. Keywords: English proficiency, competency, employability skills, global literacy skills

  18. Clinical pharmacology quality assurance program: models for longitudinal analysis of antiretroviral proficiency testing for international laboratories.

    Science.gov (United States)

    DiFrancesco, Robin; Rosenkranz, Susan L; Taylor, Charlene R; Pande, Poonam G; Siminski, Suzanne M; Jenny, Richard W; Morse, Gene D

    2013-10-01

    Among National Institutes of Health HIV Research Networks conducting multicenter trials, samples from protocols that span several years are analyzed at multiple clinical pharmacology laboratories (CPLs) for multiple antiretrovirals. Drug assay data are, in turn, entered into study-specific data sets that are used for pharmacokinetic analyses, merged to conduct cross-protocol pharmacokinetic analysis, and integrated with pharmacogenomics research to investigate pharmacokinetic-pharmacogenetic associations. The CPLs participate in a semiannual proficiency testing (PT) program implemented by the Clinical Pharmacology Quality Assurance program. Using results from multiple PT rounds, longitudinal analyses of recovery are reflective of accuracy and precision within/across laboratories. The objectives of this longitudinal analysis of PT across multiple CPLs were to develop and test statistical models that longitudinally: (1) assess the precision and accuracy of concentrations reported by individual CPLs and (2) determine factors associated with round-specific and long-term assay accuracy, precision, and bias using a new regression model. A measure of absolute recovery is explored as a simultaneous measure of accuracy and precision. Overall, the analysis outcomes assured 97% accuracy (±20% of the final target concentration of all (21) drug concentration results reported for clinical trial samples by multiple CPLs). Using the Clinical Laboratory Improvement Act acceptance of meeting criteria for ≥2/3 consecutive rounds, all 10 laboratories that participated in 3 or more rounds per analyte maintained Clinical Laboratory Improvement Act proficiency. Significant associations were present between magnitude of error and CPL (Kruskal-Wallis P Kruskal-Wallis P < 0.001).

  19. Checkpoint-dependent RNR induction promotes fork restart after replicative stress.

    Science.gov (United States)

    Morafraile, Esther C; Diffley, John F X; Tercero, José Antonio; Segurado, Mónica

    2015-01-20

    The checkpoint kinase Rad53 is crucial to regulate DNA replication in the presence of replicative stress. Under conditions that interfere with the progression of replication forks, Rad53 prevents Exo1-dependent fork degradation. However, although EXO1 deletion avoids fork degradation in rad53 mutants, it does not suppress their sensitivity to the ribonucleotide reductase (RNR) inhibitor hydroxyurea (HU). In this case, the inability to restart stalled forks is likely to account for the lethality of rad53 mutant cells after replication blocks. Here we show that Rad53 regulates replication restart through the checkpoint-dependent transcriptional response, and more specifically, through RNR induction. Thus, in addition to preventing fork degradation, Rad53 prevents cell death in the presence of HU by regulating RNR-expression and localization. When RNR is induced in the absence of Exo1 and RNR negative regulators, cell viability of rad53 mutants treated with HU is increased and the ability of replication forks to restart after replicative stress is restored.

  20. Childhood motor skill proficiency as a predictor of adolescent physical activity.

    Science.gov (United States)

    Barnett, Lisa M; van Beurden, Eric; Morgan, Philip J; Brooks, Lyndon O; Beard, John R

    2009-03-01

    Cross-sectional evidence has demonstrated the importance of motor skill proficiency to physical activity participation, but it is unknown whether skill proficiency predicts subsequent physical activity. In 2000, children's proficiency in object control (kick, catch, throw) and locomotor (hop, side gallop, vertical jump) skills were assessed in a school intervention. In 2006/07, the physical activity of former participants was assessed using the Australian Physical Activity Recall Questionnaire. Linear regressions examined relationships between the reported time adolescents spent participating in moderate-to-vigorous or organized physical activity and their childhood skill proficiency, controlling for gender and school grade. A logistic regression examined the probability of participating in vigorous activity. Of 481 original participants located, 297 (62%) consented and 276 (57%) were surveyed. All were in secondary school with females comprising 52% (144). Adolescent time in moderate-to-vigorous and organized activity was positively associated with childhood object control proficiency. Respective models accounted for 12.7% (p = .001), and 18.2% of the variation (p = .003). Object control proficient children became adolescents with a 10% to 20% higher chance of vigorous activity participation. Object control proficient children were more likely to become active adolescents. Motor skill development should be a key strategy in childhood interventions aiming to promote long-term physical activity.

  1. Language proficiency and metacognition as predictors of spontaneous rehearsal in children.

    Science.gov (United States)

    Bebko, James M; McMorris, Carly A; Metcalfe, Alisa; Ricciuti, Christina; Goldstein, Gayle

    2014-03-01

    Despite decades of research on fundamental memory strategies such as verbal rehearsal, the potential underlying skills associated with the emergence of rehearsal are still not fully understood. Two studies examined the relative roles of language proficiency and metamemory in predicting rehearsal use, as well as the prediction of metamemory performance by language proficiency. In Study 1, 59 children, 5 to 8 years old, were administered a serial recall task, 2 language measures, a nonverbal cognitive measure, and a rapid automatized naming (RAN) task. Language proficiency, RAN, and age were significant individual predictors of rehearsal use. In hierarchical regression analyses, language proficiency mediated almost completely the age → rehearsal use relation. In addition, automatized naming was a strong but partial mediator of the contribution of language proficiency to rehearsal use. In Study 2, 54 children were administered a metamemory test, a language measure, and a serial recall task. Metamemory skills and, again, language proficiency significantly predicted rehearsal use in the task. The predictive strength of metamemory skills was mediated by the children's language proficiency. The mutually supportive roles of automatized naming, language, and metamemory in the emergence of spontaneous cumulative verbal rehearsal are discussed in the context of the resulting model, along with the minimal roles of age and aspects of intelligence.

  2. STRATEGIES OF MAINTAINING PROFICIENCY BY TEACHERS OF ENGLISH IN INDONESIA

    Directory of Open Access Journals (Sweden)

    Junaidi Mistar, Alfan Zuhairini

    2011-10-01

    Full Text Available The objectives of the present study are four-fold: (1 to identify the types of strategies to maintain proficiency used by teachers of English in Indonesia, (2 to know the intensity of use of the obtained strategy types, (3 to measure the inter-correlation in the use of the obtained strategy types, and (4 to investigate the effect of proficiency level on the use of maintaining strategies. The subjects were 93 teachers applying for S2 degree in 2010/2011 at the postgraduate program of the Islamic University of Malang. They were given two sets of instrument, a Likert-scale questionnaire of English proficiency maintaining strategies and a TOEFL test. Then, a factor analysis identified nine strategy categories, including language focusing, metacognitive and affective developing, reading and writing activating, language resource utilizing, cognitive processing, culture learning, social communicating, text analyzing, and radio listening strategies. These strategy types explained 63.84% of variances of maintaining strategies and they were used at high level of intensity. Moreover, the use of the nine strategy types were found to be inter-correlated with one another. Finally, no significant effect of proficiency level on strategy use was found, indicating that teachers with different level of proficiency reported using the same strategies of maintaining their proficiency.

  3. Requirement for the Phospho-H2AX Binding Module of Crb2 in Double-Strand Break Targeting and Checkpoint Activation▿

    Science.gov (United States)

    Sanders, Steven L.; Arida, Ahmad R.; Phan, Funita P.

    2010-01-01

    Activation of DNA damage checkpoints requires the rapid accumulation of numerous factors to sites of genomic lesions, and deciphering the mechanisms of this targeting is central to our understanding of DNA damage response. Histone modification has recently emerged as a critical element for the correct localization of damage response proteins, and one key player in this context is the fission yeast checkpoint mediator Crb2. Accumulation of Crb2 at ionizing irradiation-induced double-strand breaks (DSBs) requires two distinct histone marks, dimethylated H4 lysine 20 (H4K20me2) and phosphorylated H2AX (pH2AX). A tandem tudor motif in Crb2 directly binds H4K20me2, and this interaction is required for DSB targeting and checkpoint activation. Similarly, pH2AX is required for Crb2 localization to DSBs and checkpoint control. Crb2 can directly bind pH2AX through a pair of C-terminal BRCT repeats, but the functional significance of this binding has been unclear. Here we demonstrate that loss of its pH2AX-binding activity severely impairs the ability of Crb2 to accumulate at ionizing irradiation-induced DSBs, compromises checkpoint signaling, and disrupts checkpoint-mediated cell cycle arrest. These impairments are similar to that reported for abolition of pH2AX or mutation of the H4K20me2-binding tudor motif of Crb2. Intriguingly, a combined ablation of its two histone modification binding modules yields a strikingly additive reduction in Crb2 activity. These observations argue that binding of the Crb2 BRCT repeats to pH2AX is critical for checkpoint activity and provide new insight into the mechanisms of chromatin-mediated genome stability. PMID:20679488

  4. Requirement for the phospho-H2AX binding module of Crb2 in double-strand break targeting and checkpoint activation.

    Science.gov (United States)

    Sanders, Steven L; Arida, Ahmad R; Phan, Funita P

    2010-10-01

    Activation of DNA damage checkpoints requires the rapid accumulation of numerous factors to sites of genomic lesions, and deciphering the mechanisms of this targeting is central to our understanding of DNA damage response. Histone modification has recently emerged as a critical element for the correct localization of damage response proteins, and one key player in this context is the fission yeast checkpoint mediator Crb2. Accumulation of Crb2 at ionizing irradiation-induced double-strand breaks (DSBs) requires two distinct histone marks, dimethylated H4 lysine 20 (H4K20me2) and phosphorylated H2AX (pH2AX). A tandem tudor motif in Crb2 directly binds H4K20me2, and this interaction is required for DSB targeting and checkpoint activation. Similarly, pH2AX is required for Crb2 localization to DSBs and checkpoint control. Crb2 can directly bind pH2AX through a pair of C-terminal BRCT repeats, but the functional significance of this binding has been unclear. Here we demonstrate that loss of its pH2AX-binding activity severely impairs the ability of Crb2 to accumulate at ionizing irradiation-induced DSBs, compromises checkpoint signaling, and disrupts checkpoint-mediated cell cycle arrest. These impairments are similar to that reported for abolition of pH2AX or mutation of the H4K20me2-binding tudor motif of Crb2. Intriguingly, a combined ablation of its two histone modification binding modules yields a strikingly additive reduction in Crb2 activity. These observations argue that binding of the Crb2 BRCT repeats to pH2AX is critical for checkpoint activity and provide new insight into the mechanisms of chromatin-mediated genome stability.

  5. Teaching English through English: Proficiency, Pedagogy and Performance

    Science.gov (United States)

    Richards, Jack C.

    2017-01-01

    Most of the world's English language teachers speak English as a second or third language rather than as their first language. For many, their level of proficiency in English may not reach benchmarks established by their employers, raising the issue that is the focus of this article, namely, what kind of proficiency in English is necessary to be…

  6. The English Proficiency of the Academics of the Teacher Training and Education Institutions

    Directory of Open Access Journals (Sweden)

    Ali Saukah

    2016-02-01

    Full Text Available The study is aimed at describing the general English proficiency level of the academics of Teacher Training and Education Institutions (LPTK's as indicated by their TOEFL scores. Specifically, the study is focused on finding out whether there is any difference among the academics' English proficiencies when they are grouped in terms of the geographic regions of their institutions and their fields of study. This study is also intended to reveal any possible relationship between the academics' English proficiency and their age. The results indicate that the English proficiency of the academics on the average is far below the average of that of the international students. The academics in West Java are the highest in their English proficiency, and the English group, as expected, has the best English proficiency. In addition, there is a negative correlation between English proficiency and age

  7. Proficiency testing for sensory profile panels : measuring panel performance

    NARCIS (Netherlands)

    Mcewan, J.A.; Hunter, E.A.; Gemert, L.J. van; Lea, P.

    2002-01-01

    Proficiency testing in sensory analysis is an important step towards demonstrating that results from one sensory panel are consistent with the results of other sensory panels. The uniqueness of sensory analysis poses some specific problems for measuring the proficiency of the human instrument

  8. Sequential, Multiple Assignment, Randomized Trial Designs in Immuno-oncology Research.

    Science.gov (United States)

    Kidwell, Kelley M; Postow, Michael A; Panageas, Katherine S

    2018-02-15

    Clinical trials investigating immune checkpoint inhibitors have led to the approval of anti-CTLA-4 (cytotoxic T-lymphocyte antigen-4), anti-PD-1 (programmed death-1), and anti-PD-L1 (PD-ligand 1) drugs by the FDA for numerous tumor types. In the treatment of metastatic melanoma, combinations of checkpoint inhibitors are more effective than single-agent inhibitors, but combination immunotherapy is associated with increased frequency and severity of toxicity. There are questions about the use of combination immunotherapy or single-agent anti-PD-1 as initial therapy and the number of doses of either approach required to sustain a response. In this article, we describe a novel use of sequential, multiple assignment, randomized trial (SMART) design to evaluate immune checkpoint inhibitors to find treatment regimens that adapt within an individual based on intermediate response and lead to the longest overall survival. We provide a hypothetical example SMART design for BRAF wild-type metastatic melanoma as a framework for investigating immunotherapy treatment regimens. We compare implementing a SMART design to implementing multiple traditional randomized clinical trials. We illustrate the benefits of a SMART over traditional trial designs and acknowledge the complexity of a SMART. SMART designs may be an optimal way to find treatment strategies that yield durable response, longer survival, and lower toxicity. Clin Cancer Res; 24(4); 730-6. ©2017 AACR . ©2017 American Association for Cancer Research.

  9. Interprofessional Collaboration with Immune Checkpoint Inhibitor Therapy: the Roles of Gastroenterology, Endocrinology and Neurology.

    Science.gov (United States)

    Seery, Virginia

    2017-11-01

    To discuss immune checkpoint inhibitor therapy and identify opportunities for interprofessional collaboration in the management of toxicities in the areas of gastroenterology, endocrinology, and neurology. Published research and education articles in oncology, nursing, and various specialties. The use of immune checkpoint inhibitors is expanding; timely management of toxicity is critical for positive patient outcomes. There are many opportunities for interprofessional collaboration in the diagnosis and treatment of immune-related adverse events. Nurses play key roles in recognizing immune-related adverse events, providing patient education, and helping to facilitate interprofessional collaboration. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Mechanism-based screen for G1/S checkpoint activators identifies a selective activator of EIF2AK3/PERK signalling.

    Science.gov (United States)

    Stockwell, Simon R; Platt, Georgina; Barrie, S Elaine; Zoumpoulidou, Georgia; Te Poele, Robert H; Aherne, G Wynne; Wilson, Stuart C; Sheldrake, Peter; McDonald, Edward; Venet, Mathilde; Soudy, Christelle; Elustondo, Frédéric; Rigoreau, Laurent; Blagg, Julian; Workman, Paul; Garrett, Michelle D; Mittnacht, Sibylle

    2012-01-01

    Human cancers often contain genetic alterations that disable G1/S checkpoint control and loss of this checkpoint is thought to critically contribute to cancer generation by permitting inappropriate proliferation and distorting fate-driven cell cycle exit. The identification of cell permeable small molecules that activate the G1/S checkpoint may therefore represent a broadly applicable and clinically effective strategy for the treatment of cancer. Here we describe the identification of several novel small molecules that trigger G1/S checkpoint activation and characterise the mechanism of action for one, CCT020312, in detail. Transcriptional profiling by cDNA microarray combined with reverse genetics revealed phosphorylation of the eukaryotic initiation factor 2-alpha (EIF2A) through the eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3/PERK) as the mechanism of action of this compound. While EIF2AK3/PERK activation classically follows endoplasmic reticulum (ER) stress signalling that sets off a range of different cellular responses, CCT020312 does not trigger these other cellular responses but instead selectively elicits EIF2AK3/PERK signalling. Phosphorylation of EIF2A by EIF2A kinases is a known means to block protein translation and hence restriction point transit in G1, but further supports apoptosis in specific contexts. Significantly, EIF2AK3/PERK signalling has previously been linked to the resistance of cancer cells to multiple anticancer chemotherapeutic agents, including drugs that target the ubiquitin/proteasome pathway and taxanes. Consistent with such findings CCT020312 sensitizes cancer cells with defective taxane-induced EIF2A phosphorylation to paclitaxel treatment. Our work therefore identifies CCT020312 as a novel small molecule chemical tool for the selective activation of EIF2A-mediated translation control with utility for proof-of-concept applications in EIF2A-centered therapeutic approaches, and as a chemical starting point for

  11. The subunits of the S-phase checkpoint complex Mrc1/Tof1/Csm3: dynamics and interdependence.

    Science.gov (United States)

    Uzunova, Sonya Dimitrova; Zarkov, Alexander Stefanov; Ivanova, Anna Marianova; Stoynov, Stoyno Stefanov; Nedelcheva-Veleva, Marina Nedelcheva

    2014-01-01

    The S-phase checkpoint aims to prevent cells from generation of extensive single-stranded DNA that predisposes to genome instability. The S. cerevisiae complex Tof1/Csm3/Mrc1 acts to restrain the replicative MCM helicase when DNA synthesis is prohibited. Keeping the replication machinery intact allows restart of the replication fork when the block is relieved. Although the subunits of the Tof1/Csm3/Mrc1 complex are well studied, the impact of every single subunit on the triple complex formation and function needs to be established. This work studies the cellular localization and the chromatin binding of GFP-tagged subunits when the complex is intact and when a subunit is missing. We demonstrate that the complex is formed in cell nucleus, not the cytoplasm, as Tof1, Csm3 and Mrc1 enter the nucleus independently from one another. Via in situ chromatin binding assay we show that a Tof1-Csm3 dimer formation and chromatin binding is required to ensure the attachment of Mrc1 to chromatin. Our study indicates that the translocation into the nucleus is not the process to regulate the timing of chromatin association of Mrc1. We also studied the nuclear behavior of Mrc1 subunit in the process of adaptation to the presence hydroxyurea. Our results indicate that after prolonged HU incubation, cells bypass the S-phase checkpoint and proceed throughout the cell cycle. This process is accompanied by Mrc1 chromatin detachment and Rad53 dephosphorylation. In S. cerevisiae the subunits of the S-phase checkpoint complex Mrc1/Tof1/Csm3 independently enter the cell nucleus, where a Tof1-Csm3 dimer is formed to ensure the chromatin binding of Mrc1 and favor DNA replication and S-phase checkpoint fork arrest. In the process of adaptation to the presence of hydroxyurea Mrc1 is detached from chromatin and Rad53 checkpoint activity is diminished in order to allow S-phase checkpoint escape and completion of the cell cycle.

  12. Laboratory competence evaluation through proficiency testing - mycotoxins in food

    Directory of Open Access Journals (Sweden)

    Torović Ljilja D.

    2017-01-01

    Full Text Available Laboratory for analysis of mycotoxins in food at the Institute of Public Health of Vojvodina (Novi Sad, Serbia participated in 15 proficiency testing schemes in period 2012-2016, comprising 22 determinations of regulated mycotoxins: aflatoxins B1, B2, G1, G2 and M1, ochratoxin A, deoxynivalenone, zearalenone, fumonisins and patulin, in different food commodities: wheat, corn, barley, breakfast cereals, infant food, milk, wine and fruit juice. Analyses were carried out by high performance liquid chromatography with ultraviolet (patulin, deoxynivalenol or fluorescence detection (aflatoxin M1, ochratoxin A, zearalenone using o-phthalaldehyde precolumn derivatization (fumonisins or UV postcolumn derivatization (aflatoxins B1, B2, G1, G2, following clean-up on immunoaffinity columns with specific antibodies, except in case of patulin when solvent extraction and solid-phase C-18 clean-up were used. Laboratory performance assessed in terms of z scores showed all satisfactory results. In depth evaluation revealed following distribution of z scores (absolute values: 59.1% up to 0.5, 36.4% between 0.5 and 1.0, and 4.5% above 1.0. Analysis of trends performed for multiple determinations of individual mycotoxins showed several changes of z score to better or worse rank. Overall assessment of the performance in proficiency testing demonstrated laboratory competence for analysis of mycotoxins in food.

  13. Targeting Tumor-Associated Macrophages as a Potential Strategy to Enhance the Response to Immune Checkpoint Inhibitors.

    Science.gov (United States)

    Cassetta, Luca; Kitamura, Takanori

    2018-01-01

    Inhibition of immune checkpoint pathways in CD8 + T cell is a promising therapeutic strategy for the treatment of solid tumors that has shown significant anti-tumor effects and is now approved by the FDA to treat patients with melanoma and lung cancer. However the response to this therapy is limited to a certain fraction of patients and tumor types, for reasons still unknown. To ensure success of this treatment, CD8 + T cells, the main target of the checkpoint inhibitors, should exert full cytotoxicity against tumor cells. However recent studies show that tumor-associated macrophages (TAM) can impede this process by different mechanisms. In this mini-review we will summarize recent studies showing the effect of TAM targeting on immune checkpoint inhibitors efficacy. We will also discuss on the limitations of the current strategies as well on the future scientific challenges for the progress of the tumor immunology field.

  14. EMODnet MedSea Checkpoint for sustainable Blue Growth

    Science.gov (United States)

    Moussat, Eric; Pinardi, Nadia; Manzella, Giuseppe; Blanc, Frederique

    2016-04-01

    The EMODNET checkpoint is a wide monitoring system assessment activity aiming to support the sustainable Blue Growth at the scale of the European Sea Basins by: 1) Clarifying the observation landscape of all compartments of the marine environment including Air, Water, Seabed, Biota and Human activities, pointing out to the existing programs, national, European and international 2) Evaluating fitness for use indicators that will show the accessibility and usability of observation and modeling data sets and their roles and synergies based upon selected applications by the European Marine Environment Strategy 3) Prioritizing the needs to optimize the overall monitoring Infrastructure (in situ and satellite data collection and assembling, data management and networking, modeling and forecasting, geo-infrastructure) and release recommendations for evolutions to better meet the application requirements in view of sustainable Blue Growth The assessment is designed for : - Institutional stakeholders for decision making on observation and monitoring systems - Data providers and producers to know how their data collected once for a given purpose could fit other user needs - End-users interested in a regional status and possible uses of existing monitoring data Selected end-user applications are of paramount importance for: (i) the blue economy sector (offshore industries, fisheries); (ii) marine environment variability and change (eutrophication, river inputs and ocean climate change impacts); (iii) emergency management (oil spills); and (iv) preservation of natural resources and biodiversity (Marine Protected Areas). End-user applications generate innovative products based on the existing observation landscape. The fitness for use assessment is made thanks to the comparison of the expected product specifications with the quality of the product derived from the selected data. This involves the development of checkpoint information and indicators based on Data quality and

  15. Proficiency test for tropane alkaloids in food en feed

    NARCIS (Netherlands)

    Pereboom-de Fauw, D.P.K.H.; Elbers, I.J.W.; Mulder, P.P.J.; Nijs, de W.C.M.

    2014-01-01

    Proficiency testing is conducted to provide laboratories with a powerful tool to evaluate and demonstrate the reliability of the data that are produced. Next to validation and accreditation, proficiency testing is an important requirement of the EU Additional Measures Directive 93/99/EEC [1] and is

  16. The correlation between motor proficiency and physical activity in ...

    African Journals Online (AJOL)

    Background: One of the risks associated with low physical activity levels is the insufficient development of motor proficiency, which in turn has an impact on participation in physical activity and sport during adolescence. Objectives: To determine the relationship between motor proficiency and physical activity levels in ...

  17. English language proficiency and smoking prevalence among California's Asian Americans.

    Science.gov (United States)

    Tang, Hao; Shimizu, Robin; Chen, Moon S

    2005-12-15

    The authors documented California's tobacco control initiatives for Asian Americans and the current tobacco use status among Asian subgroups and provide a discussion of the challenges ahead. The California Tobacco Control Program has employed a comprehensive approach to decrease tobacco use in Asian Americans, including ethnic-specific media campaigns, culturally competent interventions, and technical assistance and training networks. Surveillance of tobacco use among Asian Americans and the interpretation of the results have always been a challenge. Data from the 2001 The California Health Interview Survey (CHIS) were analyzed to provide smoking prevalence estimates for all Asian Americans and Asian-American subgroups, including Korean, Filipino, Japanese, South Asian, Chinese, and Vietnamese. Current smoking prevalence was analyzed by gender and by English proficiency level. Cigarette smoking prevalence among Asian males in general was almost three times of that among Asian females. Korean and Vietnamese males had higher cigarette smoking prevalence rates than males in other subgroups. Although Asian females in general had low smoking prevalence rates, significant differences were found among Asian subgroups, from 1.1% (Vietnamese) to 12.7% (Japanese). Asian men who had high English proficiency were less likely to be smokers than men with lower English proficiency. Asian women with high English proficiency were more likely to be smokers than women with lower English proficiency. Smoking prevalence rates among Asian Americans in California differed significantly on the basis of ethnicity, gender, and English proficiency. English proficiency seemed to have the effect of reducing smoking prevalence rates among Asian males but had just the opposite effect among Asian females. Cancer 2005. (c) 2005 American Cancer Society.

  18. Immunotherapy targeting immune check-point(s) in brain metastases.

    Science.gov (United States)

    Di Giacomo, Anna Maria; Valente, Monica; Covre, Alessia; Danielli, Riccardo; Maio, Michele

    2017-08-01

    Immunotherapy with monoclonal antibodies (mAb) directed to different immune check-point(s) is showing a significant clinical impact in a growing number of human tumors of different histotype, both in terms of disease response and long-term survival patients. In this rapidly changing scenario, treatment of brain metastases remains an high unmeet medical need, and the efficacy of immunotherapy in these highly dismal clinical setting remains to be largely demonstrated. Nevertheless, up-coming observations are beginning to suggest a clinical potential of cancer immunotherapy also in brain metastases, regardless the underlying tumor histotype. These observations remain to be validated in larger clinical trials eventually designed also to address the efficacy of therapeutic mAb to immune check-point(s) within multimodality therapies for brain metastases. Noteworthy, the initial proofs of efficacy on immunotherapy in central nervous system metastases are already fostering clinical trials investigating its therapeutic potential also in primary brain tumors. We here review ongoing immunotherapeutic approaches to brain metastases and primary brain tumors, and the foreseeable strategies to overcome their main biologic hurdles and clinical challenges. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. The Prediction of Training Proficiency in Firefighters: A Study of Predictive Validity in Spain

    Directory of Open Access Journals (Sweden)

    Alfredo Berges

    2018-02-01

    Full Text Available The present study provides results of criterion validity in the selection of firefighters in Spain. The predictors were cognitive skills, job knowledge, and physical aptitudes, and the criterion was training proficiency. The process involves 639 candidates, but only 44 complete successfully the selection process. Our results support previous evidence showing that general cognitive ability is the best predictor of training proficiency, with an operational validity of .57. With respect to the other predictors, job knowledge presented an operational validity of .55 and physical tests of .49. In addition, multiple regression analysis showed that cognitive aptitude explains 33% of the variance, but when physical aptitudes are included the explained variance increases to 50%. If we also add job knowledge, explained variance increases to 55%. Our study offers recent results of criterion validity in a barely investigated job, gathered in a country other than the one where prior research had been carried out.

  20. Television viewing in low-income latino children: variation by ethnic subgroup and English proficiency.

    Science.gov (United States)

    Thompson, Darcy A; Matson, Pamela A; Ellen, Jonathan M

    2013-02-01

    Television viewing is associated with an increased risk for obesity in children. Latino children are at high risk for obesity and yet little is known about differences in television viewing habits within this population. The purpose of this study is to determine if hours of television viewed by young children with low-income Latina mothers differs by maternal ethnic subgroup and English language proficiency. This was a cross-sectional analysis of data from the Welfare, Children, & Families: A Three City Study. Participants were 422 low-income Latina mothers of Mexican and Puerto Rican descent with children ages 0-4 years old. The dependent variable was hours of daily television viewed by the child. The independent variable was maternal ethnic subgroup and English language proficiency. Analyses involved the use of multiple negative binomial regression models, which were adjusted for demographic variables. Multivariable regression analyses showed that compared to children with mothers of Mexican descent, children of mothers of Puerto Rican descent watch more daily television (child television viewing (IRR=1.29, 95% CI 1.04, 1.61). No relationship was found for children of Puerto Rican descent. Child television viewing varies in low-income Latino children by maternal ethnic subgroup and English language proficiency. Interventionists must consider the varying sociocultural contexts of Latino children and their influence on television viewing.

  1. Television Viewing in Low-Income Latino Children: Variation by Ethnic Subgroup and English Proficiency

    Science.gov (United States)

    Matson, Pamela A.; Ellen, Jonathan M.

    2013-01-01

    Abstract Background Television viewing is associated with an increased risk for obesity in children. Latino children are at high risk for obesity and yet little is known about differences in television viewing habits within this population. The purpose of this study is to determine if hours of television viewed by young children with low-income Latina mothers differs by maternal ethnic subgroup and English language proficiency. Methods This was a cross-sectional analysis of data from the Welfare, Children, & Families: A Three City Study. Participants were 422 low-income Latina mothers of Mexican and Puerto Rican descent with children ages 0–4 years old. The dependent variable was hours of daily television viewed by the child. The independent variable was maternal ethnic subgroup and English language proficiency. Analyses involved the use of multiple negative binomial regression models, which were adjusted for demographic variables. Results Multivariable regression analyses showed that compared to children with mothers of Mexican descent, children of mothers of Puerto Rican descent watch more daily television (television viewing (IRR=1.29, 95% CI 1.04, 1.61). No relationship was found for children of Puerto Rican descent. Conclusions Child television viewing varies in low-income Latino children by maternal ethnic subgroup and English language proficiency. Interventionists must consider the varying sociocultural contexts of Latino children and their influence on television viewing. PMID:23301653

  2. The Geography of Deterrence: Exploring the Small Area Effects of Sobriety Checkpoints on Alcohol-Impaired Collision Rates within a City

    Science.gov (United States)

    Nunn, Samuel; Newby, William

    2011-01-01

    This article examines alcohol-impaired collision metrics around nine sobriety checkpoint locations in Indianapolis, Indiana, before and after implementation of 22 checkpoints, using a pre/post examination, a pre/post nonequivalent comparison group analysis, and an interrupted time series approach. Traffic safety officials used geographical…

  3. Reconnecting Proficiency, Literacy, and Culture: From Theory to Practice

    Science.gov (United States)

    Warford, Mark K.; White, William L.

    2012-01-01

    What does it mean to capably communicate across languages? This article introduces two theoretical models and a lesson plan format designed to facilitate the integration of proficiency, literacy, and culture teaching in foreign language teaching. The Second Symbolic Competencies Model configures proficiency and literacy as subordinate clusters of…

  4. English Proficiency and Participation in Online Discussion for Learning

    Science.gov (United States)

    Leung, Steve

    2013-01-01

    Does English proficiency affect participation in online discussion? This study polled 14 students from a postgraduate online course that require online discussion. The students are divided into groups according to their home language spoken and self-assessed English proficiency, and measure against their participation level in the required…

  5. The organizational effects of pubertal testosterone on sexual proficiency in adult male Syrian hamsters.

    Science.gov (United States)

    De Lorme, Kayla C; Sisk, Cheryl L

    2016-10-15

    Social proficiency requires making appropriate behavioral adaptations as a result of social experience. For example, male rodents become sexually proficient with experience as demonstrated by a reduction in ectopic (misdirected) mounts, mount-to-intromission ratio, and latency to ejaculation. We previously found that over a series of timed tests with a receptive female, male hamsters deprived of testosterone specifically during puberty (NoT@P) have overall lower levels of sexual behavior and continue to display high levels of ectopic mounts, compared with males that experienced endogenous testosterone during puberty (T@P). These results suggested that pubertal testosterone programs sexual proficiency in adulthood, but because NoT@P males engaged in less sexual behavior than T@P males in these tests, the amount of sexual experience may have been insufficient to improve sexual proficiency. To more rigorously test the hypothesis that pubertal testosterone is necessary for social proficiency in adulthood, the present study compared the behavior of NoT@P and T@P males in a series of 4 trials with a 48-h interval between each trial. Sexual experience was equated by limiting each trial to 5 intromissions. Sexually-naïve males were either gonadectomized prepubertally (NoT@P) or in adulthood (T@P) and received subcutaneous testosterone capsules four weeks later. Two weeks after testosterone replacement, these groups and a group of adult gonad-intact controls began sexual behavior testing. We found that NoT@P males had more ectopic mounts/min across all four tests compared to gonad-intact and T@P males. Moreover, both gonad-intact and T@P males, but not NoT@P males, showed an increase in the number of mounts and intromissions/min between trials 1 and 3. Unexpectedly, both gonad-intact and T@P, but not NoT@P, males showed a decrease in sexual behaviors during trial 4. Thus, T@P males display multiple behavioral adaptations to sexual experience that are not observed in No

  6. Testing Proficiency in Interpersonal Communication

    Science.gov (United States)

    Byers, Burton H.

    1973-01-01

    Discusses several hypotheses about the measurement of speech-communication proficiency which are being tested at the University of Hawaii and a testing instrument entitled Dy Comm'' (dyadic communication) which emerged from this research. (DD)

  7. TAM receptor tyrosine kinases as emerging targets of innate immune checkpoint blockade for cancer therapy.

    Science.gov (United States)

    Akalu, Yemsratch T; Rothlin, Carla V; Ghosh, Sourav

    2017-03-01

    Cancer immunotherapy utilizing T-cell checkpoint inhibitors has shown tremendous clinical success. Yet, this mode of treatment is effective in only a subset of patients. Unresponsive patients tend to have non-T-cell-inflamed tumors that lack markers associated with the activation of adaptive anti-tumor immune responses. Notably, elimination of cancer cells by T cells is critically dependent on the optimal activity of innate immune cells. Therefore, identifying new targets that regulate innate immune cell function and promote the engagement of adaptive tumoricidal responses is likely to lead to the development of improved therapies against cancer. Here, we review the TAM receptor tyrosine kinases-TYRO3, AXL, and MERTK-as an emerging class of innate immune checkpoints that participate in key steps of anti-tumoral immunity. Namely, TAM-mediated efferocytosis, negative regulation of dendritic cell activity, and dysregulated production of chemokines collectively favor the escape of malignant cells. Hence, disabling TAM signaling may promote engagement of adaptive immunity and complement T-cell checkpoint blockade. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. Native language predictors of foreign language proficiency and foreign language aptitude.

    Science.gov (United States)

    Sparks, Richard L; Patton, Jon; Ganschow, Leonore; Humbach, Nancy; Javorsky, James

    2006-06-01

    Fifty-four students were tested at specific time intervals over 10 years to determine best native language (NL) predictors of oral and written foreign language (FL) proficiency and FL aptitude. All participants completed two years of Spanish, French, or German. Each was administered measures of NL literacy, oral language, and cognitive ability in elementary school. A measure of FL aptitude was administered at the beginning of ninth grade and FL proficiency was evaluated at the end of the 10th grade. Among the variables, NL literacy measures were the best predictors of FL proficiency, and NL achievement and general (verbal) intelligence were strong predictors of FL aptitude. Results suggest that indices of NL literacy as early as first grade are related to FL proficiency and FL aptitude nine and 10 years later. Findings provide strong support for connections between L1 and L2 skills, and for speculation that "lower level" skills in phonological processing are important for written language development and oral proficiency in a FL.

  9. Cloud object store for checkpoints of high performance computing applications using decoupling middleware

    Science.gov (United States)

    Bent, John M.; Faibish, Sorin; Grider, Gary

    2016-04-19

    Cloud object storage is enabled for checkpoints of high performance computing applications using a middleware process. A plurality of files, such as checkpoint files, generated by a plurality of processes in a parallel computing system are stored by obtaining said plurality of files from said parallel computing system; converting said plurality of files to objects using a log structured file system middleware process; and providing said objects for storage in a cloud object storage system. The plurality of processes may run, for example, on a plurality of compute nodes. The log structured file system middleware process may be embodied, for example, as a Parallel Log-Structured File System (PLFS). The log structured file system middleware process optionally executes on a burst buffer node.

  10. The fission yeast spindle orientation checkpoint: a model that generates tension?

    Science.gov (United States)

    Gachet, Yannick; Reyes, Céline; Goldstone, Sherilyn; Tournier, Sylvie

    2006-10-15

    In all eukaryotes, the alignment of the mitotic spindle with the axis of cell polarity is essential for accurate chromosome segregation as well as for the establishment of cell fate, and thus morphogenesis, during development. Studies in invertebrates, higher eukaryotes and yeast suggest that astral microtubules interact with the cell cortex to position the spindle. These microtubules are thought to impose pushing or pulling forces on the spindle poles to affect the rotation or movement of the spindle. In the fission yeast model, where cell division is symmetrical, spindle rotation is dependent on the interaction of astral microtubules with the cortical actin cytoskeleton. In these cells, a bub1-dependent mitotic checkpoint, the spindle orientation checkpoint (SOC), is activated when the spindles fail to align with the cell polarity axis. In this paper we review the mechanism that orientates the spindle during mitosis in fission yeast, and discuss the consequences of misorientation on metaphase progression. Copyright 2006 John Wiley & Sons, Ltd.

  11. The Nevada Proficiency Examination Program: Evaluating the Writing Samples.

    Science.gov (United States)

    Howard, Edward H.

    Writing tests are part of the mandated statewide proficiency examination in Nevada. The ninth-grade screening test and the eleventh-grade diploma-certifying test require that a student write a paragraph and a business letter, each on an assigned topic and each at an acceptable level of proficiency. Pilot tests, extended discussion, and statistical…

  12. Summary of microsatellite instability test results from laboratories participating in proficiency surveys: proficiency survey results from 2005 to 2012.

    Science.gov (United States)

    Boyle, Theresa A; Bridge, Julia A; Sabatini, Linda M; Nowak, Jan A; Vasalos, Patricia; Jennings, Lawrence J; Halling, Kevin C

    2014-03-01

    The College of American Pathologists surveys are the largest laboratory peer comparison programs in the world. These programs allow laboratories to regularly evaluate their performance and improve the accuracy of the patient test results they provide. Proficiency testing is offered twice a year to laboratories performing microsatellite instability testing. These surveys are designed to emulate clinical practice, and some surveys have more challenging cases to encourage the refinement of laboratory practices. This report summarizes the results and trends in microsatellite instability proficiency testing from participating laboratories from the inception of the program in 2005 through 2012. We compiled and analyzed data for 16 surveys of microsatellite instability proficiency testing during 2005 to 2012. The number of laboratories participating in the microsatellite instability survey has more than doubled from 42 to 104 during the 8 years analyzed. An average of 95.4% of the laboratories correctly classified each of the survey test samples from the 2005A through 2012B proficiency challenges. In the 2011B survey, a lower percentage of laboratories (78.4%) correctly classified the specimen, possibly because of overlooking subtle changes of microsatellite instability and/or failing to enrich the tumor content of the specimen to meet the limit of detection of their assay. In general, laboratories performed well in microsatellite instability testing. This testing will continue to be important in screening patients with colorectal and other cancers for Lynch syndrome and guiding the management of patients with sporadic colorectal cancer.

  13. Language proficiency and the international postgraduate student experience

    OpenAIRE

    Weaver, M

    2016-01-01

    In an increasingly competitive environment, with reduced government funding, full fee-paying international students are an important source of revenue for higher education institutions (HEIs). Although many previous studies have focused on the role of English language proficiency on academic success, there is little known about the extent to which levels of English language proficiency affect these non-native English speaking students’ overall course experience. There have been a wealth of st...

  14. Immune checkpoint inhibitors: the new frontier in non–small cell lung cancer treatment

    Directory of Open Access Journals (Sweden)

    El-Osta HE

    2016-08-01

    Full Text Available Hazem El-Osta, Kamran Shahid, Glenn M Mills, Prakash Peddi Department of Medicine, Division of Hematology-Oncology, Louisiana State University Health Sciences Center, Shreveport, LA, USA Abstract: Lung cancer is the major cause for cancer-related death in the US. Although advances in chemotherapy and targeted therapy have improved the outcome of metastatic non-small-cell lung cancer, its prognosis remains dismal. A deeper understanding of the complex interaction between the immune system and tumor microenvironment has identified immune checkpoint inhibitors as new avenue of immunotherapy. Rather than acting directly on the tumor, these therapies work by removing the inhibition exerted by tumor cell or other immune cells on the immune system, promoting antitumoral immune response. To date, two programmed death-1 inhibitors, namely nivolumab and pembrolizumab, have received the US Food and Drug Administration approval for the treatment of advanced non-small-cell lung cancer that failed platinum-based chemotherapy. This manuscript provides a brief overview of the pathophysiology of cancer immune evasion, summarizes pertinent data on completed and ongoing clinical trials involving checkpoint inhibitors, discusses the different strategies to optimize their function, and outlines various challenges that are faced in this promising yet evolving field. Keywords: checkpoint inhibitors, immunotherapy, nivolumab, non-small-cell lung cancer, pembrolizumab, programmed death-1, programmed death ligand-1

  15. Development of a PROficiency-Based StePwise Endovascular Curricular Training (PROSPECT) Program.

    Science.gov (United States)

    Maertens, Heidi; Aggarwal, Rajesh; Desender, Liesbeth; Vermassen, Frank; Van Herzeele, Isabelle

    2016-01-01

    Focus on patient safety, work-hour limitations, and cost-effective education is putting pressure to improve curricula to acquire minimally invasive techniques during surgical training. This study aimed to design a structured training program for endovascular skills and validate its assessment methods. A PROficiency-based StePwise Endovascular Curricular Training (PROSPECT) program was developed, consisting of e-learning and hands-on simulation modules, focusing on iliac and superficial femoral artery atherosclerotic disease. Construct validity was investigated. Performances were assessed using multiple-choice questionnaires, valid simulation parameters, global rating scorings, and examiner checklists. Feasibility was assessed by passage of 2 final-year medical students through this PROSPECT program. Ghent University Hospital, a tertiary clinical care and academic center in Belgium with general surgery residency program. Senior-year medical students were recruited at Ghent University Hospital. Vascular surgeons were invited to participate during conferences and meetings if they had performed at least 100 endovascular procedures as the primary operator during the last 2 years. Overall, 29 medical students and 20 vascular surgeons participated. Vascular surgeons obtained higher multiple-choice questionnaire scores (median: 24.5-22.0 vs. 15.0-12.0; p train cognitive, technical, and nontechnical endovascular skills was developed. A structured, stepwise, proficiency-based valid endovascular program to train cognitive, technical, and human factor skills has been developed and proven to be feasible. A randomized controlled trial has been initiated to investigate its effect on performances in real life, patient outcomes, and cost-effectiveness. Copyright © 2015 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.

  16. Centromere replication timing determines different forms of genomic instability in Saccharomyces cerevisiae checkpoint mutants during replication stress.

    Science.gov (United States)

    Feng, Wenyi; Bachant, Jeff; Collingwood, David; Raghuraman, M K; Brewer, Bonita J

    2009-12-01

    Yeast replication checkpoint mutants lose viability following transient exposure to hydroxyurea, a replication-impeding drug. In an effort to understand the basis for this lethality, we discovered that different events are responsible for inviability in checkpoint-deficient cells harboring mutations in the mec1 and rad53 genes. By monitoring genomewide replication dynamics of cells exposed to hydroxyurea, we show that cells with a checkpoint deficient allele of RAD53, rad53K227A, fail to duplicate centromeres. Following removal of the drug, however, rad53K227A cells recover substantial DNA replication, including replication through centromeres. Despite this recovery, the rad53K227A mutant fails to achieve biorientation of sister centromeres during recovery from hydroxyurea, leading to secondary activation of the spindle assembly checkpoint (SAC), aneuploidy, and lethal chromosome segregation errors. We demonstrate that cell lethality from this segregation defect could be partially remedied by reinforcing bipolar attachment. In contrast, cells with the mec1-1 sml1-1 mutations suffer from severely impaired replication resumption upon removal of hydroxyurea. mec1-1 sml1-1 cells can, however, duplicate at least some of their centromeres and achieve bipolar attachment, leading to abortive segregation and fragmentation of incompletely replicated chromosomes. Our results highlight the importance of replicating yeast centromeres early and reveal different mechanisms of cell death due to differences in replication fork progression.

  17. Unique cytologic features of thyroiditis caused by immune checkpoint inhibitor therapy for malignant melanoma

    Directory of Open Access Journals (Sweden)

    Trevor E. Angell

    2018-03-01

    Full Text Available Blockade of immune checkpoint molecules to reverse cancer-induced immune suppression can improve anti-tumor immune responses in cancer patients. Monoclonal antibodies targeting two such molecules, Programmed cell death protein 1 (PD-1 and cytotoxic T-lymphocyte associated protein 4 (CTLA-4 have shown clinical benefit in the treatment of advanced malignancies, including metastatic melanoma. Adverse effects of these immune checkpoint inhibitors include immune-related adverse events (irAE, of which one of the most common is autoimmune thyroiditis. Though thyroiditis is increasingly recognized, there are no reports of the pathological findings that occur in immunotherapy-induced thyroiditis. We present a case of immunotherapy-induced thyroiditis demonstrating its unique cytopathologic features. A 51-year-old woman with metastatic melanoma was found to have a suppressed TSH and elevated free thyroxine concentration 14 days after starting treatment with nivolumab (PD-1 antagonist plus ipilimumab (CTLA-4 antagonist therapy. A thyroid biopsy was performed based on ultrasound findings and cytopathology revealed unique features including abundant clusters of necrotic cells, lymphocytes and CD163-positive histiocytes. This case reports cytopathologic features found in immune checkpoint inhibitor related thyroiditis. These appear to be unique findings and may help inform future research regarding the pathophysiology and mechanisms of this condition.

  18. Developing English Writing Proficiency in Limited English Proficient College Students through Cooperative Learning Strategies.

    Science.gov (United States)

    Gooden-Jones, Epsey M.; Carrasquillo, Angela L.

    A study followed ten limited-English-proficient (LEP) community college students who were taught English largely using a cooperative learning approach. For four months, the students worked together using brainstorming techniques and collaborative reading and writing tasks. Task emphasis was on development of thinking skills through collaboration…

  19. A Comprehensive Review of US FDA-Approved Immune Checkpoint Inhibitors in Urothelial Carcinoma

    Directory of Open Access Journals (Sweden)

    Fu-Shun Hsu

    2017-01-01

    Full Text Available Few effective treatment options are available for patients with advanced or metastatic urothelial carcinoma (UC after unsuccessful first-line platinum-based chemotherapy. To date, immune checkpoint inhibitors are novel therapeutic agents for UC treatment. From May 2016 to May 2017, five anti-PD-1/PD-L1 monoclonal antibodies received accelerated or regular approval from the US Food and Drug Administration (FDA for the treatment of patients with locally advanced or metastatic UC. The present comprehensive review presents the background information of these five US FDA-approved anticancer agents to provide a basic but concise understanding of these agents for advanced studies. We summarize their immune checkpoint mechanisms, clinical efficacy, recommended usage protocols, adverse events, and the limitations of the PD-L1 biomarker assays.

  20. Central Tolerance Blockade to Augment Checkpoint Immunotherapy in Melanoma

    Science.gov (United States)

    2017-09-01

    expressed at higher levels in medullary thymic epithelial cells (mTECs) than in cortical thymic epithelial cells (cTECs), addition of anti-RANKL antibody...relative Aire expression by quantitative RT-PCR in cultured thymic tissue . 12-15 90% Subtask 3. Culture human thymus sections with OPG-Fc or vehicle...PCR in cultured thymic tissue . 15-18 90% ACURO approval 13-14 100% Major Task 1. Effect of concurrent anti-RANKL and checkpoint inhibitor

  1. Identification of Current Proficiency Level of Extension Competencies and the Competencies Needed for Extension Agents to Be Successful in the 21st Century

    Directory of Open Access Journals (Sweden)

    Dona Lakai

    2014-02-01

    Full Text Available In this era of globalization, competency is an issue of concern to any field of professionals and their clients. Competency is an integrated set of skills, knowledge, and attitudes that allow one to effectively carry out the activities of a given work to the standards expected in the employment context. The purpose of this descriptive survey study was to determine the current proficiency level of North Carolina Cooperative Extension agents’ competencies and the other competencies they need to develop to be successful in Cooperative Extension. Findings indicate that the current proficiency level of competency for Extension agents in North Carolina Cooperative Extension varies from moderate to high in all 42 items listed in the survey. Multiple regression analysis confirmed that Extension agents’ years of Extension experience and age were major determinants of their overall proficiency level. Extension agents’ proficiency levels did not vary with gender, level of education, professional association affiliation, job position, or area of job responsibility. The research revealed that emotional intelligence, interpersonal skills, flexibility for adapting to changing environments, and ability to manage resources were the most significant other competencies needed for Extension agents to be successful in current context.

  2. Identifying College Students' Multiple Intelligences to Enhance Motivation and Language Proficiency

    Science.gov (United States)

    Madkour, Magda; Mohamed, Rafik Ahmed Abdel Moati

    2016-01-01

    While most research studies on the theory of multiple intelligences focused on the application of the multiple intelligences domains as separate components, this quasi-experimental research targeted the effect of multiple intelligences as integrated abilities for teaching and learning English at higher education. The purpose of this study was to…

  3. The Checkpoint Kinase 1 Inhibitor Prexasertib Induces Regression of Preclinical Models of Human Neuroblastoma.

    Science.gov (United States)

    Lowery, Caitlin D; VanWye, Alle B; Dowless, Michele; Blosser, Wayne; Falcon, Beverly L; Stewart, Julie; Stephens, Jennifer; Beckmann, Richard P; Bence Lin, Aimee; Stancato, Louis F

    2017-08-01

    Purpose: Checkpoint kinase 1 (CHK1) is a key regulator of the DNA damage response and a mediator of replication stress through modulation of replication fork licensing and activation of S and G 2 -M cell-cycle checkpoints. We evaluated prexasertib (LY2606368), a small-molecule CHK1 inhibitor currently in clinical testing, in multiple preclinical models of pediatric cancer. Following an initial assessment of prexasertib activity, this study focused on the preclinical models of neuroblastoma. Experimental Design: We evaluated the antiproliferative activity of prexasertib in a panel of cancer cell lines; neuroblastoma cell lines were among the most sensitive. Subsequent Western blot and immunofluorescence analyses measured DNA damage and DNA repair protein activation. Prexasertib was investigated in several cell line-derived xenograft mouse models of neuroblastoma. Results: Within 24 hours, single-agent prexasertib promoted γH2AX-positive double-strand DNA breaks and phosphorylation of DNA damage sensors ATM and DNA-PKcs, leading to neuroblastoma cell death. Knockdown of CHK1 and/or CHK2 by siRNA verified that the double-strand DNA breaks and cell death elicited by prexasertib were due to specific CHK1 inhibition. Neuroblastoma xenografts rapidly regressed following prexasertib administration, independent of starting tumor volume. Decreased Ki67 and increased immunostaining of endothelial and pericyte markers were observed in xenografts after only 6 days of exposure to prexasertib, potentially indicating a swift reduction in tumor volume and/or a direct effect on tumor vasculature. Conclusions: Overall, these data demonstrate that prexasertib is a specific inhibitor of CHK1 in neuroblastoma and leads to DNA damage and cell death in preclinical models of this devastating pediatric malignancy. Clin Cancer Res; 23(15); 4354-63. ©2017 AACR . ©2017 American Association for Cancer Research.

  4. [An experimental proficiency test for ability to screen 104 residual pesticides in agricultural products].

    Science.gov (United States)

    Tsumura, Yukari; Ishimitsu, Susumu; Otaki, Kayo; Uchimi, Hiroyuki; Matsumoto, Nobuyuki; Daba, Masaki; Tsuchiya, Tetsu; Ukyo, Masaho; Tonogai, Yasuhide

    2003-10-01

    An experimental proficiency test program for ability to screen 104 residual pesticides in agricultural products has been conducted. Eight Japanese laboratories joined the program. Items tested in the present study were limit of detection, internal proficiency test (self spike) and external proficiency test (blind spike). All 104 pesticides were well detected and recovered from agricultural foods in the internal proficiency test. However, the results of the external proficiency test did not completely agree with those of the internal proficiency tests. After 5 rounds of the blind spike test, the ratio of the number of correctly detected pesticides to that of actually contained ones (49 total) ranged from 65% to 100% among laboratories. The numbers of mistakenly detected pesticides by a laboratory were 0 to 15. Thus, there was a great difference among the laboratories in the ability to screen multiresidual pesticides.

  5. Grp/DChk1 is required for G(2)-M checkpoint activation in Drosophila S2 cells, whereas Dmnk/DChk2 is dispensable

    NARCIS (Netherlands)

    de Vries, HI; Uyetake, L; Lemstra, W; Brunsting, JF; Su, TT; Kampinga, HH; Sibon, OCM

    2005-01-01

    Cell-cycle checkpoints are signal-transduction pathways required to maintain genomic stability in dividing cells. Previously, it was reported that two kinases essential for checkpoint signalling, Chk1 and Chk2 are structurally conserved. In contrast to yeast, Xenopus and mammals, the Chk1- and

  6. Comparative Analysis of Immune Checkpoint Molecules and Their Potential Role in the Transmissible Tasmanian Devil Facial Tumor Disease

    Directory of Open Access Journals (Sweden)

    Andrew S. Flies

    2017-05-01

    Full Text Available Immune checkpoint molecules function as a system of checks and balances that enhance or inhibit immune responses to infectious agents, foreign tissues, and cancerous cells. Immunotherapies that target immune checkpoint molecules, particularly the inhibitory molecules programmed cell death 1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4, have revolutionized human oncology in recent years, yet little is known about these key immune signaling molecules in species other than primates and rodents. The Tasmanian devil facial tumor disease is caused by transmissible cancers that have resulted in a massive decline in the wild Tasmanian devil population. We have recently demonstrated that the inhibitory checkpoint molecule PD-L1 is upregulated on Tasmanian devil (Sarcophilus harrisii facial tumor cells in response to the interferon-gamma cytokine. As this could play a role in immune evasion by tumor cells, we performed a thorough comparative analysis of checkpoint molecule protein sequences among Tasmanian devils and eight other species. We report that many of the key signaling motifs and ligand-binding sites in the checkpoint molecules are highly conserved across the estimated 162 million years of evolution since the last common ancestor of placental and non-placental mammals. Specifically, we discovered that the CTLA-4 (MYPPPY ligand-binding motif and the CTLA-4 (GVYVKM inhibitory domain are completely conserved across all nine species used in our comparative analysis, suggesting that the function of CTLA-4 is likely conserved in these species. We also found that cysteine residues for intra- and intermolecular disulfide bonds were also highly conserved. For instance, all 20 cysteine residues involved in disulfide bonds in the human 4-1BB molecule were also present in devil 4-1BB. Although many key sequences were conserved, we have also identified immunoreceptor tyrosine-based inhibitory motifs (ITIMs and immunoreceptor tyrosine-based switch

  7. Mismatch repair proficiency is not required for radioenhancement by gemcitabine

    International Nuclear Information System (INIS)

    Bree, Chris van; Rodermond, Hans M.; Vos, Judith de; Haveman, Jaap; Franken, Nicolaas

    2005-01-01

    Purpose: Mismatch repair (MMR) proficiency has been reported to either increase or decrease radioenhancement by 24-h incubations with gemcitabine. This study aimed to establish the importance of MMR for radioenhancement by gemcitabine after short-exposure, high-dose treatment and long-exposure, low-dose treatment. Methods and Materials: Survival of MMR-deficient HCT116 and MMR-proficient HCT116 + 3 cells was analyzed by clonogenic assays. Mild, equitoxic gemcitabine treatments (4 h, 0.1 μM vs. 24 h, 6 nM) were combined with γ-irradiation to determine the radioenhancement with or without recovery. Gemcitabine metabolism and cell-cycle effects were evaluated by high-performance liquid chromatography analysis and bivariate flow cytometry. Results: Radioenhancement after 4 h of 0.1 μM of gemcitabine was similar in both cell lines, but the radioenhancement after 24 h of 6 nM of gemcitabine was reduced in MMR-proficient cells. No significant differences between both cell lines were observed in the gemcitabine metabolism or cell-cycle effects after these treatments. Gemcitabine radioenhancement after recovery was also lower in MMR-proficient cells than in MMR-deficient cells. Conclusion: Mismatch repair proficiency decreases radioenhancement by long incubations of gemcitabine but does not affect radioenhancement by short exposures to a clinically relevant gemcitabine dose. Our data suggest that MMR contributes to the recovery from gemcitabine treatment

  8. Differences in Less Proficient and More Proficient ESL College Writing in the Philippine Setting

    Science.gov (United States)

    Gustilo, Leah E.

    2016-01-01

    The present study aimed at characterizing what skilled or more proficient ESL college writing is in the Philippine setting through a contrastive analysis of three groups of variables identified from previous studies: resources, processes, and performance of ESL writers. Based on Chenoweth and Hayes' (2001; 2003) framework, the resource level…

  9. Results of the Proficiency Test, PT1 and PT2, 2012

    DEFF Research Database (Denmark)

    Vendramin, Niccolò; Nicolajsen, Nicole; Christophersen, Maj-Britt

    A comparative test of diagnostic procedures was provided by the European Union Reference Laboratory (EURL) for Fish Diseases. The test was divided into proficiency test 1 (PT1) and proficiency test 2 (PT2). The number of National Reference Laboratories (NRLs) participating in PT1 and PT2 was 43. ....... The tests were sent from the EURL in the beginning of September 2012. Both PT1 and PT2 are accredited by DANAK under registration number 515 for proficiency testing according to the quality assurance standard DS/EN ISO/IEC 17043....

  10. A phospho-proteomic screen identifies substrates of the checkpoint kinase Chk1

    DEFF Research Database (Denmark)

    Blasius, Melanie; Forment, Josep V; Thakkar, Neha

    2011-01-01

    BACKGROUND: The cell-cycle checkpoint kinase Chk1 is essential in mammalian cells due to its roles in controlling processes such as DNA replication, mitosis and DNA-damage responses. Despite its paramount importance, how Chk1 controls these functions remains unclear, mainly because very few Chk1...

  11. Immune Checkpoint Inhibitors: A New Opportunity in the Treatment of Ovarian Cancer?

    Directory of Open Access Journals (Sweden)

    Gloria Mittica

    2016-07-01

    Full Text Available Epithelial ovarian cancer (EOC is the leading cause of death for gynecological cancer. The standard treatment for advanced stage is the combination of optimal debulking surgery and platinum-based chemotherapy. Nevertheless, recurrence is frequent (around 70% and prognosis is globally poor. New therapeutic agents are needed to improve survival. Since EOC is strongly immunogenic, immune checkpoint inhibitors are under evaluation for their capacity to contrast the “turn off” signals expressed by the tumor to escape the immune system and usually responsible for self-tolerance maintenance. This article reviews the literature on anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies in EOC and highlights their possible lines of development. Further studies are needed to better define the prognostic role of the immune checkpoint inhibitors, to identify predictors of response and the optimal clinical setting in EOC.

  12. [Laboratory accreditation and proficiency testing].

    Science.gov (United States)

    Kuwa, Katsuhiko

    2003-05-01

    ISO/TC 212 covering clinical laboratory testing and in vitro diagnostic test systems will issue the international standard for medical laboratory quality and competence requirements, ISO 15189. This standard is based on the ISO/IEC 17025, general requirements for competence of testing and calibration laboratories and ISO 9001, quality management systems-requirements. Clinical laboratory services are essential to patient care and therefore should be available to meet the needs of all patients and clinical personnel responsible for human health care. If a laboratory seeks accreditation, it should select an accreditation body that operates according to this international standard and in a manner which takes into account the particular requirements of clinical laboratories. Proficiency testing should be available to evaluate the calibration laboratories and reference measurement laboratories in clinical medicine. Reference measurement procedures should be of precise and the analytical principle of measurement applied should ensure reliability. We should be prepared to establish a quality management system and proficiency testing in clinical laboratories.

  13. 76 FR 66318 - Announcement of Funding Awards; Limited English Proficiency Initiative Program (LEPI), Fiscal...

    Science.gov (United States)

    2011-10-26

    ... limited English proficiency (LEP), and develop and implement a system to provide those services so LEP... Awards; Limited English Proficiency Initiative Program (LEPI), Fiscal Year 2010/2011 AGENCY: Office of... (NOFA) for the Limited English Proficiency Initiative (LEPI) Program for Fiscal Year (FY) 2010/2011...

  14. Fission Yeast Apc15 Stabilizes MCC-Cdc20-APC/C Complexes, Ensuring Efficient Cdc20 Ubiquitination and Checkpoint Arrest.

    Science.gov (United States)

    May, Karen M; Paldi, Flora; Hardwick, Kevin G

    2017-04-24

    During mitosis, cells must segregate the replicated copies of their genome to their daughter cells with extremely high fidelity. Segregation errors lead to an abnormal chromosome number (aneuploidy), which typically results in disease or cell death [1]. Chromosome segregation and anaphase onset are initiated through the action of the multi-subunit E3 ubiquitin ligase known as the anaphase-promoting complex or cyclosome (APC/C [2]). The APC/C is inhibited by the spindle checkpoint in the presence of kinetochore attachment defects [3, 4]. Here we demonstrate that two non-essential APC/C subunits (Apc14 and Apc15) regulate association of spindle checkpoint proteins, in the form of the mitotic checkpoint complex (MCC), with the APC/C. apc14Δ mutants display increased MCC association with the APC/C and are unable to silence the checkpoint efficiently. Conversely, apc15Δ mutants display reduced association between the MCC and APC/C, are defective in poly-ubiquitination of Cdc20, and are checkpoint defective. In vitro reconstitution studies have shown that human MCC-APC/C can contain two molecules of Cdc20 [5-7]. Using a yeast strain expressing two Cdc20 genes with different epitope tags, we show by co-immunoprecipitation that this is true in vivo. MCC binding to the second molecule of Cdc20 is mediated via the C-terminal KEN box in Mad3. Somewhat surprisingly, complexes containing both molecules of Cdc20 accumulate in apc15Δ cells, and the implications of this observation are discussed. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  15. Avelumab: combining immune checkpoint inhibition and antibody-dependent cytotoxicity.

    Science.gov (United States)

    Hamilton, Gerhard; Rath, Barbara

    2017-04-01

    Immune checkpoint inhibition holds great promise for selected tumors. The human monoclonal antibody (mAB) avelumab is directed to programmed death ligand-1 (PD-L1) and is supposed to inhibit the immunosuppressive PD-L1/PD-1 interaction and, furthermore, effect antibody-dependent cytotoxicity (ADCC) lysis of tumor cells. Areas covered: This article presents an overview of the current means to activate the antitumor immune defense by targeting PD-1 or PD-L1 with mABs and their possible role in ADCC-mediated tumor cell elimination. Expert opinion: Avelumab contains a Fc region which can bind cognate receptors on immune effector cells and induce ADCC-mediated tumor cell lysis, in contrast to other mABs directed to PD-1/PD-L1 which lack the ability to trigger ADCC due to belonging to the IgG4 subclass or possessing a mutated Fc region. Preclinical and clinical data indicate that avelumab can be safely administered to cancer patients with a toxicity profile comparable to other mABs and without lysis of PD-L1-positive activated immune cells. This antibody yielded durable responses in a phase II trial in advanced Merkel cell carcinoma patients. Tumor cell lysis by avelumab prevents cells from resorting to alternative checkpoints as shown by targeting PD-1 and the upregulation of TIM-3.

  16. Proficiency Test SYKE 8/2012. Volatile organic compounds in water and soil

    OpenAIRE

    Korhonen-Ylönen, Kaija; Nuutinen, Jari; Leivuori, Mirja; Ilmakunnas, Markku

    2013-01-01

    Proftest SYKE carried out the proficiency test for analysis of volatile organic compounds from water and soil in October 2012. One artificial sample and one river water sample and one soil sample were distributed. In total, 15 laboratories participated in the proficiency test. Either the calculated concentration or the robust mean value was chosen to be the assigned value for the measurement. The performance of the participants was evaluated by using z scores. In this proficiency test 72 % of...

  17. The internal Cdc20 binding site in BubR1 facilitates both spindle assembly checkpoint signalling and silencing

    DEFF Research Database (Denmark)

    Lischetti, Tiziana; Zhang, Gang; Sedgwick, Garry G

    2014-01-01

    Improperly attached kinetochores activate the spindle assembly checkpoint (SAC) and by an unknown mechanism catalyse the binding of two checkpoint proteins, Mad2 and BubR1, to Cdc20 forming the mitotic checkpoint complex (MCC). Here, to address the functional role of Cdc20 kinetochore localization...... in the SAC, we delineate the molecular details of its interaction with kinetochores. We find that BubR1 recruits the bulk of Cdc20 to kinetochores through its internal Cdc20 binding domain (IC20BD). We show that preventing Cdc20 kinetochore localization by removal of the IC20BD has a limited effect...... on the SAC because the IC20BD is also required for efficient SAC silencing. Indeed, the IC20BD can disrupt the MCC providing a mechanism for its role in SAC silencing. We thus uncover an unexpected dual function of the second Cdc20 binding site in BubR1 in promoting both efficient SAC signalling and SAC...

  18. Disruption of spindle checkpoint function in rats following 28 days of repeated administration of renal carcinogens.

    Science.gov (United States)

    Kimura, Masayuki; Mizukami, Sayaka; Watanabe, Yousuke; Hasegawa-Baba, Yasuko; Onda, Nobuhiko; Yoshida, Toshinori; Shibutani, Makoto

    2016-02-01

    We previously reported that 28-day exposure to hepatocarcinogens that facilitate cell proliferation specifically alters the expression of G1/S checkpoint-related genes and proteins, induces aberrant early expression of ubiquitin D (UBD) at the G2 phase, and increases apoptosis in the rat liver, indicating G1/S and spindle checkpoint dysfunction. The present study aimed to determine the time of onset of carcinogen-specific cell-cycle disruption after repeated administration of renal carcinogens for up to 28 days. Rats were orally administered the renal carcinogens nitrofurantoin (NFT), 1-amino-2,4-dibromoantraquinone (ADAQ), and 1,2,3-trichloropropane (TCP) or the non-carcinogenic renal toxicants 1-chloro-2-propanol, triamterene, and carboxin for 3, 7 or 28 days. Both immunohistochemical single-molecule analysis and real-time RT-PCR analysis revealed that carcinogen-specific expression changes were not observed after 28 days of administration. However, the renal carcinogens ADAQ and TCP specifically reduced the number of cells expressing phosphorylated-histone H3 at Ser10 in both UBD(+) cells and proliferating cells, suggestive of insufficient UBD expression at the M phase and early transition of proliferating cells from the M phase, without increasing apoptosis, after 28 days of administration. In contrast, NFT, which has marginal carcinogenic potential, did not induce such cellular responses. These results suggest that it may take 28 days to induce spindle checkpoint dysfunction by renal carcinogens; however, induction of apoptosis may not be essential. Thus, induction of spindle checkpoint dysfunction may be dependent on carcinogenic potential of carcinogen examined, and marginal carcinogens may not exert sufficient responses even after 28 days of administration.

  19. DW-MRI as a Predictive Biomarker of Radiosensitization of GBM through Targeted Inhibition of Checkpoint Kinases.

    Science.gov (United States)

    Williams, Terence M; Galbán, Stefanie; Li, Fei; Heist, Kevin A; Galbán, Craig J; Lawrence, Theodore S; Holland, Eric C; Thomae, Tami L; Chenevert, Thomas L; Rehemtulla, Alnawaz; Ross, Brian D

    2013-04-01

    The inherent treatment resistance of glioblastoma (GBM) can involve multiple mechanisms including checkpoint kinase (Chk1/2)-mediated increased DNA repair capability, which can attenuate the effects of genotoxic chemotherapies and radiation. The goal of this study was to evaluate diffusion-weighted magnetic resonance imaging (DW-MRI) as a biomarker for Chk1/2 inhibitors in combination with radiation for enhancement of treatment efficacy in GBM. We evaluated a specific small molecule inhibitor of Chk1/2, AZD7762, in combination with radiation using in vitro human cell lines and in vivo using a genetically engineered GBM mouse model. DW-MRI and T1-contrast MRI were used to follow treatment effects on intracranial tumor cellularity and growth rates, respectively. AZD7762 inhibited clonal proliferation in a panel of GBM cell lines and increased radiosensitivity in p53-mutated GBM cell lines to a greater extent compared to p53 wild-type cells. In vivo efficacy of AZD7762 demonstrated a dose-dependent inhibitory effect on GBM tumor growth rate and a reduction in tumor cellularity based on DW-MRI scans along with enhancement of radiation efficacy. DW-MRI was found to be a useful imaging biomarker for the detection of radiosensitization through inhibition of checkpoint kinases. Chk1/2 inhibition resulted in antiproliferative activity, prevention of DNA damage-induced repair, and radiosensitization in preclinical GBM tumor models, both in vitro and in vivo. The effects were found to be maximal in p53-mutated GBM cells. These results provide the rationale for integration of DW-MRI in clinical translation of Chk1/2 inhibition with radiation for the treatment of GBM.

  20. An Accounting Writing Proficiency Survey

    Science.gov (United States)

    Firch, Tim; Campbell, Annhenrie; Filling, Steven; Lindsay, David H.

    2011-01-01

    Although there has been much discussion about improving college student writing with college-level courses, little is known about how accounting programs, in particular, are addressing the writing proficiency challenge. This study surveys the 852 accounting programs in the United States to identify the frequency and types of accounting writing…

  1. Language Learning Strategies and English Proficiency: Interpretations from Information-Processing Theory

    Science.gov (United States)

    Rao, Zhenhui

    2016-01-01

    The research reported here investigated the relationship between students' use of language learning strategies and their English proficiency, and then interpreted the data from two models in information-processing theory. Results showed that the students' English proficiency significantly affected their use of learning strategies, with high-level…

  2. 76 FR 81958 - Notice of Submission of Proposed Information Collection to OMB; Limited English Proficiency...

    Science.gov (United States)

    2011-12-29

    ... Proposed Information Collection to OMB; Limited English Proficiency Initiative (LEPI) Program AGENCY... that support the assistance of persons with limited English proficiency in utilizing the services...: Limited English Proficiency Initiative (LEPI) Program. OMB Approval Number: 2529-0051. Form Numbers...

  3. Asymmetric Translation between Multiple Representations in Chemistry

    Science.gov (United States)

    Lin, Yulan I.; Son, Ji Y.; Rudd, James A., II

    2016-01-01

    Experts are more proficient in manipulating and translating between multiple representations (MRs) of a given concept than novices. Studies have shown that instruction using MR can increase student understanding of MR, and one model for MR instruction in chemistry is the chemistry triplet proposed by Johnstone. Concreteness fading theory suggests…

  4. From Universal Access to Universal Proficiency.

    Science.gov (United States)

    Lewis, Anne C.

    2003-01-01

    Panel of five education experts--Elliot Eisner, John Goodlad, Patricia Graham, Phillip Schlechty, and Warren Simons--answer questions related to recent school reform efforts, such as the No Child Left Behind Act, aimed at achieving universal educational proficiency. (PKP)

  5. EXPLORING THE RELATION OF STUDENTS’ LANGUAGE PROFICIENCY, ONLINE INSTRUCTOR GUIDANCE, AND ONLINE COLLABORATION WITH THEIR LEARNING IN HONG KONG BILINGUAL CYBER EDUCATION

    Directory of Open Access Journals (Sweden)

    Simon Wong

    2015-12-01

    Full Text Available This research study adopted a quantitative approach to explore how the variables, namely student’s English proficiency, online instructor guidance, and online collaboration, influence the learning effectiveness of the students taking an online introductory information technology course in cyber education in a bilingual higher education institution in Hong Kong. This study is important for cyber education administrators, as it investigated the important pedagogical quality of cyber education. Correlation analysis was conducted to identify whether any of these variables collected from the survey could be associated with students’ online learning while multiple regression analysis was used to explore the combined effect of these variables on students’ online learning. Validity and reliability of this study are highlighted in this paper. The major findings in this study revealed that (1 the students’ English proficiency, online instructor guidance, and online collaboration are potential factors contributing to the students’ online learning, and (2 the students’ English proficiency has the largest effect while online instructor guidance and online collaboration have a moderate effect on the students’ online learning.

  6. Development and Validation of the Spanish-English Language Proficiency Scale (SELPS)

    Science.gov (United States)

    Smyk, Ekaterina; Restrepo, M. Adelaida; Gorin, Joanna S.; Gray, Shelley

    2013-01-01

    Purpose: This study examined the development and validation of a criterion-referenced Spanish-English Language Proficiency Scale (SELPS) that was designed to assess the oral language skills of sequential bilingual children ages 4-8. This article reports results for the English proficiency portion of the scale. Method: The SELPS assesses syntactic…

  7. Students’ Perceived Level of English Proficiency in Secondary Schools in Dodoma, Tanzania

    Directory of Open Access Journals (Sweden)

    Lazarus Ndiku Makewa

    2013-07-01

    Full Text Available This paper looked at students’ perceived level of English proficiency among Dodoma secondary schools in Tanzania. Factors like attitude, anxiety, classroom activities, motivation, and learning resources were considered as influencing English learning. The study was guided by three theories: Input Hypothesis, Inter-language and Vygotsky’s theory of value. Correlation design was used to describe the association between the student and teacher-related factors and students’ perceived level of English proficiency. Purposive sampling was used to select 300 form three students. Questionnaires were used to collect data from the participants. Reliability of the research instrument was determined by conducting a pilot study. Pearson Descriptive statistics and Kendall’s Tau-b were used to analyze the data. The study revealed that the students’ perceived level of proficiency in spoken English was average. The findings indicated a significant positive correlation between perceived English proficiency and attitude toward the English language, classroom activities, teacher motivation, and classroom environment. It is suggested that further studies integrate qualitative research methods to the research design in order to get an in-depth understanding of students’ perception on English proficiency.

  8. Deficiency of the Arabidopsis helicase RTEL1 triggers a SOG1-dependent replication checkpoint in response to DNA cross-links.

    Science.gov (United States)

    Hu, Zhubing; Cools, Toon; Kalhorzadeh, Pooneh; Heyman, Jefri; De Veylder, Lieven

    2015-01-01

    To maintain genome integrity, DNA replication is executed and regulated by a complex molecular network of numerous proteins, including helicases and cell cycle checkpoint regulators. Through a systematic screening for putative replication mutants, we identified an Arabidopsis thaliana homolog of human Regulator of Telomere Length 1 (RTEL1), which functions in DNA replication, DNA repair, and recombination. RTEL1 deficiency retards plant growth, a phenotype including a prolonged S-phase duration and decreased cell proliferation. Genetic analysis revealed that rtel1 mutant plants show activated cell cycle checkpoints, specific sensitivity to DNA cross-linking agents, and increased homologous recombination, but a lack of progressive shortening of telomeres, indicating that RTEL1 functions have only been partially conserved between mammals and plants. Surprisingly, RTEL1 deficiency induces tolerance to the deoxynucleotide-depleting drug hydroxyurea, which could be mimicked by DNA cross-linking agents. This resistance does not rely on the essential replication checkpoint regulator WEE1 but could be blocked by a mutation in the SOG1 transcription factor. Taken together, our data indicate that RTEL1 is required for DNA replication and that its deficiency activates a SOG1-dependent replication checkpoint. © 2015 American Society of Plant Biologists. All rights reserved.

  9. Checkpoint inhibitors in cancer immunotherapy: Cross reactivity of a CTLA-4 antibody and IDO-inhibitor L-1MT in pigs

    DEFF Research Database (Denmark)

    Al-Shatrawi, Zina Adil; Frøsig, Thomas Mørch; Jungersen, Gregers

    a non-specific activation of porcine T cells. This will be further investigated to provide the basis for in vivo studies investigating checkpoint inhibitor blockade in combination with other cancer immunotherapies. Eventually our goal is to establish pigs as an alternative large animal model......Blockade of checkpoint inhibitors has recently shown very convincing results in the treatment of cancer. One key target is CTLA-4, which has been demonstrated to be a potent negative regulator of lymphocyte activation. The treatment with the FDA-approved fully human CTLA-4 monoclonal antibody...... Ipilimumab increases anticancer T-cell reactivity and overall survival of metastatic cancer patients. Indole-amine 2,3-dioxygenase (IDO) is another checkpoint inhibitor which suppresses T-cell immunity by the depletion of tryptophan in the T-cell microenvironment, and also inhibition of IDO by L-1...

  10. National proficiency-gain curves for minimally invasive gastrointestinal cancer surgery.

    Science.gov (United States)

    Mackenzie, H; Markar, S R; Askari, A; Ni, M; Faiz, O; Hanna, G B

    2016-01-01

    Minimal access surgery for gastrointestinal cancer has short-term benefits but is associated with a proficiency-gain curve. The aim of this study was to define national proficiency-gain curves for minimal access colorectal and oesophagogastric surgery, and to determine the impact on clinical outcomes. All adult patients undergoing minimal access oesophageal, colonic and rectal surgery between 2002 and 2012 were identified from the Hospital Episode Statistics database. Proficiency-gain curves were created using risk-adjusted cumulative sum analysis. Change points were identified, and bootstrapping was performed with 1000 iterations to identify a confidence level. The primary outcome was 30-day mortality; secondary outcomes were 90-day mortality, reintervention, conversion and length of hospital stay. Some 1696, 15 008 and 16 701 minimal access oesophageal, rectal and colonic cancer resections were performed during the study period. The change point in the proficiency-gain curve for 30-day mortality for oesophageal, rectal and colonic surgery was 19 (confidence level 98·4 per cent), 20 (99·2 per cent) and three (99·5 per cent) procedures; the mortality rate fell from 4·0 to 2·0 per cent (relative risk reduction (RRR) 0·50, P = 0·033), from 2·1 to 1·2 per cent (RRR 0·43, P curve for reintervention in oesophageal, rectal and colonic resection was 19 (98·1 per cent), 32 (99·5 per cent) and 26 (99·2 per cent) procedures respectively. There were also significant proficiency-gain curves for 90-day mortality, conversion and length of stay. The introduction of minimal access gastrointestinal cancer surgery has been associated with a proficiency-gain curve for mortality and major morbidity at a national level. Unnecessary patient harm should be avoided by appropriate training and monitoring of new surgical techniques. © 2015 BJS Society Ltd Published by John Wiley & Sons Ltd.

  11. Case report on the role of radiofrequency-assisted spleen-preserving surgery for splenic metastasis in the era of check-point inhibitors.

    Science.gov (United States)

    Mudan, Satvinder; Kumar, Jayant; Mafalda, Neves C; Kusano, Tomokazu; Reccia, Isabella; Zanallato, Artur; Dalgleish, Angus; Habib, Nagy

    2017-12-01

    An isolated splenic metastasis is a rare phenomenon noted in advanced stage melanoma. We report the role of radiofrequency (RF) -based splenic-preserving splenectomy in a patient with a solitary splenic metastasis from advanced stage melanoma that was managed with checkpoint inhibitors. We report a case of a 60-year-old man who presented with multiple lung metastases and a solitary splenic metastasis with advanced stage melanoma following excision of primary from his trunk 2.3 years back. Considering the diagnosis of advanced stage melanoma with multiple lung metastases and a solitary splenic metastasis, and its ongoing progressive nature. This case was discussed in the tumour board meeting. A decision was made to commence treatment with immunotherapy in the form of PD-1 inhibitor (programmed cell death 1 receptor) pembrolizumab. Follow-up restaging computer tomography (CT) scan of the abdomen and chest showed a significant reduction in the lung and chest wall lesions, but the splenic lesion remained unchanged. Given the lack of response to treatment in the splenic metastasis and the significant decrease in lung metastases, the multidisciplinary team decided that a partial splenectomy combined with continued immunotherapy treatment would be appropriate as the success of immunotherapy was imminent within the splenic preservation. The postoperative recovery was smooth and the patient was discharged from hospital on the sixth postoperative day with normal platelets and white blood cells. The histopathological analysis of the resected specimen showed a metastatic melanoma with negative margins.At 10-month follow-up after the splenic resection the patient had not experienced further tumour recurrences. Spleen-preserving resection for an isolated, solitary splenic metastasis of melanoma is a feasible approach as it not only preserves the ongoing efficacy of checkpoint inhibitors by preserving the physiological T cell milieu, but the immunomodulation properties of RF can

  12. Adventures in Scaffold Morphing: Discovery of Fused Ring Heterocyclic Checkpoint Kinase 1 (CHK1) Inhibitors.

    Science.gov (United States)

    Yang, Bin; Vasbinder, Melissa M; Hird, Alexander W; Su, Qibin; Wang, Haixia; Yu, Yan; Toader, Dorin; Lyne, Paul D; Read, Jon A; Breed, Jason; Ioannidis, Stephanos; Deng, Chun; Grondine, Michael; DeGrace, Nancy; Whitston, David; Brassil, Patrick; Janetka, James W

    2018-02-08

    Checkpoint kinase 1 (CHK1) inhibitors are potential cancer therapeutics that can be utilized for enhancing the efficacy of DNA damaging agents. Multiple small molecule CHK1 inhibitors from different chemical scaffolds have been developed and evaluated in clinical trials in combination with chemotherapeutics and radiation treatment. Scaffold morphing of thiophene carboxamide ureas (TCUs), such as AZD7762 (1) and a related series of triazoloquinolines (TZQs), led to the identification of fused-ring bicyclic CHK1 inhibitors, 7-carboxamide thienopyridines (7-CTPs), and 7-carboxamide indoles. X-ray crystal structures reveal a key intramolecular noncovalent sulfur-oxygen interaction in aligning the hinge-binding carboxamide group to the thienopyridine core in a coplanar fashion. An intramolecular hydrogen bond to an indole NH was also effective in locking the carboxamide in the preferred bound conformation to CHK1. Optimization on the 7-CTP series resulted in the identification of lead compound 44, which displayed respectable drug-like properties and good in vitro and in vivo potency.

  13. Motor proficiency in normal children and with learning difficulty: a comparative and correlational study based on the motor proficiency test of Bruininks-Oseretsky

    Directory of Open Access Journals (Sweden)

    Nilson Roberto Moreira

    2008-06-01

    Full Text Available The aim of this investigation is to verify the difference between children with learning disabilities and children without learning disabilities through motor proficiency test of Bruininks and Ozeretsky (1978. The sample was constituted by 30 children, with 8-year average age, 15 males and 15 females, subdivided into two groups of 15 children from both sexes: children without learning disabilities attending 3rd grade and children with learning disabilities attending 2nd grade having failed a term once. All of them came from a middle class background, according to Grafar scale (adapted by Fonseca, 1991. All children presenting any other disabilities were excluded from the sample. Intelligence factor “G” was controlled by using a percentile, higher or equal to 50 (middle and high level, measured by Raven’s (1974 progressive combinations test. In motor proficiency, children with learning disabilities showed significant differences when compared with normal children of the same age, in all components of global, composed and fine motricity. The tests administered showed a strong correlation between the variables of the motor proficiency components. The results lead to the conclusion that there were significant differences in motor proficiency between normal children and children with learning disabilities, who showed specific motor difficulties evincing a more vulnerable motor profile and not the presence of neurological dysfunction signs.

  14. Effect of Patternmaker’s Proficiency On the Creation of Clothing

    Directory of Open Access Journals (Sweden)

    Kim Kyoungok

    2017-06-01

    Full Text Available The effect of the patternmaker’s proficiency on the creation of clothing was investigated by the observation of the patternmaking process for clothing that satisfies the designer. We asked Japanese and French patternmakers to make a clothing pattern for the same design. The reasons for the differences in resultant clothing patterns and toiles made by the two patternmakers are discussed. Although the patternmaking processes used by the proficient patternmakers were similar, the resultant patterns were different owing to different recognition of the design. In particular, the shape and size of the collar that the designer emphasized in the illustration were different in the resultant patterns. Differences in patternmaking originated from differences in the patternmakers′ levels of expertise in terms of education, experience, and proficiency. However, the designer was satisfied with both patterns.

  15. GE Fanuc推出Proficy Historian 3.0

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    GE基础设施旗下的GE Fanuc自动化美洲公司推出了全新的ProficyTM Historian版本3.0个全新的厂级数据历史库版本。ProficyTM Historian 3.0能采集、归档并发布所有的实时现场生产数据,使用起来非常方便,可用性很高。凭藉Proficy Historian,制造商可以有效地从多个数据源采集并聚合实时工厂数据。对于诸如因设备故障和产品质量存在问题而造成的非满意事件,它能快速找出根本原因以实现最佳绩效。

  16. Measuring receptive collocational competence across proficiency ...

    African Journals Online (AJOL)

    Kate H

    frequency bands. A proficiency measure and a collocation test were administered to English ... battery may negatively impact the test-takers' performance. ..... examples. The major finding is that raising learners' awareness constitutes the best way forward ..... Amsterdam: John Benjamins Publishing Company. Green, R.

  17. In vitro analysis of the role of replication protein A (RPA) and RPA phosphorylation in ATR-mediated checkpoint signaling.

    Science.gov (United States)

    Lindsey-Boltz, Laura A; Reardon, Joyce T; Wold, Marc S; Sancar, Aziz

    2012-10-19

    Replication protein A (RPA) plays essential roles in DNA metabolism, including replication, checkpoint, and repair. Recently, we described an in vitro system in which the phosphorylation of human Chk1 kinase by ATR (ataxia telangiectasia mutated and Rad3-related) is dependent on RPA bound to single-stranded DNA. Here, we report that phosphorylation of other ATR targets, p53 and Rad17, has the same requirements and that RPA is also phosphorylated in this system. At high p53 or Rad17 concentrations, RPA phosphorylation is inhibited and, in this system, RPA with phosphomimetic mutations cannot support ATR kinase function, whereas a non-phosphorylatable RPA mutant exhibits full activity. Phosphorylation of these ATR substrates depends on the recruitment of ATR and the substrates by RPA to the RPA-ssDNA complex. Finally, mutant RPAs lacking checkpoint function exhibit essentially normal activity in nucleotide excision repair, revealing RPA separation of function for checkpoint and excision repair.

  18. In Vitro Analysis of the Role of Replication Protein A (RPA) and RPA Phosphorylation in ATR-mediated Checkpoint Signaling*

    Science.gov (United States)

    Lindsey-Boltz, Laura A.; Reardon, Joyce T.; Wold, Marc S.; Sancar, Aziz

    2012-01-01

    Replication protein A (RPA) plays essential roles in DNA metabolism, including replication, checkpoint, and repair. Recently, we described an in vitro system in which the phosphorylation of human Chk1 kinase by ATR (ataxia telangiectasia mutated and Rad3-related) is dependent on RPA bound to single-stranded DNA. Here, we report that phosphorylation of other ATR targets, p53 and Rad17, has the same requirements and that RPA is also phosphorylated in this system. At high p53 or Rad17 concentrations, RPA phosphorylation is inhibited and, in this system, RPA with phosphomimetic mutations cannot support ATR kinase function, whereas a non-phosphorylatable RPA mutant exhibits full activity. Phosphorylation of these ATR substrates depends on the recruitment of ATR and the substrates by RPA to the RPA-ssDNA complex. Finally, mutant RPAs lacking checkpoint function exhibit essentially normal activity in nucleotide excision repair, revealing RPA separation of function for checkpoint and excision repair. PMID:22948311

  19. Loss of p53 induces M-phase retardation following G2 DNA damage checkpoint abrogation.

    Science.gov (United States)

    Minemoto, Yuzuru; Uchida, Sanae; Ohtsubo, Motoaki; Shimura, Mari; Sasagawa, Toshiyuki; Hirata, Masato; Nakagama, Hitoshi; Ishizaka, Yukihito; Yamashita, Katsumi

    2003-04-01

    Most cell lines that lack functional p53 protein are arrested in the G2 phase of the cell cycle due to DNA damage. When the G2 checkpoint is abrogated, these cells are forced into mitotic catastrophe. A549 lung adenocarcinoma cells, in which p53 was eliminated with the HPV16 E6 gene, exhibited efficient arrest in the G2 phase when treated with adriamycin. Administration of caffeine to G2-arrested cells induced a drastic change in cell phenotype, the nature of which depended on the status of p53. Flow cytometric and microscopic observations revealed that cells that either contained or lacked p53 resumed their cell cycles and entered mitosis upon caffeine treatment. However, transit to the M phase was slower in p53-negative cells than in p53-positive cells. Consistent with these observations, CDK1 activity was maintained at high levels, along with stable cyclin B1, in p53-negative cells. The addition of butyrolactone I, which is an inhibitor of CDK1 and CDK2, to the p53-negative cells reduced the floating round cell population and induced the disappearance of cyclin B1. These results suggest a relationship between the p53 pathway and the ubiquitin-mediated degradation of mitotic cyclins and possible cross-talk between the G2-DNA damage checkpoint and the mitotic checkpoint.

  20. A Blueprint for Developing Culturally Proficient/Responsive School Administrators in Special Education

    Science.gov (United States)

    Bakken, Jeffrey P.; Smith, Beverly A.

    2011-01-01

    This article addresses the important topic of culturally proficient/responsive school administrators for culturally and linguistically diverse (CLD) students with learning disabilities (LD). Culturally proficient/responsive school administrators with knowledge and strong leadership skills in multicultural education are essential to impact school…

  1. Proficiency testing schemes as a quality rating in industrial hygiene laboratories

    Directory of Open Access Journals (Sweden)

    Marek Dobecki

    2016-04-01

    Full Text Available This publication presents the principles of organization, implementation, assessment and exploitation of proficiency testing results in the work environmental laboratory based on basic requirements included in standard PN-EN ISO/IEC 17043 and ISO 13528. The basis for the proper functioning of the laboratory is to use and observe the basic requirements for the competence to carry out the tests and the guidelines on ensuring reliable and accurate results, specified e.g., according to the guidelines described in the standard PN-EN ISO/IEC 17043. The confirmation of the laboratory competence is the obtained accreditation. To obtain this certificate several conditions, including proficiency testing (PT should be met. The main aspects of this paper is to show the role of proficiency testing in the process of assuring a properly functioning quality system in the laboratory. The accreditation requirements, the types of proficiency testing schemes, methods of statistical analysis and interpretation of results are also discussed by the authors. Med Pr 2016;67(2:267–283

  2. Predictors and Outcomes of Early vs. Later English Language Proficiency Among English Language Learners

    Science.gov (United States)

    Halle, Tamara; Hair, Elizabeth; Wandner, Laura; McNamara, Michelle; Chien, Nina

    2011-01-01

    The development of English language learners (ELLs) was explored from kindergarten through eighth grade within a nationally representative sample of first-time kindergartners (N = 19,890). Growth curve analyses indicated that, compared to native English speakers, ELLs were rated by teachers more favorably on approaches to learning, self control, and externalizing behaviors in kindergarten and generally continued to grow in a positive direction on these social/behavioral outcomes at a steeper rate compared to their native English-speaking peers, holding other factors constant. Differences in reading and math achievement between ELLs and native English speakers varied based on the grade at which English proficiency is attained. Specifically, ELLs who were proficient in English by kindergarten entry kept pace with native English speakers in both reading and math initially and over time; ELLs who were proficient by first grade had modest gaps in reading and math achievement compared to native English speakers that closed narrowly or persisted over time; and ELLs who were not proficient by first grade had the largest initial gaps in reading and math achievement compared to native speakers but the gap narrowed over time in reading and grew over time in math. Among those whose home language is not English, acquiring English proficiency by kindergarten entry was associated with better cognitive and behavioral outcomes through eighth grade compared to taking longer to achieve proficiency. Multinomial regression analyses indicated that child, family, and school characteristics predict achieving English proficiency by kindergarten entry compared to achieving proficiency later. Results are discussed in terms of policies and practices that can support ELL children’s growth and development. PMID:22389551

  3. Does childhood motor skill proficiency predict adolescent fitness?

    Science.gov (United States)

    Barnett, Lisa M; Van Beurden, Eric; Morgan, Philip J; Brooks, Lyndon O; Beard, John R

    2008-12-01

    To determine whether childhood fundamental motor skill proficiency predicts subsequent adolescent cardiorespiratory fitness. In 2000, children's proficiency in a battery of skills was assessed as part of an elementary school-based intervention. Participants were followed up during 2006/2007 as part of the Physical Activity and Skills Study, and cardiorespiratory fitness was measured using the Multistage Fitness Test. Linear regression was used to examine the relationship between childhood fundamental motor skill proficiency and adolescent cardiorespiratory fitness controlling for gender. Composite object control (kick, catch, throw) and locomotor skill (hop, side gallop, vertical jump) were constructed for analysis. A separate linear regression examined the ability of the sprint run to predict cardiorespiratory fitness. Of the 928 original intervention participants, 481 were in 28 schools, 276 (57%) of whom were assessed. Two hundred and forty-four students (88.4%) completed the fitness test. One hundred and twenty-seven were females (52.1%), 60.1% of whom were in grade 10 and 39.0% were in grade 11. As children, almost all 244 completed each motor assessments, except for the sprint run (n = 154, 55.8%). The mean composite skill score in 2000 was 17.7 (SD 5.1). In 2006/2007, the mean number of laps on the Multistage Fitness Test was 50.5 (SD 24.4). Object control proficiency in childhood, adjusting for gender (P = 0.000), was associated with adolescent cardiorespiratory fitness (P = 0.012), accounting for 26% of fitness variation. Children with good object control skills are more likely to become fit adolescents. Fundamental motor skill development in childhood may be an important component of interventions aiming to promote long-term fitness.

  4. 14 CFR 61.98 - Flight proficiency.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false Flight proficiency. 61.98 Section 61.98 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRMEN...) Navigation; (viii) Slow flight and stalls; (ix) Emergency operations; and (x) Postflight procedures. (2) For...

  5. 14 CFR 61.107 - Flight proficiency.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false Flight proficiency. 61.107 Section 61.107 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRMEN... reference maneuvers; (vii) Navigation; (viii) Slow flight and stalls; (ix) Basic instrument maneuvers; (x...

  6. 14 CFR 61.127 - Flight proficiency.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false Flight proficiency. 61.127 Section 61.127 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRMEN...; (x) High-altitude operations; and (xi) Postflight procedures. (2) For an airplane category rating...

  7. Clinical features, predictive correlates, and pathophysiology of immune-related adverse events in immune checkpoint inhibitor treatments in cancer: a short review

    OpenAIRE

    Yoest, Jennifer M

    2017-01-01

    Jennifer M Yoest Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA Abstract: Identification and characterization of T-cell regulatory mechanisms, or checkpoints, have led to a wave of drug development aimed at inhibiting these targets to “remove the brakes” of the immune system. This class of anticancer therapeutics, termed immune checkpoint inhibitors (ICIs), has harnessed the potential of the body’s own immune system to reco...

  8. First year evaluation of EPA's radon contractor proficiency (RCP) program

    International Nuclear Information System (INIS)

    Salmon, G.L.

    1990-01-01

    This paper reports that the Environmental Protection Agency (EPA) has developed a voluntary program to evaluate radon reduction contractors and provide this information to the public, as part of activities mandated by the Indoor Radon Abatement Act (IRAA) of 1988. The Radon Contractor Proficiency Program consists of several elements that collectively help to ensure the proficiency of radon mitigators and give the public greater confidence in their capability. Contractors who participate in the program must pass a written examination, adhere to mitigation guidelines, keep records of work, meet continuing education requirements and pass a re-examination every two years. Upon meeting the program's requirements, mitigators are listed in EPA's National RCP Proficiency Report. The first Report released on May 15, 1990 listed 636 contractors. The second Report, to be release in August, will list 895 contractors, representing an increase of 40 per cent

  9. Evaluating the spoken English proficiency of graduates of foreign medical schools.

    Science.gov (United States)

    Boulet, J R; van Zanten, M; McKinley, D W; Gary, N E

    2001-08-01

    The purpose of this study was to gather additional evidence for the validity and reliability of spoken English proficiency ratings provided by trained standardized patients (SPs) in high-stakes clinical skills examination. Over 2500 candidates who took the Educational Commission for Foreign Medical Graduates' (ECFMG) Clinical Skills Assessment (CSA) were studied. The CSA consists of 10 or 11 timed clinical encounters. Standardized patients evaluate spoken English proficiency and interpersonal skills in every encounter. Generalizability theory was used to estimate the consistency of spoken English ratings. Validity coefficients were calculated by correlating summary English ratings with CSA scores and other external criterion measures. Mean spoken English ratings were also compared by various candidate background variables. The reliability of the spoken English ratings, based on 10 independent evaluations, was high. The magnitudes of the associated variance components indicated that the evaluation of a candidate's spoken English proficiency is unlikely to be affected by the choice of cases or SPs used in a given assessment. Proficiency in spoken English was related to native language (English versus other) and scores from the Test of English as a Foreign Language (TOEFL). The pattern of the relationships, both within assessment components and with external criterion measures, suggests that valid measures of spoken English proficiency are obtained. This result, combined with the high reproducibility of the ratings over encounters and SPs, supports the use of trained SPs to measure spoken English skills in a simulated medical environment.

  10. Measures for Determining English Language Proficiency and the Resulting Implications for Instructional Provision and Intervention

    Science.gov (United States)

    Albers, Craig A.; Kenyon, Dorry M.; Boals, Timothy J.

    2009-01-01

    Although numerous English language proficiency (ELP) measures currently exist, many were developed prior to the No Child Left Behind Act of 2001 (NCLB). These pre-NCLB measures typically focused on social language proficiency, whereas post-NCLB measures are linked to ELP standards and focus on academic language proficiency (ALP). ELP measures are…

  11. Roles of nibrin and ATM/ATR kinases on the G2 checkpoint under endogenous or radio-induced DNA damage

    Directory of Open Access Journals (Sweden)

    Katherine Marcelain

    2005-01-01

    Full Text Available Checkpoint response to DNA damage involves the activation of DNA repair and G2 lengthening subpathways. The roles of nibrin (NBS1 and the ATM/ATR kinases in the G2 DNA damage checkpoint, evoked by endogenous and radio-induced DNA damage, were analyzed in control, A-T and NBS lymphoblast cell lines. Short-term responses to G2 treatments were evaluated by recording changes in the yield of chromosomal aberrations in the ensuing mitosis, due to G2 checkpoint adaptation, and also in the duration of G2 itself. The role of ATM/ATR in the G2 checkpoint pathway repairing chromosomal aberrations was unveiled by caffeine inhibition of both kinases in G2. In the control cell lines, nibrin and ATM cooperated to provide optimum G2 repair for endogenous DNA damage. In the A-T cells, ATR kinase substituted successfully for ATM, even though no G2 lengthening occurred. X-ray irradiation (0.4 Gy in G2 increased chromosomal aberrations and lengthened G2, in both mutant and control cells. However, the repair of radio-induced DNA damage took place only in the controls. It was associated with nibrin-ATM interaction, and ATR did not substitute for ATM. The absence of nibrin prevented the repair of both endogenous and radio-induced DNA damage in the NBS cells and partially affected the induction of G2 lengthening.

  12. It Really Works: Cultural Communication Proficiency.

    Science.gov (United States)

    Bennett, Ruth, Ed.

    This paper describes the cultural communication proficiency method of indigenous language instruction, developed at Humboldt State University's Center for Indian Community Development (California), and demonstrates the method with five Hupa lesson plans. The method is based on three principles: that Native American students learn by doing, learn…

  13. Developing Adaptive Proficiency in Special Forces Officers

    National Research Council Canada - National Science Library

    White, Susan S; Mueller-Hanson, Rose A; Dorsey, David W; Pulakos, Elaine D; Wisecarver, Michelle M; Deagle, Edwin A., III; Mendini, Kip G

    2005-01-01

    Adaptive proficiency is critical for operating in the dynamic Special Forces (SF) mission environment and a recent focus on this requirement has resulted in a greater emphasis on adaptability in current training for SF...

  14. Proficiency test in the accreditation system

    International Nuclear Information System (INIS)

    Legarda, F.; Herranz, M.; Idoeta, R.

    2008-01-01

    In the accreditation process of a radioactivity measurements laboratory, according to ISO standard 17025, proficiency tests play a fundamental role. These PTs constitute an irreplaceable tool for the validation of measuring methods. In the case of Spain, ENAC, which is the Spanish accreditation national body, requires that the laboratory has to take part in a PT for each one of the accredited measuring methods in the period of time between two reassessments of the accreditation, what happens every 4-5 years. In specific areas of determination procedures, among which radioactive measurements could be included, the number of methods which can be accredited is very large. The purpose of the present work is to establish a classification into families of the different radioactivity measurement procedures, as well as to establish complementary actions that guarantee that carrying out periodically proficiency-tests on any of the included procedures in each family, every measurement procedure include in that family is controlled, complying with the criteria established by ENAC

  15. Constitutive Cdk2 activity promotes aneuploidy while altering the spindle assembly and tetraploidy checkpoints

    DEFF Research Database (Denmark)

    Jahn, Stephan C; Corsino, Patrick E; Davis, Bradley J

    2013-01-01

    instability. Expression of these complexes in the MCF10A cell line leads to retinoblastoma protein (Rb) hyperphosphorylation, a subsequent increase in proliferation rate, and increased expression of the spindle assembly checkpoint protein Mad2. This results in a strengthening of the spindle assembly...

  16. Fine motor skill proficiency in typically developing children: On or off the maturation track?

    Science.gov (United States)

    Gaul, David; Issartel, Johann

    2016-04-01

    Fine motor skill proficiency is an essential component of numerous daily living activities such as dressing, feeding or playing. Poor fine motor skills can lead to difficulties in academic achievement, increased anxiety and poor self-esteem. Recent findings have shown that children's gross motor skill proficiency tends to fall below established developmental norms. A question remains: do fine motor skill proficiency levels also fall below developmental norms? The aim of this study was to examine the current level of fine motor skill in Irish children. Children (N=253) from 2nd, 4th and 6th grades (mean age=7.12, 9.11 and 11.02 respectively) completed the Fine Motor Composite of the Bruininks Oseretsky Test of Motor Proficiency 2nd Edition (BOT-2). Analysis revealed that only 2nd grade children met the expected level of fine motor skill proficiency. It was also found that despite children's raw scores improving with age, children's fine motor skill proficiency was not progressing at the expected rate given by normative data. This leads us to question the role and impact of modern society on fine motor skills development over the past number of decades. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. LOGICAL CONDITIONS ANALYSIS METHOD FOR DIAGNOSTIC TEST RESULTS DECODING APPLIED TO COMPETENCE ELEMENTS PROFICIENCY

    Directory of Open Access Journals (Sweden)

    V. I. Freyman

    2015-11-01

    Full Text Available Subject of Research.Representation features of education results for competence-based educational programs are analyzed. Solution importance of decoding and proficiency estimation for elements and components of discipline parts of competences is shown. The purpose and objectives of research are formulated. Methods. The paper deals with methods of mathematical logic, Boolean algebra, and parametrical analysis of complex diagnostic test results, that controls proficiency of some discipline competence elements. Results. The method of logical conditions analysis is created. It will give the possibility to formulate logical conditions for proficiency determination of each discipline competence element, controlled by complex diagnostic test. Normalized test result is divided into noncrossing zones; a logical condition about controlled elements proficiency is formulated for each of them. Summarized characteristics for test result zones are imposed. An example of logical conditions forming for diagnostic test with preset features is provided. Practical Relevance. The proposed method of logical conditions analysis is applied in the decoding algorithm of proficiency test diagnosis for discipline competence elements. It will give the possibility to automate the search procedure for elements with insufficient proficiency, and is also usable for estimation of education results of a discipline or a component of competence-based educational program.

  18. Molecular basis of APC/C regulation by the spindle assembly checkpoint

    Science.gov (United States)

    Zhang, Ziguo; Yang, Jing; Maslen, Sarah; Skehel, Mark; Barford, David

    2016-01-01

    In the dividing eukaryotic cell the spindle assembly checkpoint (SAC) ensures each daughter cell inherits an identical set of chromosomes. The SAC coordinates the correct attachment of sister chromatid kinetochores to the mitotic spindle with activation of the anaphase-promoting complex/cyclosome (APC/C), the E3 ubiquitin ligase that initiates chromosome separation. In response to unattached kinetochores, the SAC generates the mitotic checkpoint complex (MCC), a multimeric assembly that inhibits the APC/C, delaying chromosome segregation. Here, using cryo-electron microscopy we determined the near-atomic resolution structure of an APC/C-MCC complex (APC/CMCC). We reveal how degron-like sequences of the MCC subunit BubR1 block degron recognition sites on Cdc20, the APC/C coactivator subunit (Cdc20APC/C) responsible for substrate interactions. BubR1 also obstructs binding of UbcH10 (APC/C’s initiating E2) to repress APC/C ubiquitination activity. Conformational variability of the complex allows for UbcH10 association, and we show from a structure of APC/CMCC in complex with UbcH10 how the Cdc20 subunit intrinsic to the MCC (Cdc20MCC) is ubiquitinated, a process that results in APC/C reactivation when the SAC is silenced. PMID:27509861

  19. Proficiency training on a virtual reality robotic surgical skills curriculum.

    Science.gov (United States)

    Bric, Justin; Connolly, Michael; Kastenmeier, Andrew; Goldblatt, Matthew; Gould, Jon C

    2014-12-01

    The clinical application of robotic surgery is increasing. The skills necessary to perform robotic surgery are unique from those required in open and laparoscopic surgery. A validated laparoscopic surgical skills curriculum (Fundamentals of Laparoscopic Surgery or FLS™) has transformed the way surgeons acquire laparoscopic skills. There is a need for a similar skills training and assessment tool for robotic surgery. Our research group previously developed and validated a robotic training curriculum in a virtual reality (VR) simulator. We hypothesized that novice robotic surgeons could achieve proficiency levels defined by more experienced robotic surgeons on the VR robotic curriculum, and that this would result in improved performance on the actual daVinci Surgical System™. 25 medical students with no prior robotic surgery experience were recruited. Prior to VR training, subjects performed 2 FLS tasks 3 times each (Peg Transfer, Intracorporeal Knot Tying) using the daVinci Surgical System™ docked to a video trainer box. Task performance for the FLS tasks was scored objectively. Subjects then practiced on the VR simulator (daVinci Skills Simulator) until proficiency levels on all 5 tasks were achieved before completing a post-training assessment of the 2 FLS tasks on the daVinci Surgical System™ in the video trainer box. All subjects to complete the study (1 dropped out) reached proficiency levels on all VR tasks in an average of 71 (± 21.7) attempts, accumulating 164.3 (± 55.7) minutes of console training time. There was a significant improvement in performance on the robotic FLS tasks following completion of the VR training curriculum. Novice robotic surgeons are able to attain proficiency levels on a VR simulator. This leads to improved performance in the daVinci surgical platform on simulated tasks. Training to proficiency on a VR robotic surgery simulator is an efficient and viable method for acquiring robotic surgical skills.

  20. Self-Efficacy Ratings of Technology Proficiency among Teachers in Mexico and Texas

    Science.gov (United States)

    Morales, Cesareo; Knezek, Gerald; Christensen, Rhonda

    2008-01-01

    The Technology Proficiency Self-Assessment (TPSA) questionnaire was administered to 978 elementary and middle school teachers from Mexico City, and 932 elementary and middle school teachers from the Dallas, Texas, metroplex in the USA, in order to examine self-efficacy similarities and differences for technology proficiency self-appraisals in a…

  1. Issues in Vertical Scaling of a K-12 English Language Proficiency Test

    Science.gov (United States)

    Kenyon, Dorry M.; MacGregor, David; Li, Dongyang; Cook, H. Gary

    2011-01-01

    One of the mandates of the No Child Left Behind Act is that states show adequate yearly progress in their English language learners' (ELLs) acquisition of English language proficiency. States are required to assess ELLs' English language proficiency annually in four language domains (listening, reading, writing, and speaking) to measure their…

  2. Self-Assessment, Preparation and Response Time on a Computerized Oral Proficiency Test

    Science.gov (United States)

    Malabonga, Valerie; Kenyon, Dorry M.; Carpenter, Helen

    2005-01-01

    Two studies investigated technical aspects of a computer-mediated test, the Computerized Oral Proficiency Instrument (COPI), particularly in contrast to a similar tape-mediated test, the Simulated Oral Proficiency Interview (SOPI). The first study investigated how examinees used self-assessment to choose an appropriate starting level on the COPI.…

  3. The Impact of Problem-Based Learning on Iranian EFL Learners’ Speaking Proficiency

    Directory of Open Access Journals (Sweden)

    Loghman Ansarian

    2016-06-01

    Full Text Available The study investigated the effect of problem-based learning through cognition-based tasks on speaking proficiency of Iranian intermediate EFL learners in comparison to the effect of objective-based tasks. To this end, a true experimental research design was employed. Ninety five (N=95 language learners studying at a language institute in the city of Esfahan, Iran were given an IELTS listening and speaking test as the proficiency test and 75 learners were selected. In the next phase of the study, a second IELTS speaking test was administered as the homogeneity test and the pre-test to seventy five (N=75 learners chosen from the population and forty-eight (N=48 homogeneous intermediate learners were selected for the study (i.e., 24 learners in control group and 24 in experimental one. The results of an independent-sample t-test gained from the study proved that not only does implementation of problem-based learning through cognition-based tasks significantly increased intermediate participants’ speaking proficiency, but also it had more positive effect in comparison to objective-based tasks on participants’ speaking proficiency. Therefore, it is suggested that problem-based learning ought to be taken into account by educational scholars, those in charge of syllabus, material producers, language teachers and language learners. Keywords: Cognition-Based Tasks, Objective-Based Tasks, EFL Learners, Speaking Proficiency, Problem-Based Learning

  4. Singing proficiency in the majority: normality and "phenotypes" of poor singing.

    Science.gov (United States)

    Dalla Bella, Simone; Berkowska, Magdalena

    2009-07-01

    Recent evidence indicates that the majority of occasional singers can carry a tune. For example, when asked to sing a well-known song (e.g., "Happy Birthday"), nonmusicians performing at a slow tempo are as proficient as professional singers. Yet, some occasional singers are poor singers, mostly in the pitch domain, and sometimes despite not having impoverished perception. Poor singing is not a monolithic deficit, but is likely to be characterized by a diversity of singing "phenotypes." Here we systematically examined singing proficiency in a group of occasional singers, with the goal of characterizing the different patterns of poor singing. Participants sang three well-known melodies (e.g., "Jingle Bells") at a natural tempo and at a slow tempo, as indicated by a metronome. For each rendition, we computed objective measures of pitch and time accuracy with an acoustical method. The results confirmed previous observations that the majority of occasional singers can sing in tune and in time. Moreover, singing at a slow tempo after the target melody to be imitated was presented with a metronome improved pitch and time accuracy. In general, poor singers were mostly impaired on the pitch dimension, although various patterns of impairment emerged. Pitch accuracy or time accuracy could be selectively impaired; moreover, absolute measures of singing proficiency (pitch or tempo transposition) dissociated from relative measures of proficiency (pitch intervals, relative duration). These patterns of dissociations point to a multicomponent system underlying proficient singing that fractionates as a result of a developmental anomaly.

  5. L2-proficiency-dependent laterality shift in structural connectivity of brain language pathways

    NARCIS (Netherlands)

    Xiang, H.; Leeuwen, T.M. van; Dediu, D.; Roberts, L.; Norris, D.; Hagoort, P.

    2015-01-01

    Diffusion tensor imaging (DTI) and a longitudinal language learning approach were applied to investigate the relationship between the achieved second language (L2) proficiency during L2 learning and the reorganization of structural connectivity between core language areas. Language proficiency tests

  6. L2-Proficiency-Dependent Laterality Shift in Structural Connectivity of Brain Language Pathways

    NARCIS (Netherlands)

    Xiang, Huadong; van Leeuwen, Tessa Marije; Dediu, Dan; Roberts, Leah; Norris, David G.; Hagoort, Peter

    2015-01-01

    Diffusion tensor imaging (DTI) and a longitudinal language learning approach were applied to investigate the relationship between the achieved second language (L2) proficiency during L2 learning and the reorganization of structural connectivity between core language areas. Language proficiency tests

  7. Biological significance of the focus on DNA damage checkpoint factors remained after irradiation of ionizing radiation

    International Nuclear Information System (INIS)

    Yamauchi, Motohiro; Suzuki, Keiji

    2005-01-01

    This paper reviews recent reports on the focus formation and participation to checkpoint of (such phosphorylated (P-d) as below) ATM and H2AX, MDC1, 53BP1 and NBS1, and discusses their role in DNA damage checkpoint induction mainly around authors' studies. When the cell is irradiated by ionizing radiation, the subtype histone like H2AX is P-d and the formed focus', seen in the nucleus on immuno-fluorographic observation, represents the P-d H2AX at the damaged site of DNA. The role of P-d ATM (the product of causative gene of ataxia-telangiectasia mutation, a protein kinase) has been first shown by laser beam irradiation. Described are discussions on the roles and functions after irradiation in focus formation and DNA damage checkpoint of P-d H2AX (a specific histone product by the radiation like γ-ray as above), P-d ATM, MDC1 (a mediator of DNA damage check point protein 1), 53BP1, (a p53 binding protein) and NBS1 (the product of the causative gene of Nijmegen Breakage Syndrome). Authors have come to point out the remained focal size increase as implications of the efficient repair of damaged DNA, and the second cycled p53 accumulation, of tumor suppression. Thus evaluation of biological significance of these aspects, scarcely noted hitherto, is concluded important. (S.I.)

  8. Research on the proficient machine system. Theoretical part; Jukutatsu machine system no chosa kenkyu. Rironhen

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1996-03-01

    The basic theory of the proficient machine system to be developed was studied. Important proficient techniques in manufacturing industries are becoming extinct because of insufficient succession to next generation. The proficient machine system was proposed to cope with such situation. This machine system includes the mechanism for progress and evolution of techniques and sensibilities to be adaptable to environmental changes by learning and recognizing various motions such as work and process. Consequently, the basic research fields are composed of thought, learning, perception and action. This machine requires not only deigned fixed functions but also introduction of the same proficient concept as human being to be adaptable to changes in situation, purpose, time and machine`s complexity. This report explains in detail the basic concept, system principle, approaching procedure and practical elemental technologies of the proficient machine system, and also describes the future prospect. 133 refs., 110 figs., 7 tabs.

  9. Gaining Proficiency through Task-Based Activities in the Portuguese Classroom (Beginning and Intermediate Year Case Studies)

    Science.gov (United States)

    Jones-Kellogg, Rebecca

    2015-01-01

    This paper describes a task-based activity used at the United States Military Academy, in their first- through third-semester Portuguese language sequence "Proficiencies" (Proficiências). The stand-alone task-based activity can be an effective tool in gaining foreign-language proficiency at even the lowest levels of classroom instruction…

  10. Incorporation of proficiency criteria for basic laparoscopic skills training: How does it work?

    NARCIS (Netherlands)

    E. Verdaasdonk (Egg); J. Dankelman (Jenny); J.F. Lange (Johan); L.P. Stassen (Laurents)

    2008-01-01

    textabstractBackground: It is desirable that surgical trainees are proficient in basic laparoscopic motor skills (eye-hand coordination). The present study evaluated the use of predefined proficiency criteria on a basic virtual reality (VR) simulator in preparation for a laparoscopic course on

  11. School-Age Test Proficiency and Special Education After Congenital Heart Disease Surgery in Infancy.

    Science.gov (United States)

    Mulkey, Sarah B; Bai, Shasha; Luo, Chunqiao; Cleavenger, Jordyn E; Gibson, Neal; Holland, Greg; Mosley, Bridget S; Kaiser, Jeffrey R; Bhutta, Adnan T

    2016-11-01

    To evaluate test proficiency and the receipt of special education services in school-age children who had undergone surgery for congenital heart disease (CHD) at age Education longitudinal database containing achievement test scores in literacy and mathematics for grades 3-4 and special education codes. The primary negative outcome was not achieving grade-level proficiency on achievement tests. Logistic regression accounting for repeated measures was used to evaluate for associations between achieving proficiency and demographic data, maternal education, and clinical factors. A total of 362 of 458 (79%) children who underwent surgery for CHD were matched to the Arkansas Department of Education database, 285 of whom had grade 3 and/or 4 achievement tests scores. Fewer students with CHD achieved proficiency in literacy and mathematics (P education predicted proficiency in literacy (P special education services (26.9% vs 11.6%; P special education services than all state students. Results from this study support the need for neurodevelopmental evaluations as standard practice in children with CHD. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Design Optimization of Time- and Cost-Constrained Fault-Tolerant Embedded Systems with Checkpointing and Replication

    DEFF Research Database (Denmark)

    Pop, Paul; Izosimov, Viacheslav; Eles, Petru

    2009-01-01

    We present an approach to the synthesis of fault-tolerant hard real-time systems for safety-critical applications. We use checkpointing with rollback recovery and active replication for tolerating transient faults. Processes and communications are statically scheduled. Our synthesis approach deci...

  13. Hi-LAB: A New Measure of Aptitude for High-Level Language Proficiency

    Science.gov (United States)

    Linck, Jared A.; Hughes, Meredith M.; Campbell, Susan G.; Silbert, Noah H.; Tare, Medha; Jackson, Scott R.; Smith, Benjamin K.; Bunting, Michael F.; Doughty, Catherine J.

    2013-01-01

    Few adult second language (L2) learners successfully attain high-level proficiency. Although decades of research on beginning to intermediate stages of L2 learning have identified a number of predictors of the rate of acquisition, little research has examined factors relevant to predicting very high levels of L2 proficiency. The current study,…

  14. Non-Discriminatory Assessment: Formal and Informal Assessment of Limited English Proficient Children.

    Science.gov (United States)

    Mares, Sharon

    PEOPLE (Pruebas de Expresion Oral y Percepcion de la Lengua Espanol) was developed as a test to help distinguish between a language difference and a language deficit in non English proficient (NEP) and limited English proficient (LEP) elementary Hispanic students. PEOPLE was developed, pilot tested in 14 school districts in Los Angeles County with…

  15. Physical activity and movement skills proficiency of young Filipino children.

    Science.gov (United States)

    Capio, Catherine M; Sit, Cindy H P; Eguia, Kathlynne F; Abernethy, Bruce

    2014-08-01

    Recent reports indicate an increasing prevalence of overweight among Filipino children. Considering the known association of physical activity (PA) with obesity, this study reports the findings of an objective monitoring of PA in a sample of Filipino children. The study also explores the relationship of PA with fundamental movement skills (FMS) proficiency. Thirty-two children (6.54 ± 2.45 years old) wore an accelerometer for 7 days of PA monitoring and were assessed on five FMS (throw, catch, kick, run, jump). The children met the World Health Organization's recommendation of 60 min of PA per day, with more active time being accrued during weekdays than weekends. Children with greater FMS proficiency were found to spend more time in PA than those who were less skillful during weekends. Further research is recommended to examine PA and FMS proficiency associations, exploring the role of social interactions on weekends and weekdays. © 2014 Japan Pediatric Society.

  16. THE OBSERVATION OF TEACHER CANDIDATE RELATED SCIENCE AND TECHNOLOGY TEACHER'S PROFICIENCY

    OpenAIRE

    BAHŞİ, Muammer; TURAN, Mehmet; YILAYAZ, Ömer

    2009-01-01

    In this study it is evaluated science and tecnology teacher's proficiency based on students insights of science and tecnology education students in education faculty. It was used Standarts for Teacher Proficiency which is prepared from Ministry of National Education. The research was conducted on 85 Science and Tecnology students (4th classes) studying at the education faculty of Firat University. Data from results of study was analysed by using SPSS.

  17. Preferential radiosensitization of G1 checkpoint--deficient cells by methylxanthines

    International Nuclear Information System (INIS)

    Russell, Kenneth J.; Wiens, Linda W.; Demers, G. William; Galloway, Denise A.; Le, Tiep; Rice, Glenn C.; Bianco, James A.; Singer, Jack W.; Groudine, Mark

    1996-01-01

    Purpose: To develop a checkpoint-based strategy for preferential radiosensitization of human tumors with deficient and/or mutant p53. Methods and Materials: A549 human lung adenocarcinoma cell lines differing in their expression of the p53 tumor suppressor gene were produced by transduction with the E6 oncogene from human papilloma virus type 16. The cells expressing E6 (E6+) lack a G1 arrest in response to ionizing radiation, are deficient in p53 and p21 expression, and exhibit a fivefold greater clonogenic survival following 10 Gy radiation. Results: Postirradiation incubation with millimolar concentrations of the methylxanthine pentoxifylline (PTX) results in preferential radiosensitization of the E6+ cells compared to the LXSN+ vector transduced controls. There is a threefold sensitization of the LXSN+ cells and a 15-fold sensitization of the E6+ cells, which results in equal clonogenic survival of the two lines. Flow cytometry reveals PTX abrogation of the radiation induced G2 arrest for both cell lines. PTX also prolongs G1 transit for both cell lines. Preliminary results are presented using a novel methylxanthine, lisofylline (LSF), which has similar cell cycle effects on G1 and G2 and achieves differential radiosensitization at micromolar concentrations that are sustainable in humans. Conclusions: This checkpoint-based strategy is a promising approach for achieving preferential radiosensitization of p53- tumors relative to p53+ normal tissues

  18. The flavonoid eupatorin inactivates the mitotic checkpoint leading to polyploidy and apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Salmela, Anna-Leena [VTT Technical Research Centre of Finland, Medical Biotechnology, P.O. Box 106, Turku (Finland); Turku Graduate School of Biomedical Sciences, Turku (Finland); Turku Centre for Biotechnology, P.O. Box 123, University of Turku (Finland); Pouwels, Jeroen; Kukkonen-Macchi, Anu [VTT Technical Research Centre of Finland, Medical Biotechnology, P.O. Box 106, Turku (Finland); Waris, Sinikka; Toivonen, Pauliina [Turku Centre for Biotechnology, P.O. Box 123, University of Turku (Finland); Jaakkola, Kimmo [VTT Technical Research Centre of Finland, Medical Biotechnology, P.O. Box 106, Turku (Finland); Maeki-Jouppila, Jenni [VTT Technical Research Centre of Finland, Medical Biotechnology, P.O. Box 106, Turku (Finland); Turku Centre for Biotechnology, P.O. Box 123, University of Turku (Finland); Drug Discovery Graduate School, University of Turku (Finland); Kallio, Lila, E-mail: lila.kallio@vtt.fi [VTT Technical Research Centre of Finland, Medical Biotechnology, P.O. Box 106, Turku (Finland); Kallio, Marko J. [VTT Technical Research Centre of Finland, Medical Biotechnology, P.O. Box 106, Turku (Finland); Turku Centre for Biotechnology, P.O. Box 123, University of Turku (Finland); Centre of Excellence for Translational Genome-Scale Biology, P.O. Box 106, Academy of Finland (Finland)

    2012-03-10

    The spindle assembly checkpoint (SAC) is a conserved mechanism that ensures the fidelity of chromosome distribution in mitosis by preventing anaphase onset until the correct bipolar microtubule-kinetochore attachments are formed. Errors in SAC function may contribute to tumorigenesis by inducing numerical chromosome anomalies (aneuploidy). On the other hand, total disruption of SAC can lead to massive genomic imbalance followed by cell death, a phenomena that has therapeutic potency. We performed a cell-based high-throughput screen with a compound library of 2000 bioactives for novel SAC inhibitors and discovered a plant-derived phenolic compound eupatorin (3 Prime ,5-dihydroxy-4 Prime ,6,7-trimethoxyflavone) as an anti-mitotic flavonoid. The premature override of the microtubule drug-imposed mitotic arrest by eupatorin is dependent on microtubule-kinetochore attachments but not interkinetochore tension. Aurora B kinase activity, which is essential for maintenance of normal SAC signaling, is diminished by eupatorin in cells and in vitro providing a mechanistic explanation for the observed forced mitotic exit. Eupatorin likely has additional targets since eupatorin treatment of pre-mitotic cells causes spindle anomalies triggering a transient M phase delay followed by impaired cytokinesis and polyploidy. Finally, eupatorin potently induces apoptosis in multiple cancer cell lines and suppresses cancer cell proliferation in organotypic 3D cell culture model.

  19. EFL Speech Production: Exploring the relationship between working memory capacity and proficiency level

    Directory of Open Access Journals (Sweden)

    Gicele Vergine Vieira PREBIANCA

    2013-12-01

    Full Text Available The present study explores the relationship between working memory capacity (WMC and proficiency level in EFL1 speech production. Forty-one participants performed two WMC tests – the Speaking Span Test in L1 and in L2. The statistical analysis indicated both a variation on WMC scores in L2 as a function of proficiency as well as a difference between WMC scores in L1 and in L2. Findings are explained mainly in respect to the interplay between automatic and controlled processes on memory retrieval and on the development of L2 proficiency.

  20. Effect of salt-inducible kinase 2 on checkpoint in response to γ-ray irradiation

    International Nuclear Information System (INIS)

    Yin Jiaojiao; Zhou Lijun; Wang Yu; Liu Xiaodan; Gu Yongqing; Zhou Pingkun

    2014-01-01

    Objective: To investigate the effect of salt-induced kinase 2 (SIK2) in the G_2/M checkpoint in response to ionizing radiation and the possible mechanism. Methods: HeLa cells were irradiated with "6"0Co γ-rays. The cell model of knockdown SIK2 expression was constrcuted by transfecting HeLa cells with a pSicoR-based lentivirus vector of expressing SIK2 shRNA by lipofectamin 2000. Western blot and flow cytometry were performed to measure the changes of SIK2 protein level and cell cycle distribution. The phosphorylated histone protein H3 on Ser 10 was used as a molecular marker of mitotic cells for detecting the function of G2/M checkpoint. Results: The expression level of SIK2 protein increased in HeLa cells after "6"0Co γ-ray irradiation. A cell model of knockdown SIK2 expression was successfully generated by transfecting the specific shRNA against SIK2. Depression of SIK2 significantly increased the cellular sensitivity at 1, 2, 4, 6 Gy post-irradiation (t = -3.445, -2.581, -3.251, -2.553, P < 0.05), and led cells to release earlier from the G_2/M boundary arrest compared to control cells at 5, 6 h post-irradiation(t = 4.341, 6.500, P < 0.05). Western blot analysis indicated that the irradiation-induced phosphorylated CHK2/T68 in SIK2 knock-down cells was earlier than that in control cells. Conclusions: salt-induced kinase 2 (SIK2) participates in the regulation of G_2/M checkpoint induced by ionizing radiation and affects cellular radiosensitivity. (authors)

  1. PROFICIENT CLASSROOM MANAGEMENT THROUGH FOCUSED MATHEMATIC TEACHING

    Directory of Open Access Journals (Sweden)

    Marcus Samuelsson

    2017-12-01

    Full Text Available A not entirely unusual position among teachers is that they believe that they must first establish a peaceful classroom before they can begin to teach the subject. This research, shows how a proficient mathematics teacher teaches his subject and thereby creates a quiet and focused classroom and exerts effective leadership, just by teaching mathematics. The researchers observed a male mathematics teacher for almost half a year, i.e. one semester. The results of research present several patterns that the researchers saw during the observations of his teaching. The teacher showed an interest in each student’s mathematical thinking and expressed explicitly how students were expected to learn mathematics. He also directed students’ attention to mathematics and established a culture where all solutions were important in the teaching process. In the teaching process, he used multiple representations to motivate students and a lot of supportive expressions that made them feel that they were able to learn mathematics. He worked patiently to establish structures, and there was almost no disruptive behaviour. Students simply did not have time to interfere because they were so engaged in learning mathematics.

  2. The relationship between fundamental movement skill proficiency and physical self-confidence among adolescents.

    Science.gov (United States)

    McGrane, Bronagh; Belton, Sarahjane; Powell, Danielle; Issartel, Johann

    2017-09-01

    This study aims to assess fundamental movement skill (FMS) proficiency, physical self-confidence levels, and the relationship between these variables and gender differences among adolescents. Three hundred and ninety five adolescents aged 13.78 years (SD = ±1.2) from 20 schools were involved in this study. The Test of Gross Motor Development-2nd Edition (TGMD), TGMD-2 and Victorian Skills Manual were used to assess 15 FMS. Participants' physical self-confidence was also assessed using a valid skill-specific scale. A significant correlation was observed between FMS proficiency and physical self-confidence for females only (r = 0.305, P < 0.001). Males rated themselves as having significantly higher physical self-confidence levels than females (P = 0.001). Males scored significantly higher than females in FMS proficiency (P < 0.05), and the lowest physical self-confidence group were significantly less proficient at FMS than the medium (P < 0.001) and high physical self-confidence groups (P < 0.05). This information not only highlights those in need of assistance to develop their FMS but will also facilitate in the development of an intervention which aims to improve physical self-confidence and FMS proficiency.

  3. Second language proficiency modulates conflict-monitoring in an oculomotor Stroop task: evidence from Hindi-English bilinguals.

    Directory of Open Access Journals (Sweden)

    Niharika eSingh

    2013-06-01

    Full Text Available Many studies have confirmed the presence of a bilingual advantage which is manifested as enhanced cognitive and attention control. However, very few studies have investigated the role of second language proficiency on the modulation of conflict-monitoring in bilinguals. We investigated this by comparing high and low proficient Hindi-English bilinguals on a modified saccadic arrow Stroop task under different monitoring conditions, and tested the predictions of the bilingual executive control advantage proposal. The task of the participants was to make an eye movement towards the colour patch in the same colour as the central arrow, ignoring the patch to which the arrow was pointing. High-proficient bilinguals had overall faster saccade latency on all types of trials as compared to the low proficient bilinguals. The overall saccadic latency for high proficiency bilinguals was similarly affected by the different types of monitoring conditions, whereas conflict resolution advantage was found only for high monitoring demanding condition. The results support a conflict-monitoring account in a novel oculomotor task and also suggest that language proficiency could modulate executive control in bilinguals.

  4. Tactical proficiency among table tennis players with and without intellectual disabilities.

    Science.gov (United States)

    Van Biesen, Debbie; Mactavish, Jennifer; Vanlandewijck, Yves

    2014-01-01

    The effect of intellectual impairment on sports performance has received limited attention by researchers. As a contribution to closing this gap, the purpose of the present investigation was to examine the differences in tactical proficiency between table tennis players with and without intellectual disabilities (ID). These groups were matched for training-volume and experience and consisted of 41 male (age = 27±8) and 30 female (age= 28±8) elite players with ID and a reference group of 12 male (age= 24±12) and 5 female (age= 20±9) players without ID. In two different test settings - one a World Championship and the other a training camp - the players in each group performed 60 semi-standardised rallies against the same opponent. Players were told that 12 sets of five identical services would be delivered, and their goal was to return the service with the intention of 'winning the point'. The test results were validated for this study, to compute tactical proficiency scores (maximal score of eight points) for each player. A two-way Analysis of Variance (ANOVA) revealed significantly lower proficiency scores for players with ID than for those without ID. Repeated-measures ANOVA revealed that within each series of five rallies, starting with identical services, all participants were able to significantly improve their tactical proficiency gradually, but players without ID scored 4.3±0.5 from the first ball on, and while athletes with ID only 3.3±0.7 after five balls. The results of this study indicate that ID is associated with decreased tactical proficiency in table tennis.

  5. Predictors of responses to immune checkpoint blockade in advanced melanoma

    DEFF Research Database (Denmark)

    Jacquelot, N; Roberti, M P; Enot, D P

    2017-01-01

    Immune checkpoint blockers (ICB) have become pivotal therapies in the clinical armamentarium against metastatic melanoma (MMel). Given the frequency of immune related adverse events and increasing use of ICB, predictors of response to CTLA-4 and/or PD-1 blockade represent unmet clinical needs....... Using a systems biology-based approach to an assessment of 779 paired blood and tumor markers in 37 stage III MMel patients, we analyzed association between blood immune parameters and the functional immune reactivity of tumor-infiltrating cells after ex vivo exposure to ICB. Based on this assay, we...

  6. Proficiency testing in the light of a new rationale in metrology

    DEFF Research Database (Denmark)

    Heydorn, Kaj

    2008-01-01

    The novel proposed definition of measurement result in the international metrology vocabulary requires a revision of standards and guidelines for proficiency testing (PT), and a new approach to processing proficiency data is needed to test the ability of laboratories to present not only unbiased...... quantity values, but reliable estimates of their uncertainty. Hence, an accepted reference value with the smallest possible uncertainty is needed to ascertain the proficiency of laboratories reporting results with lower than average uncertainty. A strategy based on the T-statistic is proposed leading...... to an accepted reference value that fully reflects the uncertainties reported by participants in a PT scheme and permits calculation of En-numbers to distinguish whether or not measurement results are consistent with the accepted definition of the measurand. The strategy is applied to PT data from a recent...

  7. Cell Phone Use and Child and Adolescent Reading Proficiency

    Science.gov (United States)

    Hofferth, Sandra L.; Moon, Ui Jeong

    2016-01-01

    This study examined the association between cell phone use, including minutes spent talking and number of text messages sent, and two measures of children’s reading proficiency — tests of word decoding and reading comprehension — in the United States. Data were drawn from the Child Development Supplement to the Panel Study of Income Dynamics, a nationally representative survey of 1,147 children 10–18 in 2009. Children whose parents were better educated, who had higher family incomes, who had fewer siblings, and who lived in urban areas were more likely to own or share a cell phone. Among those with access to a phone, children who spent more time talking on the phone were less proficient at word decoding, whereas children who spent more time sending text messages had greater reading comprehension. Although girls spent more time texting than did boys, there were no gender differences in the association between time spent talking or number of text messages sent with achievement. In spite of racial/ethnic differences in cell phone use levels, there were no racial/ethnic differences in the association between cell phone use and reading proficiency. PMID:27683624

  8. Motor Proficiency in Young Children

    Directory of Open Access Journals (Sweden)

    Fotini Venetsanou

    2016-01-01

    Full Text Available This study aimed to examine motor proficiency in young children, focusing on potential gender differences. For that purpose, the Bruininks-Oseretsky Test of Motor Proficiency–Long Form (BOTMP-LF was administered to 540 children (272 boys, 4½ to 6 years old. First, the 2 (sex × 4 (age groups ANOVA computed on children’s total BOTMP-LF scores showed that age had a statistically significant effect, whereas gender did not. Second, the one-way MANCOVA applied on subtest scores, with age as covariate, revealed statistical significant gender differences; however, η2 values were found to be small or moderate. Finally, the MANCOVA applied on items where significant gender differences have been reported showed a significant effect of gender. Nonetheless, η2 values exceeded the limit of practical significance only on two items (“standing on preferred leg on floor”, “throwing a ball at a target with preferred hand” that are associated with gender-stereotyped activities. It can be concluded that (a besides statistical significance, effect sizes should be examined for the results of a study to be adequately interpreted; (b young boys’ and girls’ motor proficiency is similar rather than different. Gender differences in specific skills should be used for movement programs to be individualized.

  9. Neuromuscular complications of immune checkpoint inhibitor therapy.

    Science.gov (United States)

    Kolb, Noah A; Trevino, Christopher R; Waheed, Waqar; Sobhani, Fatemeh; Landry, Kara K; Thomas, Alissa A; Hehir, Mike

    2018-01-17

    Immune checkpoint inhibitor (ICPI) therapy unleashes the body's natural immune system to fight cancer. ICPIs improve overall cancer survival, however, the unbridling of the immune system may induce a variety of immune-related adverse events. Neuromuscular immune complications are rare but they can be severe. Myasthenia gravis and inflammatory neuropathy are the most common neuromuscular adverse events but a variety of others including inflammatory myopathy are reported. The pathophysiologic mechanism of these autoimmune disorders may differ from that of non-ICPI-related immune diseases. Accordingly, while the optimal treatment for ICPI-related neuromuscular disorders generally follows a traditional paradigm, there are important novel considerations in selecting appropriate immunosuppressive therapy. This review presents 2 new cases, a summary of neuromuscular ICPI complications, and an approach to the diagnosis and treatment of these disorders. Muscle Nerve, 2018. © 2018 Wiley Periodicals, Inc.

  10. Direct and indirect control of the initiation of meiotic recombination by DNA damage checkpoint mechanisms in budding yeast.

    Directory of Open Access Journals (Sweden)

    Bilge Argunhan

    Full Text Available Meiotic recombination plays an essential role in the proper segregation of chromosomes at meiosis I in many sexually reproducing organisms. Meiotic recombination is initiated by the scheduled formation of genome-wide DNA double-strand breaks (DSBs. The timing of DSB formation is strictly controlled because unscheduled DSB formation is detrimental to genome integrity. Here, we investigated the role of DNA damage checkpoint mechanisms in the control of meiotic DSB formation using budding yeast. By using recombination defective mutants in which meiotic DSBs are not repaired, the effect of DNA damage checkpoint mutations on DSB formation was evaluated. The Tel1 (ATM pathway mainly responds to unresected DSB ends, thus the sae2 mutant background in which DSB ends remain intact was employed. On the other hand, the Mec1 (ATR pathway is primarily used when DSB ends are resected, thus the rad51 dmc1 double mutant background was employed in which highly resected DSBs accumulate. In order to separate the effect caused by unscheduled cell cycle progression, which is often associated with DNA damage checkpoint defects, we also employed the ndt80 mutation which permanently arrests the meiotic cell cycle at prophase I. In the absence of Tel1, DSB formation was reduced in larger chromosomes (IV, VII, II and XI whereas no significant reduction was found in smaller chromosomes (III and VI. On the other hand, the absence of Rad17 (a critical component of the ATR pathway lead to an increase in DSB formation (chromosomes VII and II were tested. We propose that, within prophase I, the Tel1 pathway facilitates DSB formation, especially in bigger chromosomes, while the Mec1 pathway negatively regulates DSB formation. We also identified prophase I exit, which is under the control of the DNA damage checkpoint machinery, to be a critical event associated with down-regulating meiotic DSB formation.

  11. Genetic variation in the major mitotic checkpoint genes associated with chromosomal aberrations in healthy humans

    Czech Academy of Sciences Publication Activity Database

    Försti, A.; Frank, Ch.; Smolková, B.; Kazimírová, A.; Barančoková, M.; Vymetálková, Veronika; Kroupa, M.; Naccarati, Alessio; Vodičková, Ludmila; Buchancová, J.; Dusinská, M.; Musak, L.; Vodička, Pavel; Hemminki, K.

    2016-01-01

    Roč. 380, č. 2 (2016), s. 442-446 ISSN 0304-3835 R&D Projects: GA ČR(CZ) GA15-14789S Institutional support: RVO:68378041 Keywords : chromosomal integrity * cytogenetics * spindle checkpoint Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 6.375, year: 2016

  12. The development and psychometric properties of the American sign language proficiency assessment (ASL-PA).

    Science.gov (United States)

    Maller, S; Singleton, J; Supalla, S; Wix, T

    1999-01-01

    We describe the procedures for constructing an instrument designed to evaluate children's proficiency in American Sign Language (ASL). The American Sign Language Proficiency Assessment (ASL-PA) is a much-needed tool that potentially could be used by researchers, language specialists, and qualified school personnel. A half-hour ASL sample is collected on video from a target child (between ages 6 and 12) across three separate discourse settings and is later analyzed and scored by an assessor who is highly proficient in ASL. After the child's language sample is scored, he or she can be assigned an ASL proficiency rating of Level 1, 2, or 3. At this phase in its development, substantial evidence of reliability and validity has been obtained for the ASL-PA using a sample of 80 profoundly deaf children (ages 6-12) of varying ASL skill levels. The article first explains the item development and administration of the ASL-PA instrument, then describes the empirical item analysis, standard setting procedures, and evidence of reliability and validity. The ASL-PA is a promising instrument for assessing elementary school-age children's ASL proficiency. Plans for further development are also discussed.

  13. Proficiency test for paracitides in salmon muscle

    NARCIS (Netherlands)

    Elbers, I.J.W.

    2012-01-01

    The aim of this proficiency study was to give laboratories the possibility to evaluate or demonstrate their competence for the analysis of parasiticides in salmon muscle. This study also provided an evaluation of the methods applied for the quantitative analysis of parasiticides in salmon muscle.

  14. A Review of Immune Checkpoint Inhibitors for the Management of Locally Advanced or Metastatic Urothelial Carcinoma.

    Science.gov (United States)

    Hanna, Kirollos S

    2017-11-01

    Urothelial carcinoma (UC) is the second most common malignancy of the genitourinary system and the sixth most common cancer in the United States. The overall incidence of UC appears to be on the decline, but death rates have remained stable. Stage IV metastatic disease is associated with only a 5% survival rate at 5 years. Gemcitabine and cisplatin combinations or dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin are the preferred regimens for individuals with advance, metastatic disease and a good performance status and organ function. Second-line therapies in this setting are limited. During the course of 1 year, five immune checkpoint inhibitors were approved for treatment of cancers in the locally advanced or metastatic setting: atezolizumab, nivolumab, durvalumab, avelumab, and pembrolizumab. Immunotherapies have played a significant role in the treatment of various cancers and have continued to expand. It is of utmost importance that practitioners include checkpoint inhibitors as treatment options for UC. Based on the limited data, pembrolizumab and atezolizumab may be the drugs of choice, as they are supported by the most influential data to date; however, further research is warranted. Ongoing clinical trials will further assess the benefits of inducing cellular immunity in the treatment of UC. These therapies mark a new landscape in the treatment of UC. In this article, the available data on immune checkpoint inhibitors for the treatment of locally advanced or metastatic UC and their place in therapy are reviewed. © 2017 Pharmacotherapy Publications, Inc.

  15. ELL High School Students' Metacognitive Awareness of Reading Strategy Use and Reading Proficiency

    Science.gov (United States)

    Hong-Nam, Kay

    2014-01-01

    This study investigated the metacognitive awareness and reading strategies use of high school-­aged English language learners (ELLs) and the relationship between ELL reading strategy use and reading proficiency as measured by a standardized reading test and self-­rated reading proficiency. Results reveal that participants reported moderate use of…

  16. English Proficiency and Acculturation among Chinese Immigrant Youth in Canada: A Reciprocal Relationship

    Science.gov (United States)

    Jia, Fanli; Gottardo, Alexandra; Chen, Xi; Koh, Pohwee; Pasquarella, Adrian

    2016-01-01

    The main focus of this study was to refine our understanding of the link between English proficiency and mainstream acculturation in adolescent Chinese immigrants. The sample consisted of 112 adolescents in grades 7-12 living in urban areas in southern Ontario, Canada. English proficiency was assessed individually using standardised tests of…

  17. Fundamental Motor Skill Proficiency of 6- to 9-Year-Old Singaporean Children.

    Science.gov (United States)

    Mukherjee, Swarup; Ting Jamie, Lye Ching; Fong, Leong Hin

    2017-06-01

    Fundamental movement proficiency (FMS) is most successfully acquired during early school years. This cross-sectional study assessed FMS proficiency in Singaporean children at the start of and following 2.5 years of primary school physical education (PE). Participants were 244 children from Primary 1 and 3 levels. Fundamental movement skills (FMS) were assessed with the Test of Gross Motor Development-Second Edition (TGMD-2) that includes locomotor (LOCO) and object control (OC) subtests. Most children were rated "average" and "below average" for LOCO skills but "poor" and "below average" for OC skills without significant gender differences on either subtest or overall FMS proficiency and without FMS mastery. These young Singaporean children failed to exhibit age-appropriate FMS proficiency despite early PE exposure, and they demonstrated lags in FMS compared with the TGMD-2 U.S. normative sample. We discuss implications for sports competence perception, difficulty in coping with later movement learning expectations and reduced later motivation to participate in PE and play. We also discuss implications for preschool and lower primary school PE curricula with a particular focus on both OC skills and LOCO skills requiring muscular fitness like hopping and jumping.

  18. The effect of tributyltin chloride on Caenorhabditis elegans germline is mediated by a conserved DNA damage checkpoint pathway.

    Science.gov (United States)

    Cheng, Zhe; Tian, Huimin; Chu, Hongran; Wu, Jianjian; Li, Yingying; Wang, Yanhai

    2014-03-21

    Tributyltin (TBT), one of the environmental pollutants, has been shown to impact the reproduction of animals. However, due to the lack of appropriate animal model, analysis of the affected molecular pathways in germ cells is lagging and has been particularly challenging. In the present study, we investigated the effects of tributyltin chloride (TBTCL) on the nematode Caenorhabditis elegans germline. We show that exposure of C. elegans to TBTCL causes significantly elevated level of sterility and embryonic lethality. TBTCL exposure results in an increased number of meiotic DNA double-strand breaks in germ cells, subsequently leading to activated DNA damage checkpoint. Exposing C. elegans to TBTCL causes dose- and time-dependent germline apoptosis. This apoptotic response was blocked in loss-of-function mutants of hus-1 (op241), mrt-2 (e2663) and p53/cep-1 (gk138), indicating that checkpoints and p53 are essential for mediating TBTCL-induced germ cell apoptosis. Moreover, TBTCL exposure can inhibit germ cell proliferation, which is also mediated by the conserved checkpoint pathway. We thereby propose that TBT exhibits its effects on the germline by inducing DNA damage and impaired maintenance of genomic integrity. Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  19. 40 CFR 798.5500 - Differential growth inhibition of repair proficient and repair deficient bacteria: “Bacterial DNA...

    Science.gov (United States)

    2010-07-01

    ... repair proficient and repair deficient bacteria: âBacterial DNA damage or repair tests.â 798.5500 Section... inhibition of repair proficient and repair deficient bacteria: “Bacterial DNA damage or repair tests.” (a... killing or growth inhibition of repair deficient bacteria in a set of repair proficient and deficient...

  20. Influence of English proficiency on patient-provider communication and shared decision-making.

    Science.gov (United States)

    Paredes, Anghela Z; Idrees, Jay J; Beal, Eliza W; Chen, Qinyu; Cerier, Emily; Okunrintemi, Victor; Olsen, Griffin; Sun, Steven; Cloyd, Jordan M; Pawlik, Timothy M

    2018-06-01

    The number of patients in the United States (US) who speak a language other than English is increasing. We evaluated the impact of English proficiency on self-reported patient-provider communication and shared decision-making. The 2013-2014 Medical Expenditure Panel Survey database was utilized to identify respondents who spoke a language other than English. Patient-provider communication (PPC) and shared decision-making (SDM) scores from 4-12 were categorized as "poor" (4-7), "average" (8-11), and "optimal." The relationship between PPC, SDM, and English proficiency was analyzed. Among 13,880 respondents, most were white (n = 10,281, 75%), age 18-39 (n = 6,677, 48%), male (n = 7,275, 52%), middle income (n = 4,125, 30%), and born outside of the US (n = 9,125, 65%). English proficiency was rated as "very well" (n = 7,221, 52%), "well" (n = 2,378, 17%), "not well" (n = 2,820, 20%), or "not at all" (n = 1,463, 10%). On multivariable analysis, patients who rated their English as "well" (OR 1.73, 95% CI 1.37-2.18) or "not well" (OR 1.53, 95% CI 1.10-2.14) were more likely to report "poor" PPC (both P English proficiency as "not well" (OR 1.31, 95% CI 1.04-1.65, P = .02). Decreased English proficiency was associated with worse self-reported patient-provider communication and shared decision-making. Attention to patients' language needs is critical to patient satisfaction and improved perception of care. Copyright © 2018 Elsevier Inc. All rights reserved.

  1. rad-Dependent response of the chk1-encoded protein kinase at the DNA damage checkpoint

    NARCIS (Netherlands)

    Walworth, N.C.; Bernards, R.A.

    1996-01-01

    Exposure of eukaryotic cells to agents that generate DNA damage results in transient arrest of progression through the cell cycle. In fission yeast, the DNA damage checkpoint associated with cell cycle arrest before mitosis requires the protein kinase p56chk1. DNA damage induced by ultraviolet

  2. Foreign language proficiency and working memory capacity

    NARCIS (Netherlands)

    Noort, M.W.M.L. van den; Bosch, M.P.C.; Hugdahl, K.

    2006-01-01

    In this study, the hypothesis that working memory capacity interacts with (foreign) language proficiency was tested on multilinguals, who were native (L1) Dutch speakers, were fluent in their second (L2) language, German, and had recently started the acquisition of their third (L3) language,

  3. Recommending a minimum English proficiency standard for entry-level nursing.

    Science.gov (United States)

    O'Neill, Thomas R; Tannenbaum, Richard J; Tiffen, Jennifer

    2005-01-01

    When nurses who are educated internationally immigrate to the United States, they are expected to have English language proficiency in order to function as a competent nurse. The purpose of this research was to provide sufficient information to the National Council of State Boards of Nursing (NCSBN) to make a defensible recommended passing standard for English proficiency. This standard was based upon the Test of English as a Foreign Language (TOEFL). A large panel of nurses and nurse regulators (N = 25) was convened to determine how much English proficiency is required to be minimally competent as an entry-level nurse. Two standard setting procedures, the Simulated Minimally Competent Candidate (SMCC) procedure and the Examinee Paper Selection Method, were combined to produce recommendations for each panelist. In conjunction with collateral information, these recommendations were reviewed by the NCSBN Examination Committee, which decided upon an NCSBN recommended standard, a TOEFL score of 220. Because the adoption of this standard rests entirely with the individual state, NCSBN has little more to do with implementing the standard, other than answering questions and providing documentation about the standard.

  4. The Reading Habits of Developmental College Students at Different Levels of Reading Proficiency.

    Science.gov (United States)

    Sheorey, Ravi; Mokhtari, Kouider

    1994-01-01

    Examines differences in reading habits of developmental college students with varying levels of reading proficiency. Finds that subjects spent an unusually low amount of time on academic reading and even less time on nonacademic reading. Finds no significant differences between high- and low-proficient readers with regard to amount of time spent…

  5. The relationship between self-efficacy and reading proficiency of first-year students: An exploratory study

    Directory of Open Access Journals (Sweden)

    Naomi A.N.Y. Boakye

    2015-04-01

    Full Text Available Self-efficacy, which is the belief about one’s ability to perform a task successfully, has been widely acknowledged as important in learning. This affective factor, though not explicitly evident, has been said to play an important role in academic performance. However, its role in reading development has not been widely investigated. To determine the relationship between self-efficacy and reading proficiency, a study was conducted with first-year students in a South African tertiary institution. Students’ self-efficacy levels were elicited through a questionnaire and their reading proficiency was obtained through the Test of Academic Literacy levels (TALL, which essentially assesses reading proficiency. An analysis of variance showed a robust relationship between reading self-efficacy and reading proficiency for this cohort of students. Regression analysis conducted with other affective factors showed self-efficacy as the best predictor of students’ reading proficiency. Results are discussed as they relate to previous research and recommendations are made to include the development of self-efficacy in reading instruction.

  6. Mutant p53 perturbs DNA replication checkpoint control through TopBP1 and Treslin.

    Science.gov (United States)

    Liu, Kang; Lin, Fang-Tsyr; Graves, Joshua D; Lee, Yu-Ju; Lin, Weei-Chin

    2017-05-09

    Accumulating evidence supports the gain-of-function of mutant forms of p53 (mutp53s). However, whether mutp53 directly perturbs the DNA replication checkpoint remains unclear. Previously, we have demonstrated that TopBP1 forms a complex with mutp53s and mediates their gain-of-function through NF-Y and p63/p73. Akt phosphorylates TopBP1 and induces its oligomerization, which inhibits its ATR-activating function. Here we show that various contact and conformational mutp53s bypass Akt to induce TopBP1 oligomerization and attenuate ATR checkpoint response during replication stress. The effect on ATR response caused by mutp53 can be exploited in a synthetic lethality strategy, as depletion of another ATR activator, DNA2, in mutp53-R273H-expressing cancer cells renders cells hypersensitive to cisplatin. Expression of mutp53-R273H also makes cancer cells more sensitive to DNA2 depletion or DNA2 inhibitors. In addition to ATR-activating function during replication stress, TopBP1 interacts with Treslin in a Cdk-dependent manner to initiate DNA replication during normal growth. We find that mutp53 also interferes with TopBP1 replication function. Several contact, but not conformational, mutp53s enhance the interaction between TopBP1 and Treslin and promote DNA replication despite the presence of a Cdk2 inhibitor. Together, these data uncover two distinct mechanisms by which mutp53 enhances DNA replication: ( i ) Both contact and conformational mutp53s can bind TopBP1 and attenuate the checkpoint response to replication stress, and ( ii ) during normal growth, contact (but not conformational) mutp53s can override the Cdk2 requirement to promote replication by facilitating the TopBP1/Treslin interaction.

  7. The application of data from proficiency testing to laboratory accreditation according to ISO 17025

    DEFF Research Database (Denmark)

    Heydorn, Kaj

    2008-01-01

    Current methods of testing laboratories for their proficiency in reporting correct measurement results are liable to substantial errors of the 2nd kind. This means that laboratories with deflated uncertainties are accepted as proficient, even though their reported measurement results pave the way...

  8. First Language Proficiency and Successful Foreign Language Learning: The Case of High School Students Learning French as a Foreign Language

    Science.gov (United States)

    Gnintedem, Antoine

    2014-01-01

    This study investigated whether there was a correlation between first language proficiency as measured by the Mississippi Curriculum Test (MCT II) Reading and Language Arts and foreign language proficiency as measured by the French Language Proficiency Test. Data for the independent variable, first language proficiency, was collected from the…

  9. Hepatic neuregulin 4 signaling defines an endocrine checkpoint for steatosis-to-NASH progression

    Science.gov (United States)

    Guo, Liang; Chen, Zhimin; Xia, Houjun; Li, Siming; Zhang, Yanqiao; Kobberup, Sune; Zou, Weiping; Lin, Jiandie D.

    2017-01-01

    Nonalcoholic steatohepatitis (NASH) is characterized by progressive liver injury, inflammation, and fibrosis; however, the mechanisms that govern the transition from hepatic steatosis, which is relatively benign, to NASH remain poorly defined. Neuregulin 4 (Nrg4) is an adipose tissue–enriched endocrine factor that elicits beneficial metabolic effects in obesity. Here, we show that Nrg4 is a key component of an endocrine checkpoint that preserves hepatocyte health and counters diet-induced NASH in mice. Nrg4 deficiency accelerated liver injury, fibrosis, inflammation, and cell death in a mouse model of NASH. In contrast, transgenic expression of Nrg4 in adipose tissue alleviated diet-induced NASH. Nrg4 attenuated hepatocyte death in a cell-autonomous manner by blocking ubiquitination and proteasomal degradation of c-FLIPL, a negative regulator of cell death. Adeno-associated virus–mediated (AAV-mediated) rescue of hepatic c-FLIPL expression in Nrg4-deficent mice functionally restored the brake for steatosis to NASH transition. Thus, hepatic Nrg4 signaling serves as an endocrine checkpoint for steatosis-to-NASH progression by activating a cytoprotective pathway to counter stress-induced liver injury. PMID:29106384

  10. Chronological age and its impact on associative learning proficiency and brain structure in middle adulthood.

    Science.gov (United States)

    Diwadkar, Vaibhav A; Bellani, Marcella; Ahmed, Rizwan; Dusi, Nicola; Rambaldelli, Gianluca; Perlini, Cinzia; Marinelli, Veronica; Ramaseshan, Karthik; Ruggeri, Mirella; Bambilla, Paolo

    2016-01-15

    The rate of biological change in middle-adulthood is relatively under-studied. Here, we used behavioral testing in conjunction with structural magnetic resonance imaging to examine the effects of chronological age on associative learning proficiency and on brain regions that previous functional MRI studies have closely related to the domain of associative learning. Participants (n=66) completed a previously established associative learning paradigm, and consented to be scanned using structural magnetic resonance imaging. Age-related effects were investigated both across sub-groups in the sample (younger vs. older) and across the entire sample (using regression approaches). Chronological age had substantial effects on learning proficiency (independent of IQ and Education Level), with older adults showing a decrement compared to younger adults. In addition, decreases in estimated gray matter volume were observed in multiple brain regions including the hippocampus and the dorsal prefrontal cortex, both of which are strongly implicated in associative learning. The results suggest that middle adulthood may be a more dynamic period of life-span change than previously believed. The conjunctive application of narrowly focused tasks, with conjointly acquired structural MRI data may allow us to enrich the search for, and the interpretation of, age-related changes in cross-sectional samples. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. Self-efficacy and Its Relation to ESL Writing Proficiency and Academic Disciplines

    Directory of Open Access Journals (Sweden)

    Saeid Raoofi

    2017-07-01

    Full Text Available Writing is an essential skill for academic development within any disciplinary area. Despite the rapidly growing body of research on the various aspects of second language writing, research on writing self-efficacy remains scarce. This study investigated the relationship the between writing self-efficacy and writing proficiency in English as a second language. In this cross-sectional study, 304 Malaysian undergraduate students completed a writing self-efficacy questionnaire. The participants’ writing proficiency was assessed using two different writing tasks. The results showed that there was a significant difference in writing self-efficacy among the three writing proficiency groups. It was also found that science students had significantly higher writing self-efficacy than those in social sciences. Limitations of the study and Implications for second language writing instruction are also discussed.

  12. Fluctuation analysis of proficient and dysgraphic handwriting in children

    Science.gov (United States)

    Rosenblum, S.; Roman, H. E.

    2009-03-01

    We analyze handwriting records from several school children with the aim of characterizing the fluctuating behavior of the writing speed. It will be concluded that remarkable differences exist between proficient and dysgraphic handwritings which were unknown so far. It is shown that in the case of proficient handwriting, the variations in handwriting speed are strongly autocorrelated within times corresponding to the completion of a single character or letter, while become uncorrelated at longer times. In the case of dysgraphia, such correlations persist on longer time scales and the autocorrelation function seems to display algebraic time decay, indicating the presence of strong anomalies in the handwriting process. Applications of the results in educational/clinical programs are envisaged.

  13. Digital Games and the US National Research Council's Science Proficiency Goals

    Science.gov (United States)

    Martinez-Garza, Mario; Clark, Douglas B.; Nelson, Brian C.

    2013-01-01

    This review synthesises research on digital games and science learning as it supports the goals for science proficiency outlined in the report by the US National Research Council on science education reform. The review is organised in terms of these research-based goals for science proficiency in light of their alignment with current science…

  14. PCP-B class pollen coat proteins are key regulators of the hydration checkpoint in Arabidopsis thaliana pollen-stigma interactions.

    Science.gov (United States)

    Wang, Ludi; Clarke, Lisa A; Eason, Russell J; Parker, Christopher C; Qi, Baoxiu; Scott, Rod J; Doughty, James

    2017-01-01

    The establishment of pollen-pistil compatibility is strictly regulated by factors derived from both male and female reproductive structures. Highly diverse small cysteine-rich proteins (CRPs) have been found to play multiple roles in plant reproduction, including the earliest stages of the pollen-stigma interaction. Secreted CRPs found in the pollen coat of members of the Brassicaceae, the pollen coat proteins (PCPs), are emerging as important signalling molecules that regulate the pollen-stigma interaction. Using a combination of protein characterization, expression and phylogenetic analyses we identified a novel class of Arabidopsis thaliana pollen-borne CRPs, the PCP-Bs (for pollen coat protein B-class) that are related to embryo surrounding factor (ESF1) developmental regulators. Single and multiple PCP-B mutant lines were utilized in bioassays to assess effects on pollen hydration, adhesion and pollen tube growth. Our results revealed that pollen hydration is severely impaired when multiple PCP-Bs are lost from the pollen coat. The hydration defect also resulted in reduced pollen adhesion and delayed pollen tube growth in all mutants studied. These results demonstrate that AtPCP-Bs are key regulators of the hydration 'checkpoint' in establishment of pollen-stigma compatibility. In addition, we propose that interspecies diversity of PCP-Bs may contribute to reproductive barriers in the Brassicaceae. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

  15. The Effects of Type and Quantity of Input on Iranian EFL Learners’ Oral Language Proficiency

    Directory of Open Access Journals (Sweden)

    Zahra Hassanzadeh

    2014-05-01

    Full Text Available In the written texts on foreign language learning, a group of studies has stressed the function of learning context and learning chances for learners’ language input. The present thesis had two main goals: on the one hand, different types of input to which Iranian grade four high school EFL learners’ are exposed were looked at; on the other hand, the possible relationship between types and quantity of input and Iranian EFL learners’ oral proficiency was investigated. It was supposed that EFL learners who have access to more input will show better oral proficiency than those who do not have. Instruments used in the present study for the purpose of data collation included  PET test, researcher- made questionnaire, oral language proficiency test and face- to -face interview. Data were gathered from 50 Iranian female grade four high school foreign language learners who were selected from among 120 students whose score on PET test were +1SD from the mean score. The results of the Spearman rank –order correlation test for the types of input and oral language proficiency scores, showed that the participants’ oral proficiency score significantly correlated with the intended four sources of input including spoken (rho= 0.416, sig=0.003, written (rho= 0.364, sig=0.009, aural (rho= 0.343, sig=0.015 and visual or audio-visual types of input (rho= 0.47, sig=0.00. The findings of Spearman rank –order correlation test for the quantity of input and oral language proficiency scores also showed a significant relationship between quantity of input and oral language proficiency (rho= 0.543, sig= 0.00. The findings showed that EFL learners’ oral proficiency is significantly correlated with efficient and effective input. The findings may also suggest  answers to the question why most Iranian English learners fail to speak English fluently, which might be due to  lack of effective input. This may emphasize the importance of the types and quantity of

  16. The role of race and english proficiency on the health of older immigrants.

    Science.gov (United States)

    Nguyen, Duy; Reardon, Leigh J

    2013-01-01

    This study applies the Commission on Social Determinants of Health model to identify the effect of ethnicity/race and English proficiency on the health of older immigrants. California Health Interview Survey data of foreign-born respondents aged 65 and over were used to examine the four outcomes of health-related quality of life (HRQOL). The study included 1,196 immigrant Latinos, Asians, and non-Hispanic Whites. The results show that ethnicity/race-based differences in HRQOL exist. Furthermore, the results indicate that English proficiency has a significant moderating relationship on racial/ethnic background. The likelihood of reporting more Limited Combined Days increased with lower levels of English proficiency for both Latino and Asian-American old adults as compared to non-Hispanic Whites. In addition to focusing on racial disparities, health promotion efforts with older immigrants need to examine language-based stratification. Social work and gerontological advocates need to develop and employ evidence-based interventions that reach limited-English-proficient older immigrants to address the health, psychosocial, and access to health care challenges they face.

  17. The Oral Proficiency Interview: A Research Agenda

    Science.gov (United States)

    Chalhoub-Deville, Micheline; Fulcher, Glenn

    2003-01-01

    Many researchers and practitioners maintain that ACTFL's efforts to improve instructional practices and promote proficiency assessments tied to descriptors of what learners can do in real life have contributed significantly to second language teaching and testing. Similar endeavors in the area of research, however, are critically needed. Focusing…

  18. Rad9 contribution to radiosensitivity and the G2 checkpoint in a DT40 cell line

    Energy Technology Data Exchange (ETDEWEB)

    Kumano, Tomoyasu [Kanazawa Univ. (Japan). Graduate School of Medical Science

    2002-12-01

    In fission yeast, the rad9 (radiation sensitive) gene was cloned from a mutant that is sensitive to ionizing radiation, ultraviolet and hydroxyurea. This gene has also been shown to be required for a DNA damage checkpoint. Orthologues of the rad9 gene have recently been identified in higher eukaryote cells including human. Here we generated Rad9 knockout (Rad9-/-) cells from the chicken B lymphocyte line DT40 to examine the role of Rad9 in higher eukaryotes. First we isolated a part of the chicken Rad9 gene which was 54% identical with human Rad9 at the amino acid sequence level. Next we isolated genomic clones, determined exons and introns, and constructed targeting vectors designed to disrupt exon 1-3 of the chicken Rad9 gene by replacement with a drug-resistant gene. Successful targeted integration was verified by Southern blot analysis and the disruption of the Rad9 gene was confirmed by reverse transcription polymerase chain reaction (RT-PCR). To analyze the radiosensitivity of these Rad9-/- cells, we monitored the clonogenic survival after various degrees of X-ray irradiation. Rad9-/- cells were more sensitive to X-rays than wild type cells at all dosages. However, these cells were less sensitive than ATM knockout (ATM-/-) cells that are known to be X-ray sensitive and that showed a defective checkpoint control. In contrast, Rad9-/- cells were markedly more sensitive to ultraviolet and hydroxyruea. In addition, we assessed the G2 checkpoint by measurement of the mitotic index that is the fraction of the accumulating number of cells in mitosis at various times after X-ray irradiation. While the number of mitotic wild type cells did not increase until 2 hrs after X-ray irradiation, the number of mitotic Rad9-/- cells showed an increase similar to that of ATM-/- cells. These results suggest that just as in fission yeast, in higher eukaryotes Rad9 also contributes to X-ray, ultraviolet and hydroxyurea sensitivity, and plays an important role in the G2 checkpoint

  19. Rad9 contribution to radiosensitivity and the G2 checkpoint in a DT40 cell line

    International Nuclear Information System (INIS)

    Kumano, Tomoyasu

    2002-01-01

    In fission yeast, the rad9 (radiation sensitive) gene was cloned from a mutant that is sensitive to ionizing radiation, ultraviolet and hydroxyurea. This gene has also been shown to be required for a DNA damage checkpoint. Orthologues of the rad9 gene have recently been identified in higher eukaryote cells including human. Here we generated Rad9 knockout (Rad9-/-) cells from the chicken B lymphocyte line DT40 to examine the role of Rad9 in higher eukaryotes. First we isolated a part of the chicken Rad9 gene which was 54% identical with human Rad9 at the amino acid sequence level. Next we isolated genomic clones, determined exons and introns, and constructed targeting vectors designed to disrupt exon 1-3 of the chicken Rad9 gene by replacement with a drug-resistant gene. Successful targeted integration was verified by Southern blot analysis and the disruption of the Rad9 gene was confirmed by reverse transcription polymerase chain reaction (RT-PCR). To analyze the radiosensitivity of these Rad9-/- cells, we monitored the clonogenic survival after various degrees of X-ray irradiation. Rad9-/- cells were more sensitive to X-rays than wild type cells at all dosages. However, these cells were less sensitive than ATM knockout (ATM-/-) cells that are known to be X-ray sensitive and that showed a defective checkpoint control. In contrast, Rad9-/- cells were markedly more sensitive to ultraviolet and hydroxyruea. In addition, we assessed the G2 checkpoint by measurement of the mitotic index that is the fraction of the accumulating number of cells in mitosis at various times after X-ray irradiation. While the number of mitotic wild type cells did not increase until 2 hrs after X-ray irradiation, the number of mitotic Rad9-/- cells showed an increase similar to that of ATM-/- cells. These results suggest that just as in fission yeast, in higher eukaryotes Rad9 also contributes to X-ray, ultraviolet and hydroxyurea sensitivity, and plays an important role in the G2 checkpoint

  20. Proficiency-based laparoscopic and endoscopic training with virtual reality simulators: a comparison of proctored and independent approaches.

    Science.gov (United States)

    Snyder, Christopher W; Vandromme, Marianne J; Tyra, Sharon L; Hawn, Mary T

    2009-01-01

    Virtual reality (VR) simulators for laparoscopy and endoscopy may be valuable tools for resident education. However, the cost of such training in terms of trainee and instructor time may vary depending upon whether an independent or proctored approach is employed. We performed a randomized controlled trial to compare independent and proctored methods of proficiency-based VR simulator training. Medical students were randomized to independent or proctored training groups. Groups were compared with respect to the number of training hours and task repetitions required to achieve expert level proficiency on laparoscopic and endoscopic simulators. Cox regression modeling was used to compare time to proficiency between groups, with adjustment for appropriate covariates. Thirty-six medical students (18 independent, 18 proctored) were enrolled. Achievement of overall simulator proficiency required a median of 11 hours of training (range, 6-21 hours). Laparoscopic and endoscopic proficiency were achieved after a median of 11 (range, 6-32) and 10 (range, 5-27) task repetitions, respectively. The number of repetitions required to achieve proficiency was similar between groups. After adjustment for covariates, trainees in the independent group achieved simulator proficiency with significantly fewer hours of training (hazard ratio, 2.62; 95% confidence interval, 1.01-6.85; p = 0.048). Our study quantifies the cost, in instructor and trainee hours, of proficiency-based laparoscopic and endoscopic VR simulator training, and suggests that proctored instruction does not offer any advantages to trainees. The independent approach may be preferable for surgical residency programs desiring to implement VR simulator training.

  1. T cells in chronic lymphocytic leukemia display dysregulated expression of immune checkpoints and activation markers.

    Science.gov (United States)

    Palma, Marzia; Gentilcore, Giusy; Heimersson, Kia; Mozaffari, Fariba; Näsman-Glaser, Barbro; Young, Emma; Rosenquist, Richard; Hansson, Lotta; Österborg, Anders; Mellstedt, Håkan

    2017-03-01

    Chronic lymphocytic leukemia is characterized by impaired immune functions largely due to profound T-cell defects. T-cell functions also depend on co-signaling receptors, inhibitory or stimulatory, known as immune checkpoints, including cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed death-1 (PD-1). Here we analyzed the T-cell phenotype focusing on immune checkpoints and activation markers in chronic lymphocytic leukemia patients (n=80) with different clinical characteristics and compared them to healthy controls. In general, patients had higher absolute numbers of CD3 + cells and the CD8 + subset was particularly expanded in previously treated patients. Progressive patients had higher numbers of CD4 + and CD8 + cells expressing PD-1 compared to healthy controls, which was more pronounced in previously treated patients ( P =0.0003 and P =0.001, respectively). A significant increase in antigen-experienced T cells was observed in patients within both the CD4 + and CD8 + subsets, with a significantly higher PD-1 expression. Higher numbers of CD4 + and CD8 + cells with intracellular CTLA-4 were observed in patients, as well as high numbers of proliferating (Ki67 + ) and activated (CD69 + ) CD4 + and CD8 + cells, more pronounced in patients with active disease. The numbers of Th1, Th2, Th17 and regulatory T cells were substantially increased in patients compared to controls ( P leukemia T cells display increased expression of immune checkpoints, abnormal subset distribution, and a higher proportion of proliferating cells compared to healthy T cells. Disease activity and previous treatment shape the T-cell profile of chronic lymphocytic leukemia patients in different ways. Copyright© Ferrata Storti Foundation.

  2. Requirement for PLK1 kinase activity in the maintenance of a robust spindle assembly checkpoint

    Directory of Open Access Journals (Sweden)

    Aisling O'Connor

    2016-01-01

    Full Text Available During mitotic arrest induced by microtubule targeting drugs, the weakening of the spindle assembly checkpoint (SAC allows cells to progress through the cell cycle without chromosome segregation occurring. PLK1 kinase plays a major role in mitosis and emerging evidence indicates that PLK1 is also involved in establishing the checkpoint and maintaining SAC signalling. However, mechanistically, the role of PLK1 in the SAC is not fully understood, with several recent reports indicating that it can cooperate with either one of the major checkpoint kinases, Aurora B or MPS1. In this study, we assess the role of PLK1 in SAC maintenance. We find that in nocodazole-arrested U2OS cells, PLK1 activity is continuously required for maintaining Aurora B protein localisation and activity at kinetochores. Consistent with published data we find that upon PLK1 inhibition, phosphoThr3-H3, a marker of Haspin activity, is reduced. Intriguingly, Aurora B inhibition causes PLK1 to relocalise from kinetochores into fewer and much larger foci, possibly due to incomplete recruitment of outer kinetochore proteins. Importantly, PLK1 inhibition, together with partial inhibition of Aurora B, allows efficient SAC override to occur. This phenotype is more pronounced than the phenotype observed by combining the same PLK1 inhibitors with partial MPS1 inhibition. We also find that PLK1 inhibition does not obviously cooperate with Haspin inhibition to promote SAC override. These results indicate that PLK1 is directly involved in maintaining efficient SAC signalling, possibly by cooperating in a positive feedback loop with Aurora B, and that partially redundant mechanisms exist which reinforce the SAC.

  3. Drosophila MOF controls Checkpoint protein2 and regulates genomic stability during early embryogenesis.

    Science.gov (United States)

    Pushpavalli, Sreerangam N C V L; Sarkar, Arpita; Ramaiah, M Janaki; Chowdhury, Debabani Roy; Bhadra, Utpal; Pal-Bhadra, Manika

    2013-01-24

    In Drosophila embryos, checkpoints maintain genome stability by delaying cell cycle progression that allows time for damage repair or to complete DNA synthesis. Drosophila MOF, a member of MYST histone acetyl transferase is an essential component of male X hyperactivation process. Until recently its involvement in G2/M cell cycle arrest and defects in ionizing radiation induced DNA damage pathways was not well established. Drosophila MOF is highly expressed during early embryogenesis. In the present study we show that haplo-insufficiency of maternal MOF leads to spontaneous mitotic defects like mitotic asynchrony, mitotic catastrophe and chromatid bridges in the syncytial embryos. Such abnormal nuclei are eliminated and digested in the yolk tissues by nuclear fall out mechanism. MOF negatively regulates Drosophila checkpoint kinase 2 tumor suppressor homologue. In response to DNA damage the checkpoint gene Chk2 (Drosophila mnk) is activated in the mof mutants, there by causing centrosomal inactivation suggesting its role in response to genotoxic stress. A drastic decrease in the fall out nuclei in the syncytial embryos derived from mof¹/+; mnkp⁶/+ females further confirms the role of DNA damage response gene Chk2 to ensure the removal of abnormal nuclei from the embryonic precursor pool and maintain genome stability. The fact that mof mutants undergo DNA damage has been further elucidated by the increased number of single and double stranded DNA breaks. mof mutants exhibited genomic instability as evidenced by the occurance of frequent mitotic bridges in anaphase, asynchronous nuclear divisions, disruption of cytoskeleton, inactivation of centrosomes finally leading to DNA damage. Our findings are consistent to what has been reported earlier in mammals that; reduced levels of MOF resulted in increased genomic instability while total loss resulted in lethality. The study can be further extended using Drosophila as model system and carry out the interaction of MOF

  4. Drosophila MOF controls Checkpoint protein2 and regulates genomic stability during early embryogenesis

    Directory of Open Access Journals (Sweden)

    Pushpavalli Sreerangam NCVL

    2013-01-01

    Full Text Available Abstract Background In Drosophila embryos, checkpoints maintain genome stability by delaying cell cycle progression that allows time for damage repair or to complete DNA synthesis. Drosophila MOF, a member of MYST histone acetyl transferase is an essential component of male X hyperactivation process. Until recently its involvement in G2/M cell cycle arrest and defects in ionizing radiation induced DNA damage pathways was not well established. Results Drosophila MOF is highly expressed during early embryogenesis. In the present study we show that haplo-insufficiency of maternal MOF leads to spontaneous mitotic defects like mitotic asynchrony, mitotic catastrophe and chromatid bridges in the syncytial embryos. Such abnormal nuclei are eliminated and digested in the yolk tissues by nuclear fall out mechanism. MOF negatively regulates Drosophila checkpoint kinase 2 tumor suppressor homologue. In response to DNA damage the checkpoint gene Chk2 (Drosophila mnk is activated in the mof mutants, there by causing centrosomal inactivation suggesting its role in response to genotoxic stress. A drastic decrease in the fall out nuclei in the syncytial embryos derived from mof1/+; mnkp6/+ females further confirms the role of DNA damage response gene Chk2 to ensure the removal of abnormal nuclei from the embryonic precursor pool and maintain genome stability. The fact that mof mutants undergo DNA damage has been further elucidated by the increased number of single and double stranded DNA breaks. Conclusion mof mutants exhibited genomic instability as evidenced by the occurance of frequent mitotic bridges in anaphase, asynchronous nuclear divisions, disruption of cytoskeleton, inactivation of centrosomes finally leading to DNA damage. Our findings are consistent to what has been reported earlier in mammals that; reduced levels of MOF resulted in increased genomic instability while total loss resulted in lethality. The study can be further extended using

  5. Parallel reorganization of protein function in the spindle checkpoint pathway through evolutionary paths in the fitness landscape that appear neutral in laboratory experiments.

    Directory of Open Access Journals (Sweden)

    Alex N Nguyen Ba

    2017-04-01

    Full Text Available Regulatory networks often increase in complexity during evolution through gene duplication and divergence of component proteins. Two models that explain this increase in complexity are: 1 adaptive changes after gene duplication, such as resolution of adaptive conflicts, and 2 non-adaptive processes such as duplication, degeneration and complementation. Both of these models predict complementary changes in the retained duplicates, but they can be distinguished by direct fitness measurements in organisms with short generation times. Previously, it has been observed that repeated duplication of an essential protein in the spindle checkpoint pathway has occurred multiple times over the eukaryotic tree of life, leading to convergent protein domain organization in its duplicates. Here, we replace the paralog pair in S. cerevisiae with a single-copy protein from a species that did not undergo gene duplication. Surprisingly, using quantitative fitness measurements in laboratory conditions stressful for the spindle-checkpoint pathway, we find no evidence that reorganization of protein function after gene duplication is beneficial. We then reconstruct several evolutionary intermediates from the inferred ancestral network to the extant one, and find that, at the resolution of our assay, there exist stepwise mutational paths from the single protein to the divergent pair of extant proteins with no apparent fitness defects. Parallel evolution has been taken as strong evidence for natural selection, but our results suggest that even in these cases, reorganization of protein function after gene duplication may be explained by neutral processes.

  6. Checkpoint Inhibition: Programmed Cell Death 1 and Programmed Cell Death 1 Ligand Inhibitors in Hodgkin Lymphoma.

    Science.gov (United States)

    Villasboas, Jose Caetano; Ansell, Stephen

    2016-01-01

    Hodgkin lymphoma (HL) is a lymphoid malignancy characterized by a reactive immune infiltrate surrounding relatively few malignant cells. In this scenario, active immune evasion seems to play a central role in allowing tumor progression. Immune checkpoint inhibitor pathways are normal mechanisms of T-cell regulation that suppress immune effector function following an antigenic challenge. Hodgkin lymphoma cells are able to escape immune surveillance by co-opting these mechanisms. The programmed cell death 1 (PD-1) pathway in particular is exploited in HL as the malignant Hodgkin and Reed-Sternberg cells express on their surface cognate ligands (PD-L1/L2) for the PD-1 receptor and thereby dampen the T-cell-mediated antitumoral response. Monoclonal antibodies that interact with and disrupt the PD-1:PD-L1/L2 axis have now been developed and tested in early-phase clinical trials in patients with advanced HL with encouraging results. The remarkable clinical activity of PD-1 inhibitors in HL highlights the importance of immune checkpoint pathways as therapeutic targets in HL. In this review, we discuss the rationale for targeting PD-1 and PD-L1 in the treatment of HL. We will evaluate the published clinical data on the different agents and highlight the safety profile of this class of agents. We discuss the available evidence on the use of biomarkers as predictors of response to checkpoint blockade and summarize the areas under active investigation in the use of PD-1/PD-L1 inhibitors for the treatment of HL.

  7. Incorporation of Immune Checkpoint Blockade into Chimeric Antigen Receptor T Cells (CAR-Ts): Combination or Built-In CAR-T.

    Science.gov (United States)

    Yoon, Dok Hyun; Osborn, Mark J; Tolar, Jakub; Kim, Chong Jai

    2018-01-24

    Chimeric antigen receptor (CAR) T cell therapy represents the first U.S. Food and Drug Administration approved gene therapy and these engineered cells function with unprecedented efficacy in the treatment of refractory CD19 positive hematologic malignancies. CAR translation to solid tumors is also being actively investigated; however, efficacy to date has been variable due to tumor-evolved mechanisms that inhibit local immune cell activity. To bolster the potency of CAR-T cells, modulation of the immunosuppressive tumor microenvironment with immune-checkpoint blockade is a promising strategy. The impact of this approach on hematological malignancies is in its infancy, and in this review we discuss CAR-T cells and their synergy with immune-checkpoint blockade.

  8. Incorporation of Immune Checkpoint Blockade into Chimeric Antigen Receptor T Cells (CAR-Ts: Combination or Built-In CAR-T

    Directory of Open Access Journals (Sweden)

    Dok Hyun Yoon

    2018-01-01

    Full Text Available Chimeric antigen receptor (CAR T cell therapy represents the first U.S. Food and Drug Administration approved gene therapy and these engineered cells function with unprecedented efficacy in the treatment of refractory CD19 positive hematologic malignancies. CAR translation to solid tumors is also being actively investigated; however, efficacy to date has been variable due to tumor-evolved mechanisms that inhibit local immune cell activity. To bolster the potency of CAR-T cells, modulation of the immunosuppressive tumor microenvironment with immune-checkpoint blockade is a promising strategy. The impact of this approach on hematological malignancies is in its infancy, and in this review we discuss CAR-T cells and their synergy with immune-checkpoint blockade.

  9. A influência do sistema de gestão de laboratórios nos resultados dos ensaios de proficiência da construção civil The influence of the laboratory management system on the results of civil construction proficiency testing

    Directory of Open Access Journals (Sweden)

    Morgana Pizzolato

    2008-12-01

    Full Text Available A participação de laboratórios em atividades de ensaio de proficiência (EP é uma das formas de avaliar e demonstrar a confiabilidade das suas atividades de medição. Isso significa dizer que, por intermédio dos ensaios de proficiência (EP, pode-se avaliar a habilidade do laboratório de realizar ensaios e calibrações de forma competente. Os ensaios de proficiência fornecem informações importantes para avaliação de laboratórios, postulantes à acreditação, acreditados, notificados ou designados por agências reguladoras e para os laboratórios em geral. Este artigo teve por objetivo verificar se o tipo de sistema de gestão dos laboratórios de ensaio da construção civil do Brasil influencia nos resultados dos ensaios de proficiência (EP. Objetiva ainda discutir como contemplar o resultado dos ensaios de proficiência no cálculo da incerteza de medição dos ensaios. Como resultado do estudo, conclui-se que não existe efeito dos tipos de sistema de gestão sobre os resultados dos ensaios de proficiência (EP. Logo, foi sugerido o uso do desvio padrão dos resultados de um grupo representativo de ensaios de proficiência de determinados ensaios (químico, físico, etc. para gerar um cálculo genérico da incerteza de medição para o setor de atuação do laboratório. Esta abordagem, além de simplificar o cálculo da incerteza de medição contempla um maior número de fontes de incerteza de medição.Laboratories participation in proficiency testing is one way to evaluate and demonstrate the reliability of their measurement results. That is to say, through the proficiency testing, the laboratory ability of accomplishing tests and calibrations successfully can be evaluated. The proficiency testing supplies important information for the evaluation of laboratories, candidates to accreditation, accredited laboratories, notified or designated laboratories by regulatory bodies, and laboratories in general. This paper aims at

  10. The Interplay among Emotional Intelligence, Classroom Management, and Language Proficiency of Iranian EFL Teachers

    Directory of Open Access Journals (Sweden)

    Hadi Hamidi

    2016-06-01

    Full Text Available The present study was an attempt to investigate the interplay among Iranian EFL teachers’ emotional intelligence, classroom management, and their general English language proficiency. The result of the data analysis showed that: 1 there was a statistically significant relationship between the emotional intelligence and the classroom management of Iranian EFL teachers, 2 there was a statistically significant relationship between the emotional intelligence and the language proficiency of Iranian EFL teachers, and 3 there was a statistically significant relationship between the classroom management and the language proficiency of Iranian EFL teachers. Teacher trainers, researchers in teacher education, and language teachers may benefit from the findings of the present research.

  11. Reading Habits of University ESL Students at Different Levels of English Proficiency and Education.

    Science.gov (United States)

    Mokhtari, Kouider; Sheorey, Ravi

    1994-01-01

    Examines the degree to which the levels of English proficiency (high vs. low) and education (graduate vs. undergraduate) of English-as-a-Second-Language (ESL) students were associated with differences in their reading behaviors. Finds that the subjects' level of education and English proficiency were associated with their reading behavior…

  12. The Interaction between Checkpoint Kinase 1 (Chk1) and the Minichromosome Maintenance (MCM) Complex Is Required for DNA Damage-induced Chk1 Phosphorylation*

    Science.gov (United States)

    Han, Xiangzi; Aslanian, Aaron; Fu, Kang; Tsuji, Toshiya; Zhang, Youwei

    2014-01-01

    Chk1 is an essential mediator of the DNA damage response and cell cycle checkpoint. However, how exactly Chk1 transduces the checkpoint signaling is not fully understood. Here we report the identification of the heterohexamic minichromosome maintenance (MCM) complex that interacts with Chk1 by mass spectrometry. The interaction between Chk1 and the MCM complex was reduced by DNA damage treatment. We show that the MCM complex, at least partially, contributes to the chromatin association of Chk1, allowing for immediate phosphorylation of Chk1 by ataxia telangiectasia mutated and Rad3-related (ATR) in the presence of DNA damage. Further, phosphorylation of Chk1 at ATR sites reduces the interaction between Chk1 and the MCM complex, facilitating chromatin release of phosphorylated Chk1, a critical step in the initiation and amplification of cell cycle checkpoint. Together, these data provide novel insights into the activation of Chk1 in response to DNA damage. PMID:25049228

  13. Evaluation of Mycology Laboratory Proficiency Testing

    OpenAIRE

    Reilly, Andrew A.; Salkin, Ira F.; McGinnis, Michael R.; Gromadzki, Sally; Pasarell, Lester; Kemna, Maggi; Higgins, Nancy; Salfinger, Max

    1999-01-01

    Changes over the last decade in overt proficiency testing (OPT) regulations have been ostensibly directed at improving laboratory performance on patient samples. However, the overt (unblinded) format of the tests and regulatory penalties associated with incorrect values allow and encourage laboratorians to take extra precautions with OPT analytes. As a result OPT may measure optimal laboratory performance instead of the intended target of typical performance attained during routine patient te...

  14. Radon Measurement Proficiency (RMP) Program methods and devices

    International Nuclear Information System (INIS)

    Harrison, J.; Hoornbeek, J.; Jalbert, P.; Sensintaffar, E.; Hopper, R.

    1991-01-01

    The US EPA developed the voluntary Radon Measurement Proficiency Program in 1986 in response to a Federal and State need for measurement services firms to demonstrate their proficiency with radon measurement methods and devices. Since that time, the program has set basic standards for the radon measurement industry. The program has grown dramatically since its inception. In 1986, fewer than 50 companies participated in the program. By 1989, more than 5,000 companies were participating. Participants represent firms with an analytical capability as well as firms that rely upon another firm for analysis service. Since the beginning of the RMP Program, the Agency has learned a great deal about radon measurement methods and devices. This paper reviews the measurement devices used in the program and what the EPA has learned about them since the program's inception. Performance data from the RMP Program are used to highlight relevant findings

  15. Proficiency in Motivational Interviewing among Nurses in Child Health Services Following Workshop and Supervision with Systematic Feedback.

    Directory of Open Access Journals (Sweden)

    Johanna Enö Persson

    Full Text Available Research on training in motivational interviewing (MI has shown eroding skills after workshops not followed by additional training input (supervision/coaching. There is a need for more research evaluating different types and lengths of post-workshop training with follow-up periods extending six months. This study is an extension of a previous evaluation of the level of proficiency in MI after workshop and four sessions of supervision among nurses in Swedish child health services.To explore the level of MI proficiency among nurses participating in an intervention to prevent childhood obesity (n = 33, after receiving five additional sessions of supervision including feedback on observed practice, as well as level of proficiency at follow-up.Level of proficiency was measured 4 and 12 months after completed supervision using recorded practice samples coded according to the Motivational Interviewing Treatment Integrity (MITI Code. Potential predictors of outcome were investigated.Proficiency remained on the same levels after nine sessions of supervision as after four sessions, and was generally low. The percentage of nurses reaching the proficiency level ranged from 18.2 to 54.5% across indicators. MI-spirit had increased significantly at follow-up, and the rest of the indicators remained on the same levels. No predictors of outcome were found.Comprehensive training programs with prolonged post-workshop supervision and feedback on observed practice may help to sustain but not improve participants' proficiency in MI. Potential explanations to the results and suggestions for future research are discussed.

  16. Motor Proficiency and Body Mass Index of Preschool Children: In Relation to Socioeconomic Status

    Science.gov (United States)

    Mülazimoglu-Balli, Özgür

    2016-01-01

    The aim of the study was to investigate the correlation between motor proficiency and body mass index and to assess the socioeconomic status differences in motor proficiency and body mass index of preschool children. Sixty preschool children in the different socioeconomic status areas of central Denizli in Turkey participated in the study. The…

  17. Technological Proficiency as a Key to Job Security. Trends and Issues Alert No. 6.

    Science.gov (United States)

    Imel, Susan

    Although not all current jobs require basic computer skills, technological advances in society have created new jobs and changed the ways many existing jobs are performed. Clearly, workers who are proficient in technology have a greater advantage in the current workplace and the need for technologically proficient workers will only continue to…

  18. Immune Checkpoint Inhibitors: An Innovation in Immunotherapy for the Treatment and Management of Patients with Cancer.

    Science.gov (United States)

    Dine, Jennifer; Gordon, RuthAnn; Shames, Yelena; Kasler, Mary Kate; Barton-Burke, Margaret

    2017-01-01

    Cancer survival rates are generally increasing in the United States. These trends have been partially attributed to improvement in therapeutic strategies. Cancer immunotherapy is an example of one of the newer strategies used to fight cancer, which primes or activates the immune system to produce antitumor effects. The first half of this review paper concisely describes the cell mechanisms that control antitumor immunity and the major immunotherapeutic strategies developed to target these mechanisms. The second half of the review discusses in greater depth immune checkpoint inhibitors that have recently demonstrated tremendous promise for the treatment of diverse solid tumor types, including melanoma, non-small cell lung cancer, and others. More specifically, the mechanisms of action, side effects, and patient and family management and education concerns are discussed to provide oncology nurses up-to-date information relevant to caring for cancer-affected patients treated with immune checkpoint inhibitors. Future directions for cancer immunotherapy are considered.

  19. Students' proficiency scores within multitrait item response theory

    Science.gov (United States)

    Scott, Terry F.; Schumayer, Daniel

    2015-12-01

    In this paper we present a series of item response models of data collected using the Force Concept Inventory. The Force Concept Inventory (FCI) was designed to poll the Newtonian conception of force viewed as a multidimensional concept, that is, as a complex of distinguishable conceptual dimensions. Several previous studies have developed single-trait item response models of FCI data; however, we feel that multidimensional models are also appropriate given the explicitly multidimensional design of the inventory. The models employed in the research reported here vary in both the number of fitting parameters and the number of underlying latent traits assumed. We calculate several model information statistics to ensure adequate model fit and to determine which of the models provides the optimal balance of information and parsimony. Our analysis indicates that all item response models tested, from the single-trait Rasch model through to a model with ten latent traits, satisfy the standard requirements of fit. However, analysis of model information criteria indicates that the five-trait model is optimal. We note that an earlier factor analysis of the same FCI data also led to a five-factor model. Furthermore the factors in our previous study and the traits identified in the current work match each other well. The optimal five-trait model assigns proficiency scores to all respondents for each of the five traits. We construct a correlation matrix between the proficiencies in each of these traits. This correlation matrix shows strong correlations between some proficiencies, and strong anticorrelations between others. We present an interpretation of this correlation matrix.

  20. An exploratory study of proficient undergraduate Chemistry II students' application of Lewis's model

    Science.gov (United States)

    Lewis, Sumudu R.

    This exploratory study was based on the assumption that proficiency in chemistry must not be determined exclusively on students' declarative and procedural knowledge, but it should be also described as the ability to use variety of reasoning strategies that enrich and diversify procedural methods. The study furthermore assumed that the ability to describe the structure of a molecule using Lewis's model and use it to predict its geometry as well as some of its properties is indicative of proficiency in the essential concepts of covalent bonding and molecule structure. The study therefore inquired into the reasoning methods and procedural techniques of proficient undergraduate Chemistry II students when solving problems, which require them to use Lewis's model. The research design included an original survey, designed by the researcher for this study, and two types of interviews, with students and course instructors. The purpose of the survey was two-fold. First and foremost, the survey provided a base for the student interview selection, and second it served as the foundation for the inquiry into the strategies the student use when solving survey problems. Twenty two students were interviewed over the course of the study. The interview with six instructors allowed to identify expected prior knowledge and skills, which the students should have acquired upon completion of the Chemistry I course. The data, including videos, audios, and photographs of the artifacts produced by students during the interviews, were organized and analyzed manually and using QSR NVivo 10. The research found and described the differences between proficient and non-proficient students' reasoning and procedural strategies when using Lewis's model to describe the structure of a molecule. One of the findings clearly showed that the proficient students used a variety of cues to reason, whereas other students used one memorized cue, or an algorithm, which often led to incorrect representations in

  1. Deaf college students' mathematical skills relative to morphological knowledge, reading level, and language proficiency.

    Science.gov (United States)

    Kelly, Ronald R; Gaustad, Martha G

    2007-01-01

    This study of deaf college students examined specific relationships between their mathematics performance and their assessed skills in reading, language, and English morphology. Simple regression analyses showed that deaf college students' language proficiency scores, reading grade level, and morphological knowledge regarding word segmentation and meaning were all significantly correlated with both the ACT Mathematics Subtest and National Technical Institute for the Deaf (NTID) Mathematics Placement Test scores. Multiple regression analyses identified the best combination from among these potential independent predictors of students' performance on both the ACT and NTID mathematics tests. Additionally, the participating deaf students' grades in their college mathematics courses were significantly and positively associated with their reading grade level and their knowledge of morphological components of words.

  2. Language proficiency and health status: are bilingual immigrants healthier?

    Science.gov (United States)

    Schachter, Ariela; Kimbro, Rachel T; Gorman, Bridget K

    2012-03-01

    Bilingual immigrants appear to have a health advantage, and identifying the mechanisms responsible for this is of increasing interest to scholars and policy makers in the United States. Utilizing the National Latino and Asian American Study (NLAAS; n = 3,264), we investigate the associations between English and native-language proficiency and usage and self-rated health for Asian and Latino U.S. immigrants from China, the Philippines, Vietnam, Mexico, Cuba, and Puerto Rico. The findings demonstrate that across immigrant ethnic groups, being bilingual is associated with better self-rated physical and mental health relative to being proficient in only English or only a native language, and moreover, these associations are partially mediated by socioeconomic status and family support but not by acculturation, stress and discrimination, or health access and behaviors.

  3. Program Director Perceptions of Proficiency in the Core Entrustable Professional Activities.

    Science.gov (United States)

    Pearlman, R Ellen; Pawelczak, Melissa; Yacht, Andrew C; Akbar, Salaahuddin; Farina, Gino A

    2017-10-01

    The Association of American Medical Colleges describes 13 core entrustable professional activities (EPAs) that every graduating medical student should be expected to perform proficiently on day 1 of residency, regardless of chosen specialty. Studies have shown wide variability in program director (PD) confidence in interns' abilities to perform these core EPAs. Little is known regarding comparison of United States Medical Licensing Examination (USMLE) scores with proficiency in EPAs. We determined if PDs from a large health system felt confident in their postgraduate year 1 residents' abilities to perform the 13 core EPAs, and compared perceived EPA proficiency with USMLE Step 1 and Step 2 scores. The PDs were asked to rate their residents' proficiency in each EPA and to provide residents' USMLE scores. Timing coincided with the reporting period for resident milestones. Surveys were completed on 204 of 328 residents (62%). PDs reported that 69% of residents (140 of 204) were prepared for EPA 4 (orders/prescriptions), 61% (117 of 192) for EPA 7 (form clinical questions), 68% (135 of 198) for EPA 8 (handovers), 63% (116 of 185) for EPA 11 (consent), and 38% (49 of 129) for EPA 13 (patient safety). EPA ratings and USMLE 1 and 2 were negatively correlated ( r (101) = -0.23, P  = .031). PDs felt that a significant percentage of residents were not adequately prepared in order writing, forming clinical questions, handoffs, informed consent, and promoting a culture of patient safety. We found no positive association between USMLE scores and EPA ratings.

  4. The Relationship between Actual Fundamental Motor Skill Proficiency, Perceived Motor Skill Confidence and Competence, and Physical Activity in 8–12-Year-Old Irish Female Youth

    Directory of Open Access Journals (Sweden)

    Orlagh Farmer

    2017-09-01

    Full Text Available This study examines the relationship between actual fundamental motor skill (FMS proficiency, perceived motor confidence and competence, and physical activity (PA among female children (n= 160; mean age = 10.69 ± 1.40 years. The Test of Gross Motor Development-2nd Edition (TGMD-2 was used to assess seven FMSs (locomotor, object-control, and stability. Motor confidence and competence were assessed using a valid skill-specific scale, and a modified version of the Self-Perception Profile for Children. PA levels were assessed using self-report (PA Questionnaire for Older Children (PAQ-C and classified as low, moderate, and high active. One-way and two-way ANOVAs (post-hoc honest significant difference (HSD and correlation coefficients were used to analyse the data. Findings indicate that the majority of youth (71.8% were not meeting the minimum 60 min of daily PA recommended for health, and that 98.1% did not achieve the FMS proficiency expected for their age. While there were high levels of perceived physical self-confidence (PSC reported within FMS skill-specific tasks, there was no significant correlation observed between actual FMS proficiency and perceived PSC among the cohort. Results show that low, moderately, and highly active female participants differ significantly in terms of their overall FMS (p = 0.03 and locomotor (LOC control scores (p = 0.03. Results from a two-way between-groups analysis of variance also revealed no statistically significant interaction effect between PA grouping and physical performance self-concept (PPSC on overall FMS proficiency levels. Results of a multiple linear regression indicate that perceived PSC is a significant predictor (beta = 0.183 of participants’ overall PA levels. Data show a need for targeting low levels of PA, and low FMS proficiency in female youth, and for developing interventions aiming to enhance perceived PSC levels.

  5. Relationship between motor proficiency and body composition in 6- to 10-year-old children.

    Science.gov (United States)

    Marmeleira, José; Veiga, Guida; Cansado, Hugo; Raimundo, Armando

    2017-04-01

    The aim of this study is to examine the relationship between motor skill competence and body composition of 6- to 10-year-old children. Seventy girls and 86 boys participated. Body composition was measured by body mass index and skinfold thickness. Motor proficiency was evaluated through the Bruininks-Oseretsky Test of Motor Proficiency-Short Form, which included measures of gross motor skills and fine motor skills. Significant associations were found for both sexes between the percentage of body fat and (i) the performance in each gross motor task, (ii) the composite score for gross motor skills and (iii) the motor proficiency score. The percentage of body fat was not significantly associated with the majority of the fine motor skills items and with the respective composite score. Considering body weigh categories, children with normal weight had significantly higher scores than their peers with overweight or with obesity in gross motor skills and in overall motor proficiency. Children's motor proficiency is negatively associated with body fat, and normal weight children show better motor competence than those who are overweight or obese. The negative impact of excessive body weight is stronger for gross motor skills that involve dynamic body movements than for stationary object control skills; fine motor skills appear to be relatively independent of the constraints imposed by excessive body weight. © 2017 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).

  6. Nordic proficiency test for whole body counting facilities

    Energy Technology Data Exchange (ETDEWEB)

    del Risco Norrlid, L. (Swedish Radiation Safety Authority (Sweden)); Halldorsson, O. (Icelandic Radiation Safety Authority, GR (Iceland)); Holm, S. (Copenhagen Univ. Hospital. NM and PET (Denmark)); Huikari, J. (Radiation and Nuclear Safety Authority (Finland)); Isaksson, M. (Goeteborg Univ., Dep. Radiation Physics Sahlgren Academy (Sweden)); Lind, B. (Norwegian Radiation Protection Authority (Norway))

    2012-01-15

    The PIANOLIB activity aims to harmonize the calibrations of the measurement equipment in the region and to evaluate the quality of this kind of measurement by means of a proficiency test exercise. In this report the results of the proficiency test are presented. The exercise consisted in determining the activity of a phantom filled with two sets of certified radioactive materials, K-40 and Cs-137, in radioactive rods, uniformly spaced inside of the phantom. Most of the participants were able to quantify correctly the activities of K-40 and Cs-137 and by comparison with the results of a previous exercise of this kind, the overall performance is equally good. The problems experienced by laboratories which submitted non-acceptable results could generally be attributed to the calibration of their systems. It is important to keep the practice of intercomparison and NKS continues to be the best framework for supporting this kind of activity. (Author)

  7. Understanding the Relationship between Language Proficiency, Language Impairment and Rehabilitation: Evidence from a Case Study

    Science.gov (United States)

    Kiran, Swathi; Iakupova, Regina

    2011-01-01

    The goal of this study was to address the relationship between language proficiency, language impairment and rehabilitation in bilingual Russian-English individuals with aphasia. As a first step, we examined two Russian-English patients' pre-stroke language proficiency using a detailed and comprehensive language use and history questionnaire and…

  8. Why do some countries publish more than others? An international comparison of research funding, English proficiency and publication output in highly ranked general medical journals.

    Science.gov (United States)

    Man, Jonathan P; Weinkauf, Justin G; Tsang, Monica; Sin, Don D

    2004-01-01

    National factor(s) influencing publication output in the highest ranked medical journals are largely unknown. We sought to examine the relationship between national research funding and English proficiency on publication output. We identified all original research articles appearing in the five highest ranked general medical journals between 1997 and 2001. Using the country of the corresponding author as the source nation for each article, we determined a standardized publication rate across developed nations. We used multiple regression techniques to determine the influence of national expenditures on research and scores from the Test of English as a Foreign Language (TOEFL), a surrogate for English proficiency, on publication output. There was a significant relationship of national spending on research and TOEFL scores to publication output of developed countries (p = 0.04; p < 0.01, respectively). These two variables explained approximately 71.5% of the variation in publication rate across developed nations around the world (R = 0.85; p < 0.01). Normalized for population size, English-speaking nations and certain northern European countries such as Denmark, The Netherlands, Switzerland, and Sweden had the highest rate of publication in the five highest ranked general medical journals, while Asian countries had generally low rates of publication. Research spending and English proficiency were strongly associated with publication output in the highest ranked general medical journals. While these data cannot be considered definitive due to their observational nature, they do suggest that for English-language medical journals, research funding and English proficiency may be important determinants of publication.

  9. The Effect of English Language on Multiple Choice Question Scores of Thai Medical Students.

    Science.gov (United States)

    Phisalprapa, Pochamana; Muangkaew, Wayuda; Assanasen, Jintana; Kunavisarut, Tada; Thongngarm, Torpong; Ruchutrakool, Theera; Kobwanthanakun, Surapon; Dejsomritrutai, Wanchai

    2016-04-01

    Universities in Thailand are preparing for Thailand's integration into the ASEAN Economic Community (AEC) by increasing the number of tests in English language. English language is not the native language of Thailand Differences in English language proficiency may affect scores among test-takers, even when subject knowledge among test-takers is comparable and may falsely represent the knowledge level of the test-taker. To study the impact of English language multiple choice test questions on test scores of medical students. The final examination of fourth-year medical students completing internal medicine rotation contains 120 multiple choice questions (MCQ). The languages used on the test are Thai and English at a ratio of 3:1. Individual scores of tests taken in both languages were collected and the effect of English language on MCQ was analyzed Individual MCQ scores were then compared with individual student English language proficiency and student grade point average (GPA). Two hundred ninety five fourth-year medical students were enrolled. The mean percentage of MCQ scores in Thai and English were significantly different (65.0 ± 8.4 and 56.5 ± 12.4, respectively, p English was fair (Spearman's correlation coefficient = 0.41, p English than in Thai language. Students were classified into six grade categories (A, B+, B, C+, C, and D+), which cumulatively measured total internal medicine rotation performance score plus final examination score. MCQ scores from Thai language examination were more closely correlated with total course grades than were the scores from English language examination (Spearman's correlation coefficient = 0.73 (p English proficiency score was very high, at 3.71 ± 0.35 from a total of 4.00. Mean student GPA was 3.40 ± 0.33 from a possible 4.00. English language MCQ examination scores were more highly associated with GPA than with English language proficiency. The use of English language multiple choice question test may decrease scores

  10. Procedures and reasoning for skill proficiency testing in physical education teacher education programs

    Directory of Open Access Journals (Sweden)

    Timothy Baghurst

    2015-12-01

    Full Text Available This study sought to determine how the testing of skill proficiency is being conducted in physical education teacher education (PETE programs in the USA and how fitness or skill proficiencies, as attributes of a physical educator, are perceived. Participants were 312 college PETE program coordinators who completed an online survey about skill testing in their program. The eligible respondents yielded a 52.7% total response rate. Most participants believed that skill proficiency for PETE students was important, but only 46% of programs reported testing within their program. Many participants stated it was possible for their students to graduate without demonstrating proficiency in skill technique, yet were confident their students would pass an independent skill test. Only 46.2% of respondents indicated their students needed to demonstrate proper skill technique in order to graduate, and there was no consistent method of assessment. Responses were evenly split regarding the importance of a physical educator being able to demonstrate proper skill technique or be physically fit. The lack of skill testing in programs, combined with the variation in assessment, is concerning, and the development of a standardized skill-based test may provide more rigor to this important area of teacher credibility and effectiveness.

  11. Metacognitive awareness of reading strategies of University of Botswana English as Second Language students of different academic reading proficiencies

    Directory of Open Access Journals (Sweden)

    Joel M. Magogwe

    2013-02-01

    Full Text Available This study explored metacognitive awareness level of University of Botswana students in the Faculty of Social Sciences. It also considered the more recent research focusing on the role of metacognitive awareness in reading and how it relates to proficiency. The following questions are addressed: (1 What are the self-reported reading proficiencies of the University of Botswana students? (2 Are the University of Botswana students aware of their metacognitive reading strategies? (3 What kind of metacognitive reading strategies are frequently used? (4 Is there a difference in metacognitive awareness of reading strategies used by high- and low-proficiency students respectively? The Survey of Reading Strategies Questionnaire (SORS developed by Mokhtari and Sheorey (2002, and the semi-structured interview technique were used to collect data for this study. The findings indicate that University of Botswana English as Second Language (ESL students reported high reading proficiency and high use of metacognitive strategies, but there was no vast difference in terms of proficiency. Students who reported their proficiency as high had an edge over low-proficiency ones mainly because their management and monitoring of reading was guided more by the goals they have set themselves than by the tests and assignments they were supposed to write.

  12. Development of a train-to-proficiency curriculum for the technical skills component of the fundamentals of endoscopic surgery exam.

    Science.gov (United States)

    Gearhart, Susan; Marohn, Michael; Ngamruengphong, Saowanee; Adrales, Gina; Owodunni, Oluwafemi; Duncan, Kim; Petrusa, Emil; Lipsett, Pamela

    2018-01-08

    The demonstration of competency in endoscopy is required prior to obtaining American Board of Surgery Certification. To demonstrate competency, the resident must pass a national high-stakes cognitive test and a technical skills exam on a virtual reality simulator. The purpose of this preliminary study was to design a proficiency-based endoscopy simulation curriculum to meet this competency requirement. This is a mixed methods prospective cohort study at a single academic medical institution. Prior to taking the national exam, surgery residents were required to participate in a skills lab and demonstrate proficiency on 10 simulation tasks. Proficiency was based on time and percent of objects targeted/mucosa seen. Simulation practice time, number of task repetitions to proficiency, and prior endoscopic experience were recorded. Resident's self-reported confidence scores in endoscopic skills prior to and following simulation lab training were obtained. From January 1, 2016 through August 1, 2017, 20 surgical residents (8 PGY2, 8 PGY3, 4 PGY4) completed both a faculty-supervised endoscopy skills lab and independent learning with train-to-proficiency simulation tasks. Median overall simulator time per resident was 306 min (IQR: 247-405 min). Median overall time to proficiency in all tasks was 235 min (IQR: 208-283 min). The median time to proficiency decreased with increasing PGY status (r = 0.4, P = 0.05). There was no correlation between prior real-time endoscopic experience and time to proficiency. Reported confidence in endoscopic skills increased significantly from mean of 5.75 prior to 7.30 following the faculty-supervised endoscopy skills lab (P = 0.0002). All 20 residents passed the national exam. In this preliminary study, a train-to-proficiency curriculum in endoscopy improved surgical resident's confidence in their endoscopic skills and 100% of residents passed the FES technical skills test on their first attempt. Our findings also indicate

  13. ProAtlantic - The Atlantic Checkpoint - Data Availability and Adequacy in the Atlantic Basin

    Science.gov (United States)

    McGrath, F.

    2017-12-01

    DG MAREs Atlantic Checkpoint is a basin scale wide monitoring system assessment activity based upon targeted end-user applications. It is designed to be a benchmark for the assessment of hydrographic, geological, habitat, climate and fisheries data existence and availability in the Atlantic basin. DG MAREs Atlantic Checkpoint service will be delivered by the ProAtlantic project. The objective of this project is to investigate, through appropriate methodologies in the framework of 11 key marine challenges, how current international and national data providers - e.g. EMODNet, Copernicus - meet the requirements of the stakeholders and deliver fit for purpose data. By so doing, the main thematic and geographic gaps will be readily identified in the Atlantic basin for future consideration by DG MARE. For each challenge, specific web products in the form of maps, metadata, spreadsheets and reports will be delivered. These products are not an end by themselves but rather a means of showing whether data were available, let alone accessible. For example, the Fisheries Impact Challenge outputs include data grids (VMS/Seabed) and data adequacy reports. Production of gridded data layers in order to show the extent of fisheries impact on the seafloor involved the identification, acquisition and collation of data sources for the required data types (VMS/Seabed/Habitats Data) in the Atlantic basin. The resulting spatial coverage of these grids indicates the relatively low level of data availability and adequacy across the Atlantic basin. Aside from the data delivered by programmes such as EMODNet and Copernicus, there are a lot of initiatives by regional bodies such as OSPAR and ICES that consist of assembling and disseminating data to address specific issues. Several international projects have delivered research, data collection, and networking around several of the Atlantic Checkpoint challenge topics, namely MPAs, renewable energy assessment, seabed mapping, oil spill

  14. Radiation-induced apoptosis and cell cycle checkpoints in human colorectal tumour cell lines

    International Nuclear Information System (INIS)

    Playle, L.C.

    2001-03-01

    The p53 tumour suppressor gene is mutated in 75% of colorectal carcinomas and is critical for DNA damage-induced G1 cell cycle arrest. Data presented in this thesis demonstrate that after treatment with Ionizing Radiation (IR), colorectal tumour cell lines with mutant p53 are unable to arrest at G1 and undergo cell cycle arrest at G2. The staurosporine derivative, UCN-01, was shown to abrogate the IR-induced G2 checkpoint in colorectal tumour cell lines. Furthermore, in some cell lines, abrogation of the G2 checkpoint was associated with radiosensitisation. Data presented in this study demonstrate that 2 out of 5 cell lines with mutant p53 were sensitised to IR by UCN-01. In order to determine whether radiosensitisation correlated with lack of functional p53, transfected derivatives of an adenoma-derived cell line were studied, in which endogenous wild type p53 was disrupted by expression of a dominant negative p53 mutant protein (and with a vector control). In both these cell lines UCN-01 abrogated the G2 arrest however this was not associated with radiosensitisation, indicating that radiosensitisation is a cell type-specific phenomenon. Although 2 colorectal carcinoma cell lines, with mutant p53, were sensitised to IR by UCN-01, the mechanisms of p53-independent IR-induced apoptosis in the colon are essentially unknown. The mitogen-activated protein kinase (MAPK) pathways (that is the JNK, p38 and ERK pathways) have been implicated in apoptosis in a range of cell systems and in IR-induced apoptosis in some cell types. Data presented in this study show that, although the MAPKs can be activated by the known activator anisomycin, there is no evidence of a role for MAPKs in IR-induced apoptosis in colorectal tumour cell lines, regardless of p53 status. In summary, some colorectal tumour cell lines with mutant p53 can be sensitised to IR-induced cell death by G2 checkpoint abrogation and this may be an important treatment strategy, however mechanisms of IR-induced p53

  15. Listening and Reading Proficiency Levels of College Students

    Science.gov (United States)

    Tschirner, Erwin

    2016-01-01

    This article examines listening and reading proficiency levels of U.S. college foreign language students at major milestones throughout their undergraduate career. Data were collected from more than 3,000 participants studying seven languages at 21 universities and colleges across the United States. The results show that while listening…

  16. Role of Immune Checkpoint Inhibitors in Small Cell Lung Cancer.

    Science.gov (United States)

    Cooper, Maryann R; Alrajhi, Abdullah M; Durand, Cheryl R

    Small cell lung cancer (SCLC) accounts for approximately 13% of all lung cancer diagnoses each year. SCLC is characterized by a rapid doubling time, early metastatic spread, and an unfavorable prognosis overall. Most patients with SCLC will respond to initial treatment; however, the majority will experience a disease recurrence and response to second-line therapies is poor. Immune checkpoint inhibitors may be an option given the success in other diseases. A literature search was conducted using Medline (1946-July week 1, 2017) and Embase (1996-2017 week 28) with the search terms small cell lung cancer combined with nivolumab or ipilimumab or pembrolizumab or atezolizumab or tremelimumab or durvalumab. Five clinical trials, including extended follow-up for 2, that evaluated immune checkpoint inhibitors in limited stage or extensive stage SCLC were included. In 2 phase 2 trials, ipilimumab was added to upfront chemotherapy. In both trials, an improvement in progression-free survival was seen. Toxicity, when combined with a platinum and etoposide, was significant. In a confirmatory phase 3 trial, ipilimumab did not prolong overall survival when added to first-line chemotherapy. Overall, response rates were similar between the placebo and ipilimumab groups. A phase 1/2 trial evaluated nivolumab alone or in combination with ipilimumab in recurrent SCLC. Results revealed that nivolumab monotherapy and the combination of nivolumab and ipilimumab were relatively safe and had antitumor activity. Pembrolizumab has been evaluated in a multicohort, phase 1b trial. Preliminary data showed a durable response in the second-line setting. Given the lack of overall survival data and significant toxicity associated with the combination of ipilimumab with first-line chemotherapy, this treatment is not a reasonable option at this time. Nivolumab alone or in combination with ipilimumab is a valid option for recurrent SCLC.

  17. Using genre pedagogy to promote student proficiency in the language required for interpreting line graphs

    Science.gov (United States)

    Smit, Jantien; Bakker, Arthur; van Eerde, Dolly; Kuijpers, Maggie

    2016-09-01

    The importance of language in mathematics learning has been widely acknowledged. However, little is known about how to make this insight productive in the design and enactment of language-oriented mathematics education. In a design-based research project, we explored how language-oriented mathematics education can be designed and enacted. We drew on genre pedagogy to promote student proficiency in the language required for interpreting line graphs. In the intervention, the teacher used scaffolding strategies to focus students' attention on the structure and linguistic features of the language involved in this particular domain. The research question addressed in this paper is how student proficiency in this language may be promoted. The study comprised nine lessons involving 22 students in grades 5 and 6 (aged 10-12); of these students, 19 had a migrant background. In light of the research aim, we first describe the rationale behind our design. Next, we illustrate how the design was enacted by means of a case study focusing on one student in the classroom practice of developing proficiency in the language required for interpreting line graphs. On the basis of pre- and posttest scores, we conclude that overall their proficiency has increased. Together, the results indicate that and how genre pedagogy may be used to help students become more proficient in the language required in a mathematical domain.

  18. Is there a role for immune checkpoint blockade with ipilimumab in prostate cancer?

    International Nuclear Information System (INIS)

    Cha, Edward; Small, Eric J

    2013-01-01

    Treatment for advanced prostate cancer has and will continue to grow increasingly complex, owing to the introduction of multiple new therapeutic approaches with the potential to substantially improve outcomes for this disease. Agents that modulate the patient's immune system to fight prostate cancer – immunotherapeutics – are among the most exciting of these new approaches. The addition of antigen-specific immunotherapy to the treatment of castration-resistant prostate cancer (CRPC) has paved the way for additional research that seeks to augment the activity of the immune system itself. The monoclonal antibody ipilimumab, approved in over 40 countries to treat advanced melanoma and currently under phase 2 and 3 investigation in prostate cancer, is thought to act by augmenting immune responses to tumors through blockade of cytotoxic T-lymphocyte antigen 4, an inhibitory immune checkpoint molecule. Ipilimumab has been studied in seven phase 1 and 2 clinical trials that evaluated various doses, schedules, and combinations across the spectrum of patients with advanced prostate cancer. The CRPC studies of ipilimumab to date suggest that the agent is active in prostate cancer as monotherapy or in combination with radiotherapy, docetaxel, or other immunotherapeutics, and that the adverse event profile is as expected given the safety data in advanced melanoma. The ongoing phase 3 program will further characterize the risk/benefit profile of ipilimumab in chemotherapy-naïve and -pretreated CRPC

  19. A case of pembrolizumab-induced type-1 diabetes mellitus and discussion of immune checkpoint inhibitor-induced type 1 diabetes.

    Science.gov (United States)

    Chae, Young Kwang; Chiec, Lauren; Mohindra, Nisha; Gentzler, Ryan; Patel, Jyoti; Giles, Francis

    2017-01-01

    Immune checkpoint inhibitors such as pembrolizumab, ipilimumab, and nivolumab, now FDA-approved for use in treating several types of cancer, have been associated with immune-related adverse effects. Specifically, the antibodies targeting the programmed-cell death-1 immune checkpoint, pembrolizumab and nivolumab, have been rarely reported to induce the development of type 1 diabetes mellitus. Here we describe a case of a patient who developed antibody-positive type 1 diabetes mellitus following treatment with pembrolizumab in combination with systemic chemotherapy for metastatic adenocarcinoma of the lung. We will also provide a brief literature review of other rarely reported cases of type 1 diabetes presenting after treatment with pembrolizumab and nivolumab, as well as discussion regarding potential mechanisms of this adverse effect and its importance as these drugs continue to become even more widespread.

  20. Volunteer Administration Leadership Proficiency and Leadership Styles: Perceptions of Southern Region 4-H County Faculty

    Science.gov (United States)

    Stedman, Nicole L. P.; Rudd, Rick D.

    2005-01-01

    Volunteers play an integral role in supporting the mission of 4-H programs in the southern region. For this reason their proficiency in volunteer administration competence and perceived leadership style is important. The researchers sought to examine both the perceived proficiency of 4-H faculty in the southern region in seven competencies…

  1. Cultutal Factors Affecting English Proficiency in Rural Areas

    Science.gov (United States)

    Ler, Ee Chop

    2012-01-01

    The purpose of this study is to investigate the rural "cultural" problems and to determine their effect on the learning of English. Twenty students from different ethnic backgrounds and English language proficiency in six rural schools in Terengganu, Malaysia were interviewed. In addition the teachers also from different rural schools…

  2. Measuring Oral Proficiency in Distance, Face-to-Face, and Blended Classrooms

    Directory of Open Access Journals (Sweden)

    Robert Blake

    2008-10-01

    Full Text Available Although the foreign-language profession routinely stresses the importance of technology for the curriculum, many teachers still harbor deep-seated doubts as to whether or not a hybrid course, much less a completely distance-learning class, could provide L2 learners with a way to reach linguistic proficiency, especially with respect to oral language skills. In this study, we examine the case of Spanish Without Walls (SWW, a first-year language course offered at the University of California - Davis in both hybrid and distance-learning formats. The SWW curriculum includes materials delivered via CD-ROM/DVD programs, online content-based web pages, and synchronous bimodal chat that includes sound and text. The contribution of each of these components is evaluated in the context of a successful technologically assisted course. To address the issue of oral proficiency, we compare the results from both classroom and distance-learning students who took the 20-minute Versant for Spanish test, delivered by phone and automatically graded. The data generated by this instrument shows that classroom, hybrid, and distance L2 learners reach comparable levels of oral proficiency during their first year of study. Reference is also made to two other ongoing efforts to provide distance-learning courses in Arabic and Punjabi, two languages where special difficulties in their writing systems have an impact on the design of the distant-learning format. The rationale for offering language courses in either a hybrid or distance-learning format is examined in light of increasing societal pressures to help L2 learners reach advanced proficiency, especially in less commonly taught languages (LCTLs.

  3. Online Assessment of Oral Proficiency for Intercultural Professional Communication

    NARCIS (Netherlands)

    Rusman, Ellen; Stoyanov, Slavi

    2012-01-01

    Rusman, E., & Stoyanov, S. (2011, 18 May). Online Assessment of Oral Proficiency for Intercultural Professional Communication. Presentation about the CEFcult project (www.cefcult.eu) at the workshop ‘Crossing borders’ organised by the Talenacademie, Heerlen, The Netherlands: Open University in the

  4. The Neurospora crassa UVS-3 epistasis group encodes homologues of the ATR/ATRIP checkpoint control system.

    Science.gov (United States)

    Kazama, Yusuke; Ishii, Chizu; Schroeder, Alice L; Shimada, Hisao; Wakabayashi, Michiyoshi; Inoue, Hirokazu

    2008-02-01

    The mutagen sensitive uvs-3 and mus-9 mutants of Neurospora show mutagen and hydroxyurea sensitivity, mutator effects and duplication instability typical of recombination repair and DNA damage checkpoint defective mutants. To determine the nature of these genes we used cosmids from a genomic library to clone the uvs-3 gene by complementation for MMS sensitivity. Mutation induction by transposon insertion and RIP defined the coding sequence. RFLP analysis confirmed that this sequence maps in the area of uvs-3 at the left telomere of LG IV. Analysis of the cDNA showed that the UVS-3 protein contains an ORF of 969 amino acids with one intron. It is homologous to UvsD of Aspergillus nidulans, a member of the ATRIP family of checkpoint proteins. It retains the N' terminal coiled-coil motif followed by four basic amino acids typical of these proteins and shows the highest homology in this region. The uvsD cDNA partially complements the defects of the uvs-3 mutation. The uvs-3 mutant shows a higher level of micronuclei in conidia and failure to halt germination and nuclear division in the presence of hydroxyurea than wild type, suggesting checkpoint defects. ATRIP proteins bind tightly to ATR PI-3 kinase (phosphatidylinositol 3-kinase) proteins. Therefore, we searched the Neurospora genome sequence for homologues of the Aspergillus nidulans ATR, UvsB. A uvsB homologous sequence was present in the right arm of chromosome I where the mus-9 gene maps. A cosmid containing this genomic DNA complemented the mus-9 mutation. The putative MUS-9 protein is 2484 amino acids long with eight introns. Homology is especially high in the C-terminal 350 amino acids that correspond to the PI-3 kinase domain. In wild type a low level of constitutive mRNA is present for both genes. It is transiently induced upon UV exposure.

  5. WEB-BASED LANGUAGE CLUB AFFECTING EFL LEARNERS’ PROFICIENCY: A CASE OF IRANIAN LEARNERS

    Directory of Open Access Journals (Sweden)

    Hamid Ashraf

    2014-06-01

    Full Text Available Language clubs have been reported to be effective in learning languages, increasing motivation and independence (Gao, 2009. The present study was an attempt to investigate the effect of a web-based language club on the language proficiency of Iranian EFL learners. A number of pre-intermediate learners form two universities (118 were selected among 154 through a test of proficiency (TOEFL PBL, then they were put into experimental and control groups. The participants in experimental group got on line and acted as a member of a virtual language club for a period of 6 months. They got involved with activities like emailing, chatting, and weblogging. Data were collected through TOEFL PBL. The analyzed data from the test of proficiency indicated the outperformance of those in experimental group. Consequently, it might be proposed that web-based language clubs can make language learning easier and more efficient.

  6. High second-language proficiency protects against the effects of reverberation on listening comprehension.

    Science.gov (United States)

    Sörqvist, Patrik; Hurtig, Anders; Ljung, Robert; Rönnberg, Jerker

    2014-04-01

    The purpose of this experiment was to investigate whether classroom reverberation influences second-language (L2) listening comprehension. Moreover, we investigated whether individual differences in baseline L2 proficiency and in working memory capacity (WMC) modulate the effect of reverberation time on L2 listening comprehension. The results showed that L2 listening comprehension decreased as reverberation time increased. Participants with higher baseline L2 proficiency were less susceptible to this effect. WMC was also related to the effect of reverberation (although just barely significant), but the effect of WMC was eliminated when baseline L2 proficiency was statistically controlled. Taken together, the results suggest that top-down cognitive capabilities support listening in adverse conditions. Potential implications for the Swedish national tests in English are discussed. © 2014 The Authors. Scandinavian Journal of Psychology published by Scandinavian Psychological Associations and John Wiley & Sons Ltd.

  7. Beam walking can detect differences in walking balance proficiency across a range of sensorimotor abilities.

    Science.gov (United States)

    Sawers, Andrew; Ting, Lena H

    2015-02-01

    The ability to quantify differences in walking balance proficiency is critical to curbing the rising health and financial costs of falls. Current laboratory-based approaches typically focus on successful recovery of balance while clinical instruments often pose little difficulty for all but the most impaired patients. Rarely do they test motor behaviors of sufficient difficulty to evoke failures in balance control limiting their ability to quantify balance proficiency. Our objective was to test whether a simple beam-walking task could quantify differences in walking balance proficiency across a range of sensorimotor abilities. Ten experts, ten novices, and five individuals with transtibial limb loss performed six walking trials across three different width beams. Walking balance proficiency was quantified as the ratio of distance walked to total possible distance. Balance proficiency was not significantly different between cohorts on the wide-beam, but clear differences between cohorts on the mid and narrow-beams were identified. Experts walked a greater distance than novices on the mid-beam (average of 3.63±0.04m verus 2.70±0.21m out of 3.66m; p=0.009), and novices walked further than amputees (1.52±0.20m; p=0.03). Amputees were unable to walk on the narrow-beam, while experts walked further (3.07±0.14m) than novices (1.55±0.26m; p=0.0005). A simple beam-walking task and an easily collected measure of distance traveled detected differences in walking balance proficiency across sensorimotor abilities. This approach provides a means to safely study and evaluate successes and failures in walking balance in the clinic or lab. It may prove useful in identifying mechanisms underlying falls versus fall recoveries. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. The Relationship between Reading Proficiency and Reading Strategy Use: A Study of Adult ESL Learners

    Science.gov (United States)

    Huang, Jiuhan; Nisbet, Deanna

    2014-01-01

    This article explores the relationship between reading strategy use and reading proficiency among 121 adult ESL learners. Reading strategy use was measured by the SORS, and reading proficiency was determined by the CASAS Reading Test and BEST Literacy Test. Findings of the study reveal that (a) adult ESL learners are active strategies users; (b)…

  9. The English proficiency and academic language skills of Australian bilingual children during the primary school years.

    Science.gov (United States)

    Dennaoui, Kamelia; Nicholls, Ruth Jane; O'Connor, Meredith; Tarasuik, Joanne; Kvalsvig, Amanda; Goldfeld, Sharon

    2016-04-01

    Evidence suggests that early proficiency in the language of school instruction is an important predictor of academic success for bilingual children. This study investigated whether English-proficiency at 4-5 years of age predicts academic language and literacy skills among Australian bilingual children at 10-11 years of age, as part of the Longitudinal Study of Australian Children ( LSAC, 2012 ). The LSAC comprises a nationally representative clustered cross-sequential sample of Australian children. Data were analysed from a sub-sample of 129 bilingual children from the LSAC Kindergarten cohort (n = 4983), for whom teachers completed the Australian Early Development Index (AEDI) checklist (a population measure of early childhood development) and the Academic Rating Scale (ARS) language and literacy subscale. Linear regression analyses revealed that bilingual children who commenced school with stronger English proficiency had higher academic language and literacy scores at the end of primary school (β = 0.45). English proficiency remained a significant predictor, even when accounting for gender and socio-economic disadvantage (β = 0.38). The findings indicate that bilingual children who begin school without English proficiency are at risk of difficulties with academic language and literacy, even after 6 years of schooling. Risk factors need to be identified so early support can be targeted towards the most vulnerable children.

  10. Wip1 phosphatase is associated with chromatin and dephosphorylates gammaH2AX to promote checkpoint inhibition

    Czech Academy of Sciences Publication Activity Database

    Macůrek, Libor; Lindqvist, A.; Voets, O.; Kool, J.; Vos, H.R.; Medema, R.H.

    2010-01-01

    Roč. 29, č. 15 (2010), s. 2281-2291 ISSN 0950-9232 R&D Projects: GA ČR GPP305/10/P420 Institutional research plan: CEZ:AV0Z50520514 Keywords : DNA damage * checkpoint * phosphatase Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 7.414, year: 2010

  11. The Effects of Elementary Departmentalization on Mathematics Proficiency

    Science.gov (United States)

    Taylor-Buckner, Nicole C.

    2014-01-01

    Mathematics education in the elementary schools has experienced many changes in recent decades. With the curriculum becoming more complex as a result of each modification, immense pressure has been put on schools to increase student proficiency. The Common Core State Standards is the latest example of this. These revisions to the mathematics…

  12. Using ergonomics checkpoints to support a participatory ergonomics intervention in an industrially developing country (IDC)--a case study.

    Science.gov (United States)

    Helali, Faramarz

    2009-01-01

    To achieve ergonomics awareness in 3 subsidiary companies, an intervention team was formed. The aims of this study were to implement basic ergonomics through a participatory ergonomics intervention process that can support a continuous learning process and lead to an improvement in health and safety as well as in the work systems in the organization. The findings of this study (i.e., method, continuous learning and integration) were key to making the participatory ergonomics intervention successful. Furthermore, 4 issues of the ergonomics checkpoints (i.e., work schedules, work tasks, healthy work organization and learning) for assessing the work system were found suitable for both changing work schedules and for improving the work system. This paper describes the result of this project and also the experiences gained and the conclusions reached from using the International Labour Office's ergonomics checkpoints in the industries of industrially developing country.

  13. Defining English Language Proficiency for Malaysian Tertiary Education: Past, Present and Future Efforts

    Directory of Open Access Journals (Sweden)

    Chan Swee Heng

    2012-07-01

    Full Text Available Any attempt to define English language proficiency can never be divorced from the theories that describe the nature of language, language acquisition and human cognition. By virtue of such theories being socially constructed, the descriptions are necessarily value-laden. Thus, a definition of language proficiency can only, at best, be described as developmental, following changes that are linguistic, pragmatic, cultural and political. In defining English proficiency for tertiary education, the context is naturally also linked to the focus on university education. The argument has been that an ‘acceptable’ level of language competence of a university applicant is anything but constant. Tremendous social changes have seen traditional values of elitism in university education giving way to the ‘massification’ of education. As Kaplan and Baldauf (1997:257 affirms, “The principal problem in tertiary education is not declining literacy standards but rather it is about meeting changed societal, cultural and informational requirements and circumstances”. In the light of these changes, this paper attempts to trace influencing factors that help define an ‘acceptable’ level of English proficiency for Malaysian tertiary education. The paper examines past and present efforts of establishing an English language policy and assessment practice for tertiary education, and concludes with some views on future development that could evolve from the current indicative pursuits of establishing language learning and ability.

  14. Teacher Professionalism--An Innovative Programme for Teaching Mathematics to Foundation Level Learners with Limited Language Proficiency.

    Science.gov (United States)

    Naude, H.; Pretorius, E.; Vandeyar, S.

    2003-01-01

    Details a study of the ways that limited language proficiency affected learners' readiness for mathematics instruction among disadvantaged preschoolers within a Griqua community in South Africa. Notes a link between limited language proficiency and nonreadiness for foundation level mathematics due to limited thinking skills, which constitute…

  15. Cognitive Proficiency Index for the Canadian Edition of the Wechsler Intelligence Scale for Children-Fourth Edition

    Science.gov (United States)

    Saklofske, Donald H.; Zhu, Jianjun; Coalson, Diane L.; Raiford, Susan E.; Weiss, Lawrence G.

    2010-01-01

    The Cognitive Proficiency Index (CPI) developed for the most recent Wechsler intelligence scales comprises the working memory and processing speed subtests. It reflects the proficiency and efficiency of cognitive processing and provides another lens for analyzing children's abilities assessed by the Wechsler Intelligence Scale for Children--Fourth…

  16. Linguistic Proficiency and Strategies on Reading Performance in English

    Directory of Open Access Journals (Sweden)

    Seyed Hassan Talebi

    2015-01-01

    Full Text Available General English (L2 proficiency and reading strategies are believed to be highly effective in successful reading performance. However, available studies rarely investigated the combined effects of these two variables on successful reading. To fill this gap, 78 university students were divided into four groups of different degrees of these two variables in L2 and given a reading test in English and an interview for assessing how much of the problems in L2 reading among the four groups were rooted in linguistic competence and/or strategic competence. Findings evinced that the high general proficiency level coupled with high awareness and use of reading strategies would result in best performance and that the pattern of answers to different components of reading question is different in different groups. It is concluded that both of the variables should be emphasized simultaneously for the best performance in reading comprehension.

  17. The relationship between automatic assessment of oral proficiency and other indicators of first year students' linguistic abilities

    CSIR Research Space (South Africa)

    De Wet, Febe

    2012-11-01

    Full Text Available Academic literacy proficiency is key to the success of a student at university. Currently, the large-scale assessment of language proficiency, particularly at higher education levels, is dominated by reading and writing tests because listening...

  18. Vaccination targeting human HER3 alters the phenotype of infiltrating T cells and responses to immune checkpoint inhibition.

    Science.gov (United States)

    Osada, Takuya; Morse, Michael A; Hobeika, Amy; Diniz, Marcio A; Gwin, William R; Hartman, Zachary; Wei, Junping; Guo, Hongtao; Yang, Xiao-Yi; Liu, Cong-Xiao; Kaneko, Kensuke; Broadwater, Gloria; Lyerly, H Kim

    2017-01-01

    Expression of human epidermal growth factor family member 3 (HER3), a critical heterodimerization partner with EGFR and HER2, promotes more aggressive biology in breast and other epithelial malignancies. As such, inhibiting HER3 could have broad applicability to the treatment of EGFR- and HER2-driven tumors. Although lack of a functional kinase domain limits the use of receptor tyrosine kinase inhibitors, HER3 contains antigenic targets for T cells and antibodies. Using novel human HER3 transgenic mouse models of breast cancer, we demonstrate that immunization with recombinant adenoviral vectors encoding full length human HER3 (Ad-HER3-FL) induces HER3-specific T cells and antibodies, alters the T cell infiltrate in tumors, and influences responses to immune checkpoint inhibitions. Both preventative and therapeutic Ad-HER3-FL immunization delayed tumor growth but were associated with both intratumoral PD-1 expressing CD8 + T cells and regulatory CD4 + T cell infiltrates. Immune checkpoint inhibition with either anti-PD-1 or anti-PD-L1 antibodies increased intratumoral CD8 + T cell infiltration and eliminated tumor following preventive vaccination with Ad-HER3-FL vaccine. The combination of dual PD-1/PD-L1 and CTLA4 blockade slowed the growth of tumor in response to Ad-HER3-FL in the therapeutic model. We conclude that HER3-targeting vaccines activate HER3-specific T cells and induce anti-HER3 specific antibodies, which alters the intratumoral T cell infiltrate and responses to immune checkpoint inhibition.

  19. Proficiency testing of skin prick testers as part of a quality assurance system

    DEFF Research Database (Denmark)

    Malling, Hans-Jørgen; Allesen-Holm, Pernille; Karved, Lisbeth Sys

    2016-01-01

    BACKGROUND: Skin prick test is an important diagnostic procedure in clinical allergy but documentation of the quality is often missing. METHODS: We describe a proficiency system to evaluate staff members in relation to the international recommended reproducibility in terms of coefficient...... of variation (CV 0.85) based on blinded octuplicate histamine testing using histamine 3, 10, 30 and 100 mg/ml. RESULTS: Fourteen trained allergy nurses participated in the proficiency testing. More than 95 % of the nurses, generated coefficient of variation...

  20. INFLUENCE OF STUDENT ENGLISH UTILITY AND TEACHER EFFICACY ON ENGLISH PROFICIENCY OF HIGH SCHOOL STUDENTS

    Directory of Open Access Journals (Sweden)

    Ruth A. ORTEGA-DELA CRUZ

    2016-12-01

    Full Text Available Learning second language considers a number of factors that influence the manner in which the language is taught. Understanding of the learners’ goals and motivation for learning is one. Using descriptive-correlational research design, this study determined the influence of student English utility and teacher efficacy on the students’ English proficiency. A total of 101 students from first year to fourth year level served as the respondents of the study. The study quantified the students’ perception towards English utility and their evaluation of English teacher efficacy which employed a researcher-made survey questionnaire. Results revealed high positive perceptions of students towards English utility. Analysis of variance revealed significant differences in the perceptions of high school students on the efficacy of their English teachers. Correlation coefficients indicated a positive linear relationship among the given variables. The p-value revealed significant relationship of teacher efficacy (r = .691, p-value = .000 and English utility (r = .467, p-value = .000 to students’ English proficiency. Results of regression statistics revealed that English utility has no significant influence on the student English proficiency. Therefore, the main factor that must still be considered then should be the teacher. Finally, there is an explicit indication that high level of teachers’ efficacy performing in teaching has much powerful influence on the English proficiency of high school students. Thus improving the methods of teaching English provides a better way of motivating students to achieve higher levels of proficiency in the future.

  1. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints

    DEFF Research Database (Denmark)

    Bartkova, Jirina; Rezaei, Nousin; Liontos, Michalis

    2006-01-01

    Recent studies have indicated the existence of tumorigenesis barriers that slow or inhibit the progression of preneoplastic lesions to neoplasia. One such barrier involves DNA replication stress, which leads to activation of the DNA damage checkpoint and thereby to apoptosis or cell cycle arrest...... and senescence markers cosegregate closely. Thus, senescence in human preneoplastic lesions is a manifestation of oncogene-induced DNA replication stress and, together with apoptosis, provides a barrier to malignant progression....

  2. Differential Effects of Learning Games on Mathematics Proficiency

    Science.gov (United States)

    Chang, Mido; Evans, Michael A.; Kim, Sunha; Norton, Anderson; Samur, Yavuz

    2015-01-01

    This study examined the effects of a learning game, [The Math App] on the mathematics proficiency of middle school students. For the study, researchers recruited 306 students, Grades 6-8, from two schools in rural southwest Virginia. Over a nine-week period, [The Math App] was deployed as an intervention for investigation. Students were assigned…

  3. Socio-Demographic and Practice-Oriented Factors Related to Proficiency in Problem Solving: A Lifelong Learning Perspective

    Science.gov (United States)

    Desjardins, Richard; Ederer, Peer

    2015-01-01

    This article explores the relative importance of different socio-demographic and practice-oriented factors that are related to proficiency in problem solving in technology-rich environments (PSTREs) and by extension may be related to complex problem solving (CPS). The empirical analysis focuses on the proficiency measurements of PSTRE made…

  4. ATM/Wip1 activities at chromatin control Plk1 re-activation to determine G2 checkpoint duration

    Czech Academy of Sciences Publication Activity Database

    Jaiswal, H.; Benada, Jan; Müllers, E.; Akopyan, K.; Burdová, Kamila; Koolmeister, T.; Helleday, T.; Medema, R.H.; Macůrek, Libor; Lindqvist, A.

    2017-01-01

    Roč. 36, č. 14 (2017), s. 2161-2176 ISSN 0261-4189 R&D Projects: GA ČR GA13-18392S Institutional support: RVO:68378050 Keywords : ATM * ATR * checkpoint recovery * G2 * Pik1 Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Cell biology Impact factor: 9.792, year: 2016

  5. Proficiency evaluation of maintenance personnel: Training equivalency determination

    International Nuclear Information System (INIS)

    Price, W.J.

    1991-01-01

    The nuclear industry has recognized the importance of safe, quality, productive maintenance practices and has taken a number of initiatives that have generally improved maintenance programs. Because proficient maintenance practices are critical to plant safety and reliability, most plants have also recognized the need for reliable, valid testing techniques that demonstrate and assure the competence of their maintenance personnel. Until now, resource demands were too great to develop in-plant testing programs. In the past, maintenance supervisors have exempted personnel from training, using informal judgment of the employees' previous training and experience and informal observation of the employee on the job. While this procedure may have some degree of validity, it fails to provide the documentation for training equivalency that is required to satisfy the US Nuclear Regulatory Commission (NRC) regulations and Institute of Nuclear Power Operations (INPO) guidelines. To assess and demonstrate the proficiency levels of personnel, Calvert Cliffs needed to establish an objective, reliable, time-saving, and valid system to evaluate the competency levels of personnel. This was done in a joint effort with the Electric Power Research Institute

  6. Structural Biology of the Immune Checkpoint Receptor PD-1 and Its Ligands PD-L1/PD-L2

    NARCIS (Netherlands)

    Zak, Krzysztof M.; Grudnik, Przemyslaw; Magiera, Katarzyna; Dömling, Alexander; Dubin, Grzegorz; Holak, Tad A.

    2017-01-01

    Cancer cells can avoid and suppress immune responses through activation of inhibitory immune checkpoint proteins, such as PD-1, PD-L1, and CTLA-4. Blocking the activities of these proteins with monoclonal antibodies, and thus restoring T cell function, has delivered breakthrough therapies against

  7. Key Factors in Obstetric Delivery Decision-Making among Asian and Pacific Islander Women by English Proficiency.

    Science.gov (United States)

    Davis, Chevelle Ma; Guo, Mary; Miyamura, Jill; Chang, Ann; Nelson-Hurwitz, Denise C; Sentell, Tetine

    2017-10-01

    Childbirth is the most common reason women are hospitalized in the United States. Understanding (1) how expectant mothers gather information to decide where to give birth, and (2) who helps make that decision, provides critical health communication and decision-making insights. Diverse Asian American and Pacific Islander (AA/PI) perspectives on such topics are understudied, particularly among those with limited English proficiency (LEP). LEP is defined as having a limited ability to read, write, speak, or understand English. To address this research gap, we interviewed 400 women (18+ years) with a recent live birth on O'ahu, Hawai'i. Participants completed a 1-hour, in-person interview in English (n=291), Tagalog (n=42), Chinese (n=36), or Marshallese (n=31). Women were asked (1) what information was most important in deciding where to deliver and why; and (2) who participated in the decision-making and why. Responses were compared by LEP (n=71; 18%) vs English-proficient (n=329; 82%) in qualitative and quantitative analyses. Both LEP and English-proficient participants reported their obstetrician as the most important source of health information. Significantly more LEP participants valued advice from family or acquaintances as important sources of information compared to English-proficient participants. The top three health decision-makers for both those with LEP and English-proficient participants were themselves, their obstetrician, and their spouse, which did not differ significantly by language proficiency. These findings provide insights into health information sources and decision-making across diverse AA/PI populations, including those with LEP, and can help direct health interventions such as disseminating patient education and healthcare quality information.

  8. The Education Consequences of Language Proficiency for Young Children

    NARCIS (Netherlands)

    Yao, Yuxin; Ohinata, Asako; van Ours, Jan

    2016-01-01

    This paper studies the educational consequences of language proficiency by investigating the relationship between dialect-speaking and academic performance of 5-6 year old children in the Netherlands. We find that dialect-speaking has a modestly negative effect on boys' language test scores. In

  9. The educational consequences of language proficiency for young children

    NARCIS (Netherlands)

    Yao, Yuxin; Ohinata, Asako; van Ours, Jan

    2016-01-01

    Our paper studies the educational consequences of language proficiency by investigating the relationship between dialect-speaking and academic performance of 5–6 year old children in the Netherlands. We find that dialect-speaking has a modestly negative effect on boys’ language test scores. In

  10. Study on team evaluation (6). Relationships among technical skill proficiency, leadership, and teamwork behaviors

    International Nuclear Information System (INIS)

    Misawa, Ryo; Sasou, Kunihide

    2011-01-01

    To maintain and improve the efficiency and safety of operations in numerous industries, it is necessary to develop programs that enhance teamwork. This can be achieved through empirical investigations that identify influential factors contributing to teamwork. This study focused on technical skill proficiency and leadership as influential factors and examined the relationships among these factors and teamwork behaviors. A series of measurements was performed on 54 operations teams with the cooperation of the training center of thermal power plants. Teamwork behaviors in training under simulated abnormal conditions were evaluated through instructors' observation using a behavior checklist. Technical skill proficiency was measured by conducting a brief survey on instructors. Leadership was measured on the basis of followers' responses on questionnaire scales. Based on the scores of technical skill proficiency and leadership, hierarchical cluster analysis revealed three types of teams: (a) F-type - the technical skills of followers are superior to those of leaders; (b) LF-type - both leaders and followers are proficient in technical skills; and (c) L-type - the technical skills of leaders are superior to those of followers. ANOVAs were conducted to examine differences in teamwork behavior for the three types of teams. The main results revealed that LF-type teams actively engaged in information gathering and that leaders played a central role in these activities. In addition, the followers of F-type teams freely exchanged their ideas and opinions regarding problems and actively discussed how to solve them. These findings suggest that teamwork behaviors can vary depending on technical skill proficiency and leadership in teams. Future research is needed to identify additional factors affecting teamwork that are not measured in this study. (author)

  11. The accreditation programs and proficiency test in Taiwan for personnel dosimeter services (1991-1998)

    International Nuclear Information System (INIS)

    Lee, B.T.; Hwang, W.S.; Su, S.H.

    2000-01-01

    According to the ionizing radiation safety regulation approved by the ROC Atomic Energy Council (AEC), personnel dosimeter processors shall be accredited by the Chinese National Laboratory Accreditation (CNLA) program before offering dosimeter services and shall be accredited every two years (now has been rescheduled to be every three years since 1996). The aim of this program is to secure quality and technical capability of personnel dosimeters, and to provide systematic improvement for the internal calibration and testing laboratory applying for accreditation by means of assessment procedures. The criteria used to evaluate the capability at laboratories are ISO/IEC 25 (1990) and technical guide in different accreditation fields. The Institute of Nuclear Energy Research (INER) was entrusted by CNLA as the central laboratory to perform the proficiency test of personnel dosimeters for laboratory accreditation in December 1990. Such proficiency tests, based on ANSI N13.11 (1983), which is mainly separated to accident categories and protection categories which consists of eight parts of tests including single and mixture radiation of x-ray, gamma, beta and neutron, have been conducted four times, in 1991, 1993, 1995 and 1998. This paper deals with the test procedures and results of proficiency tests of personnel dosimeters from 1991 until 1998. The results of the four proficiency tests showed that, for accident categories, the pass rate is about 91%; for protection categories, the pass rate is about 98%. Meanwhile, the central laboratory will adopt a new version of HPS N13.11 (1993) to replace ANSI N13.11 (1983) as new criteria for the next proficiency test to be conducted in 2001. (author)

  12. EMPLOYERS’ VIEWS ON IMPORTANCE OF ENGLISH PROFICIENCY AND COMMUNICATION SKILL FOR EMPLOYABILITY IN MALAYSIA

    Directory of Open Access Journals (Sweden)

    Su-Hie Ting

    2017-09-01

    Full Text Available Employability of graduates is a concern in many countries, including Malaysia, and the high unemployment rate among graduates is often attributed to their lack of English proficiency and communication skills. These two distinctive elements are often collated, and it is important to find out which is more important to employers. The study examined the employers’ views on the importance of English proficiency and communication skill for graduates to be employed in the Malaysian private sector. The data were from semi-structured interviews conducted with 10 employers in the private sector who were in the position to recruit staff. The 21,433-word interview transcripts were analyzed. The results revealed that employers in the Malaysian private sector view language proficiency and communication skills as separate qualities. The employers are willing to consider employing candidates with average English proficiency if they have good communication skills, except for jobs which require more communication in English such as customer service and marketing. The results also revealed that good communication skills can increase employability and opportunities for career advancement. The findings highlight the communication skills that universities need to emphasize so that their graduates have the necessary skills to perform well in employment interviews and in their work.

  13. Fundamental motor skill proficiency is necessary for children's motor activity inclusion

    Directory of Open Access Journals (Sweden)

    José Angelo Barela

    2013-09-01

    Full Text Available Motor development is influenced by many factors such as practice and appropriate instruction, provided by teachers, even in preschool and elementary school. The goal of this paper was to discuss the misconception that maturation underlies children's motor skill development and to show that physical education, even in early years of our school system, is critical to promote proficiency and enrolment of children's in later motor activities. Motor skill development, as a curricular focus, has been marginalized in many of our physical education proposal and in doing so, we have not promote motor competence in our children who lack proficiency to engage and to participate in later motor activities such as sport-related or recreational.

  14. Naming Abilities in Low-Proficiency Second Language Learners

    Science.gov (United States)

    Borodkin, Katy; Faust, Miriam

    2014-01-01

    Difficulties in second language (L2) learning are often associated with recognizable learning difficulties in native language (L1), such as in dyslexia. However, some individuals have low L2 proficiency but intact L1 reading skills. These L2 learners experience frequent tip-of-the-tongue states while naming in L1, which indicates that they have a…

  15. Acute inflammatory thyromegaly following checkpoint inhibition: A new imaging entity?

    Directory of Open Access Journals (Sweden)

    Erik H. Middlebrooks, MD

    2018-02-01

    Full Text Available Immune checkpoint blockade (CPB utilizing such agents as ipilimumab, nivolumab, or pembrolizumab has revolutionized melanoma therapy and has seen continued utilization in numerous other malignancies in recent years. However, these agents come at the price of inflammatory immune-related adverse events. Despite the increasing recognition of biochemical thyroid dysfunction associated with CPB, information regarding potential imaging findings is sparse. We describe the first 2 cases of acute thyroiditis following CPB presenting as diffuse thyromegaly documented by computed tomography, ultrasound, and iodine uptake imaging. Given the rise in the use of CPB, it is important for radiologists to recognize potential imaging manifestations of therapy immune-related adverse events to avoid erroneous diagnosis and to prompt the biochemical investigation of thyroid function.

  16. Race cars and the hellbox:Understanding the development of proficiency among digital art students

    OpenAIRE

    Paquette, Andrew; Reedy, Gabriel; Hatzipanagos, Stylianos

    2016-01-01

    Educating students in the discipline of digital art to a professional standard has generally proven difficult. In an effort to understand the problem, a first-year undergraduate modelling course cohort was observed. Some students in this course progressed from being novices to acquiring proficiency during the nine-week term of the course. Computer Graphics (CG) modelling professionals evaluated student work to confirm their progress. Traditional models of proficiency development expect that p...

  17. Vietnamese Immigrant and Refugee Women's Mental Health: An Examination of Age of Arrival, Length of Stay, Income, and English Language Proficiency

    Science.gov (United States)

    Brown, Chris; Schale, Codi L.; Nilsson, Johanna E.

    2010-01-01

    Vietnamese immigrant and refugee women (N = 83) were surveyed regarding their mental health, English language proficiency, age of arrival, length of stay, and income. English language proficiency and age of arrival correlated with reduced symptomatology. Moreover, English language proficiency was the sole predictor of somatic distress. (Contains 1…

  18. Development of reference material for proficiency tests: arsenic in fish tissue

    International Nuclear Information System (INIS)

    Santana, Luciana Vieira de; Sarkis, Jorge E.S.; Ulrich, Joao C.; Hortellani, Marcos Antonio

    2013-01-01

    Proficiency tests (PT) are extensively used to evaluate the analytical competence of laboratories, and are also used as a part of accreditation processes. For this reason are important tool for quality control of laboratories including laboratories that act directly with food exporting companies. In Brazil there are no providers of proficiency testing for toxic metals, such as arsenic in fish tissue. This study presents a protocol to produce reference material to be used in proficiency test for arsenic in fish tissue following the recommendations of the ISO Guide 35. The preparation scheme consisted of: selecting of individuals, cleaning of scale and skin, trituration, homogenization, and spiking with arsenic at two levels of concentration. The mixture was then irradiated in a cyclotron Cyclone 30 Applications ion beam with cobalt 60 at 10.00 ± 1.05 KGy, before being packed into sachets. To verify the efficacy of the irradiation procedure, 26 (randomly selected) irradiated sachets and 26 non-irradiated sachets were assessed for homogeneity and stability. The results indicate that irradiation with cobalt 60 is crucial for ensuring the preservation of the integrity of the material, providing stable material at room temperature for 2 months. The samples can therefore be transported at room temperature. (author)

  19. Development of reference material for proficiency tests: arsenic in fish tissue

    Energy Technology Data Exchange (ETDEWEB)

    Santana, Luciana Vieira de; Sarkis, Jorge E.S.; Ulrich, Joao C.; Hortellani, Marcos Antonio, E-mail: santana-luciana@ig.com.br, E-mail: jesarkis@ipen.br, E-mail: jculrich@ipen.br, E-mail: mahortel@ipen.br [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)

    2013-07-01

    Proficiency tests (PT) are extensively used to evaluate the analytical competence of laboratories, and are also used as a part of accreditation processes. For this reason are important tool for quality control of laboratories including laboratories that act directly with food exporting companies. In Brazil there are no providers of proficiency testing for toxic metals, such as arsenic in fish tissue. This study presents a protocol to produce reference material to be used in proficiency test for arsenic in fish tissue following the recommendations of the ISO Guide 35. The preparation scheme consisted of: selecting of individuals, cleaning of scale and skin, trituration, homogenization, and spiking with arsenic at two levels of concentration. The mixture was then irradiated in a cyclotron Cyclone 30 Applications ion beam with cobalt 60 at 10.00 ± 1.05 KGy, before being packed into sachets. To verify the efficacy of the irradiation procedure, 26 (randomly selected) irradiated sachets and 26 non-irradiated sachets were assessed for homogeneity and stability. The results indicate that irradiation with cobalt 60 is crucial for ensuring the preservation of the integrity of the material, providing stable material at room temperature for 2 months. The samples can therefore be transported at room temperature. (author)

  20. The Minnesota Articulation Project and Its Proficiency-Based Assessments.

    Science.gov (United States)

    Chalhoub-Deville, Micheline

    1997-01-01

    Reports on the Minnesota Articulation Project, providing an overview of the projects' three principal working groups: political action, curriculum, and assessment. The article then outlines the theoretical underpinnings of the proficiency-based assessment instruments developed in French, German, and Spanish and describes in detail the content and…

  1. Evaluation of Mycology Laboratory Proficiency Testing

    Science.gov (United States)

    Reilly, Andrew A.; Salkin, Ira F.; McGinnis, Michael R.; Gromadzki, Sally; Pasarell, Lester; Kemna, Maggi; Higgins, Nancy; Salfinger, Max

    1999-01-01

    Changes over the last decade in overt proficiency testing (OPT) regulations have been ostensibly directed at improving laboratory performance on patient samples. However, the overt (unblinded) format of the tests and regulatory penalties associated with incorrect values allow and encourage laboratorians to take extra precautions with OPT analytes. As a result OPT may measure optimal laboratory performance instead of the intended target of typical performance attained during routine patient testing. This study addresses this issue by evaluating medical mycology OPT and comparing its fungal specimen identification error rates to those obtained in a covert (blinded) proficiency testing (CPT) program. Identifications from 188 laboratories participating in the New York State mycology OPT from 1982 to 1994 were compared with the identifications of the same fungi recovered from patient specimens in 1989 and 1994 as part of the routine procedures of 88 of these laboratories. The consistency in the identification of OPT specimens was sufficient to make accurate predictions of OPT error rates. However, while the error rates in OPT and CPT were similar for Candida albicans, significantly higher error rates were found in CPT for Candida tropicalis, Candida glabrata, and other common pathogenic fungi. These differences may, in part, be due to OPT’s use of ideal organism representatives cultured under optimum growth conditions. This difference, as well as the organism-dependent error rate differences, reflects the limitations of OPT as a means of assessing the quality of routine laboratory performance in medical mycology. PMID:10364601

  2. Student Engagement in Long-Term Collaborative EFL Storytelling Activities: An Analysis of Learners with English Proficiency Differences

    Science.gov (United States)

    Huang, Yun-Yin; Liu, Chen-Chung; Wang, Yu; Tsai, Chin-Chung; Lin, Hung-Ming

    2017-01-01

    English proficiency difference among students is a challenging pedagogical issue in EFL classrooms worldwide. Collaborative digital storytelling has been adopted in language learning settings to increase motivation and engagement, especially for young learners. However, it remains unknown whether students of different proficiency levels can…

  3. Comparing Multiple-Group Multinomial Log-Linear Models for Multidimensional Skill Distributions in the General Diagnostic Model. Research Report. ETS RR-08-35

    Science.gov (United States)

    Xu, Xueli; von Davier, Matthias

    2008-01-01

    The general diagnostic model (GDM) utilizes located latent classes for modeling a multidimensional proficiency variable. In this paper, the GDM is extended by employing a log-linear model for multiple populations that assumes constraints on parameters across multiple groups. This constrained model is compared to log-linear models that assume…

  4. Performance Monitoring and Response Inhibition in a Saccadic Countermanding Task in High and Low proficient bilinguals.

    Directory of Open Access Journals (Sweden)

    Niharika eSingh

    2015-01-01

    Full Text Available We compared Hindi-English bilinguals differing in their L2 fluency on a saccadic countermanding task which taps inhibitory control as well as monitoring. We particularly explored whether response inhibition and performance monitoring within the oculomotor domain are affected by language proficiency in bilinguals. There were two different oculomotor redirect tasks: Visually Guided Redirect (VGR task (Experiment1 and Memory Guided Redirect (MGR task (Experiment 2. In this task typically a target is presented to which subject must make saccade (No step trials, unless a new target appears on the other location after some delay from the first target onset (Step trials. On such trials participants are required to inhibit and cancel the saccade to the first instead program a saccade to the new target. Using trial switch reaction time (TSRT, which is the time taken to inhibit the initiated saccade to the first target, as a measure of response inhibition, and post-stop slowing as a measure of performance monitoring, we observed two important results. It was found that high proficiency bilinguals showed more post-stop slowing on the no-step trials as compared to the low proficiency bilinguals for both VGR and MGR. Secondly, high and low proficiency bilingual exhibited comparable TSRT in both VGR and MGR, showing no altering effect of language proficiency on the response inhibition in bilinguals. These results suggest that bilingualism impacts performance monitoring which is modulated by language proficiency if not the inhibitory control system. Higher fluency may lead to superior cognitive flexibility, and ability to adjust behaviour that facilitates attainment of cognitive goal. These findings are in consonance with other current studies that suggest a top-down effect of bilingualism on action control systems.

  5. Structural basis of a novel PD-L1 nanobody for immune checkpoint blockade.

    Science.gov (United States)

    Zhang, Fei; Wei, Hudie; Wang, Xiaoxiao; Bai, Yu; Wang, Pilin; Wu, Jiawei; Jiang, Xiaoyong; Wang, Yugang; Cai, Haiyan; Xu, Ting; Zhou, Aiwu

    2017-01-01

    The use of antibodies to target immune checkpoints, particularly PD-1/PD-L1, has made a profound impact in the field of cancer immunotherapy. Here, we identified KN035, an anti-PD-L1 nanobody that can strongly induce T-cell responses and inhibit tumor growth. The crystal structures of KN035 complexed with PD-L1 and free PD-L1, solved here at 1.7 and 2.7 Å resolution, respectively, show that KN035 competes with PD-1 (programmed death protein 1) for the same flat surface on PD-L1, mainly through a single surface loop of 21 amino acids. This loop forms two short helices and develops key hydrophobic and ionic interactions with PD-L1 residues, such as Ile54, Tyr56 and Arg113, which are also involved in PD-1 binding. The detailed mutagenesis study identified the hotspot residues of the PD-L1 surface and provides an explanation for the stronger (~1 000-fold) binding of KN035 to PD-L1 than PD-1 and its lack of binding to PD-L2. Overall, this study reveals how a single immunoglobulin-variable scaffold of KN035 or PD-1 can bind to a flat protein surface through either a single surface loop or beta-sheet strands; and provides a basis for designing new immune checkpoint blockers and generating bi-specific antibodies for combination therapy.

  6. Second foreign language learning strategies and their variations across language proficiency levels among Iranian EFL learners

    Directory of Open Access Journals (Sweden)

    Pazhakh, A

    2006-07-01

    Full Text Available The present study has attempted to determine weather there is any relationship between language learning strategies employed by language learners, and if so what relationship exists between them. Furthermore, it has tried to investigate what effective and useful strategies the learners employ while learning English as a foreign language correspondent with their proficiency levels. A simulated TOEFL (REA, 1993 test was initially administered to classify the learners into three classes of proficiency levels. Oxford‟s Strategy Inventory, SILL, (Oxford, 1990 was used to determine the frequency of the language learning strategies applied by learners. The results of this study provide confirmation of previous research findings concerning the direct relationship between language learning strategies and language proficiency level, and represent the types of the strategies adopted by advanced, intermediate and elementary language learners. The implications of this study are to suggest both the metacognitive compensatory strategies, the most frequent strategies employed by advanced learners be instructed to the language learners in order to upgrade their proficiency level.

  7. Developing Autonomous Learning for Oral Proficiency Using Digital Storytelling

    Science.gov (United States)

    Kim, SoHee

    2014-01-01

    Since online educational technology can support a ubiquitous language learning environment, there are many ways to develop English learners' autonomy through self-access learning. This study investigates whether English as a second language (ESL) learners can improve their oral proficiency through independent study by using online self-study…

  8. Statistical analysis of nematode counts from interlaboratory proficiency tests

    NARCIS (Netherlands)

    Berg, van den W.; Hartsema, O.; Nijs, Den J.M.F.

    2014-01-01

    A series of proficiency tests on potato cyst nematode (PCN; n=29) and free-living stages of Meloidogyne and Pratylenchus (n=23) were investigated to determine the accuracy and precision of the nematode counts and to gain insights into possible trends and potential improvements. In each test, each

  9. Checkpoint-based forward recovery using lookahead execution and rollback validation in parallel and distributed systems. Ph.D. Thesis, 1992

    Science.gov (United States)

    Long, Junsheng

    1994-01-01

    This thesis studies a forward recovery strategy using checkpointing and optimistic execution in parallel and distributed systems. The approach uses replicated tasks executing on different processors for forwared recovery and checkpoint comparison for error detection. To reduce overall redundancy, this approach employs a lower static redundancy in the common error-free situation to detect error than the standard N Module Redundancy scheme (NMR) does to mask off errors. For the rare occurrence of an error, this approach uses some extra redundancy for recovery. To reduce the run-time recovery overhead, look-ahead processes are used to advance computation speculatively and a rollback process is used to produce a diagnosis for correct look-ahead processes without rollback of the whole system. Both analytical and experimental evaluation have shown that this strategy can provide a nearly error-free execution time even under faults with a lower average redundancy than NMR.

  10. Heritage Language Proficiency in Relation to Attitudes, Motivation, and Age at Immigration: A Case of Korean-Australians

    Science.gov (United States)

    Jee, Min Jung

    2018-01-01

    This study investigated Korean heritage speakers' Korean language proficiency (i.e. morphosyntax, collocation, and lexicon) in relation to their attitudes, motivation, and age at immigration (AI). Seventy-six adult Korean-Australians with Korean literacy participated. Overall, participants showed high levels of Korean proficiency in all three…

  11. Proficiency testing as a basis for estimating uncertainty of measurement: application to forensic alcohol and toxicology quantitations.

    Science.gov (United States)

    Wallace, Jack

    2010-05-01

    While forensic laboratories will soon be required to estimate uncertainties of measurement for those quantitations reported to the end users of the information, the procedures for estimating this have been little discussed in the forensic literature. This article illustrates how proficiency test results provide the basis for estimating uncertainties in three instances: (i) For breath alcohol analyzers the interlaboratory precision is taken as a direct measure of uncertainty. This approach applies when the number of proficiency tests is small. (ii) For blood alcohol, the uncertainty is calculated from the differences between the laboratory's proficiency testing results and the mean quantitations determined by the participants; this approach applies when the laboratory has participated in a large number of tests. (iii) For toxicology, either of these approaches is useful for estimating comparability between laboratories, but not for estimating absolute accuracy. It is seen that data from proficiency tests enable estimates of uncertainty that are empirical, simple, thorough, and applicable to a wide range of concentrations.

  12. The role of computer use and English proficiency in gender wage inequality

    DEFF Research Database (Denmark)

    Chen, Long Hwa; Chen, Hsin-Fan

    2007-01-01

    This paper uses the Blinder-Oaxaca decomposition and accounts for potential identification bias in order to shed light on the role of computer use as well as English ability on the gender wage differential in Taiwan. The results show that both computer use and English proficiency benefit female w...... wage earners and contribute to an equalization of the gender wage gap.......This paper uses the Blinder-Oaxaca decomposition and accounts for potential identification bias in order to shed light on the role of computer use as well as English ability on the gender wage differential in Taiwan. The results show that both computer use and English proficiency benefit female...

  13. Paris Chamber of Commerce Examinations and ACTFL/ETS Proficiency Levels.

    Science.gov (United States)

    Cummins, Patricia W.

    1987-01-01

    Compares the Paris Chamber of Commerce Exams (both certificate and diploma levels) and the ACTFL Guidelines for language proficiency for the benefit of language teachers. Teaching strategies are suggested for preparing students for the Chamber of Commerce exams. (LMO)

  14. Pch2 acts through Xrs2 and Tel1/ATM to modulate interhomolog bias and checkpoint function during meiosis.

    Directory of Open Access Journals (Sweden)

    Hsuan-Chung Ho

    2011-11-01

    Full Text Available Proper segregation of chromosomes during meiosis requires the formation and repair of double-strand breaks (DSBs to form crossovers. Repair is biased toward using the homolog as a substrate rather than the sister chromatid. Pch2 is a conserved member of the AAA(+-ATPase family of proteins and is implicated in a wide range of meiosis-specific processes including the recombination checkpoint, maturation of the chromosome axis, crossover control, and synapsis. We demonstrate a role for Pch2 in promoting and regulating interhomolog bias and the meiotic recombination checkpoint in response to unprocessed DSBs through the activation of axial proteins Hop1 and Mek1 in budding yeast. We show that Pch2 physically interacts with the putative BRCT repeats in the N-terminal region of Xrs2, a member of the MRX complex that acts at sites of unprocessed DSBs. Pch2, Xrs2, and the ATM ortholog Tel1 function in the same pathway leading to the phosphorylation of Hop1, independent of Rad17 and the ATR ortholog Mec1, which respond to the presence of single-stranded DNA. An N-terminal deletion of Xrs2 recapitulates the pch2Δ phenotypes for signaling unresected breaks. We propose that interaction with Xrs2 may enable Pch2 to remodel chromosome structure adjacent to the site of a DSB and thereby promote accessibility of Hop1 to the Tel1 kinase. In addition, Xrs2, like Pch2, is required for checkpoint-mediated delay conferred by the failure to synapse chromosomes.

  15. The tumor suppressor homolog in fission yeast, myh1+, displays a strong interaction with the checkpoint gene rad1+

    International Nuclear Information System (INIS)

    Jansson, Kristina; Warringer, Jonas; Farewell, Anne; Park, Han-Oh; Hoe, Kwang-Lae; Kim, Dong-Uk; Hayles, Jacqueline; Sunnerhagen, Per

    2008-01-01

    The DNA glycosylase MutY is strongly conserved in evolution, and homologs are found in most eukaryotes and prokaryotes examined. This protein is implicated in repair of oxidative DNA damage, in particular adenine mispaired opposite 7,8-dihydro-8-oxoguanine. Previous investigations in Escherichia coli, fission yeast, and mammalian cells show an association of mutations in MutY homologs with a mutator phenotype and carcinogenesis. Eukaryotic MutY homologs physically associate with several proteins with a role in replication, DNA repair, and checkpoint signaling, specifically the trimeric 9-1-1 complex. In a genetic investigation of the fission yeast MutY homolog, myh1 + , we show that the myh1 mutation confers a moderately increased UV sensitivity alone and in combination with mutations in several DNA repair genes. The myh1 rad1, and to a lesser degree myh1 rad9, double mutants display a synthetic interaction resulting in enhanced sensitivity to DNA damaging agents and hydroxyurea. UV irradiation of myh1 rad1 double mutants results in severe chromosome segregation defects and visible DNA fragmentation, and a failure to activate the checkpoint. Additionally, myh1 rad1 double mutants exhibit morphological defects in the absence of DNA damaging agents. We also found a moderate suppression of the slow growth and UV sensitivity of rhp51 mutants by the myh1 mutation. Our results implicate fission yeast Myh1 in repair of a wider range of DNA damage than previously thought, and functionally link it to the checkpoint pathway

  16. Metodologia para caracterização de proficiência em leitura de resultados baciloscópicos para o diagnóstico da tuberculose Methodology for characterizing proficiency in interpreting sputum smear microscopy results in the diagnosis of tuberculosis

    Directory of Open Access Journals (Sweden)

    Francisco Duarte Vieira

    2008-05-01

    Full Text Available OBJETIVO: Propor uma metodologia para caracterizar proficiência na pesquisa de bacilos álcool-ácido resistentes (BAAR em baciloscopias de escarro para diagnóstico da tuberculose, assim como determinar o número necessário de baciloscopias para estabelecer essa proficiência, a qualidade da transcrição dos resultados, as causas das discordâncias nas leituras (leitor e/ou microscópio utilizado e o critério de classificação de resultados baciloscópicos que causa maior dificuldade na caracterização de proficiência. MÉTODOS: Quatrocentas baciloscopias de escarro para diagnóstico da tuberculose foram analisadas, mediante leituras duplo-cegas, por seis profissionais que usualmente efetuam leitura/supervisão de baciloscopias realizadas na rede básica de saúde. A amostragem foi determinada visando a obter, no mínimo, 90% de concordância nas leituras duplo-cegas, erro alfa de 5% e precisão de 3%. Os resultados foram analisados mediante concordância observada/índice kappa. RESULTADOS: Constataram-se 13 erros de transcrição dos resultados (0,27%. A concordância aumentou quando as três categorias distintas de resultados baciloscópicos positivos (BAAR+, BAAR++ e BAAR+++ foram agrupadas ou foram excluídos da análise os exames com resultados inconclusivos. A quantificação da carga bacilar foi o critério de classificação que causou maior dificuldade para caracterização de proficiência. A qualidade do microscópio utilizado foi importante para o aumento da concordância. A estabilização dos valores de concordância somente foi obtida a partir da leitura de 75 baciloscopias. CONCLUSÕES: O uso de leituras baciloscópicas duplo-cegas utilizando-se painel composto por 75 lâminas (36 negativas, 4 inconclusivas e 35 positivas mostra-se adequado para caracterizar a proficiência em baciloscopia para diagnóstico da tuberculose quando essa proficiência pretende reproduzir a rotina laboratorial.OBJECTIVE: To propose a

  17. Immune Checkpoint Molecules on Tumor-Infiltrating Lymphocytes and Their Association with Tertiary Lymphoid Structures in Human Breast Cancer

    Directory of Open Access Journals (Sweden)

    Cinzia Solinas

    2017-10-01

    Full Text Available There is an exponentially growing interest in targeting immune checkpoint molecules in breast cancer (BC, particularly in the triple-negative subtype where unmet treatment needs remain. This study was designed to analyze the expression, localization, and prognostic role of PD-1, PD-L1, PD-L2, CTLA-4, LAG3, and TIM3 in primary BC. Gene expression analysis using the METABRIC microarray dataset found that all six immune checkpoint molecules are highly expressed in basal-like and HER2-enriched compared to the other BC molecular subtypes. Flow cytometric analysis of fresh tissue homogenates from untreated primary tumors show that PD-1 is principally expressed on CD4+ or CD8+ T cells and CTLA-4 is expressed on CD4+ T cells. The global proportion of PD-L1+, PD-L2+, LAG3+, and TIM3+ tumor-infiltrating lymphocytes (TIL was low and detectable in only a small number of tumors. Immunohistochemically staining fixed tissues from the same tumors was employed to score TIL and tertiary lymphoid structures (TLS. PD-L1+, PD-L2+, LAG3+, and TIM3+ cells were detected in some TLS in a pattern that resembles secondary lymphoid organs. This observation suggests that TLS are important sites of immune activation and regulation, particularly in tumors with extensive baseline immune infiltration. Significantly improved overall survival was correlated with PD-1 expression in the HER2-enriched and PD-L1 or CTLA-4 expression in basal-like BC. PD-1 and CTLA-4 proteins were most frequently detected on TIL, which supports the correlations observed between their gene expression and improved long-term outcome in basal-like and HER2-enriched BC. PD-L1 expression by tumor or immune cells is uncommon in BC. Overall, the data presented here distinguish PD-1 as a marker of T cell activity in both the T and B cell areas of BC associated TLS. We found that immune checkpoint molecule expression parallels the extent of TIL and TLS, although there is a noteworthy amount of heterogeneity

  18. Pathways from Toddler Information Processing to Adolescent Lexical Proficiency

    Science.gov (United States)

    Rose, Susan A.; Feldman, Judith F.; Jankowski, Jeffery J.

    2015-01-01

    This study examined the relation of 3-year core information-processing abilities to lexical growth and development. The core abilities covered four domains--memory, representational competence (cross-modal transfer), processing speed, and attention. Lexical proficiency was assessed at 3 and 13 years with the Peabody Picture Vocabulary Test (PPVT)…

  19. Linguistic Proficiency and Strategies on Reading Performance in English

    Science.gov (United States)

    Talebi, Seyed Hassan

    2015-01-01

    General English (L2) proficiency and reading strategies are believed to be highly effective in successful reading performance. However, available studies rarely investigated the combined effects of these two variables on successful reading. To fill this gap, 78 university students were divided into four groups of different degrees of these two…

  20. Advisory Working Alliance, Perceived English Proficiency, and Acculturative Stress

    Science.gov (United States)

    Wei, Meifen; Tsai, Pei-Chun; Chao, Ruth Chu-Lien; Du, Yi; Lin, Shu-Ping

    2012-01-01

    The aim of this study was to examine the moderators of (a) general or cross-cultural advisory working alliances and (b) perceived English proficiency on the association between acculturative stress and psychological distress. A total of 143 East Asian international students completed an online survey. Results from a hierarchical regression…

  1. Rater Judgment and English Language Speaking Proficiency. Research Report

    Science.gov (United States)

    Chalhoub-Deville, Micheline; Wigglesworth, Gillian

    2005-01-01

    The paper investigates whether there is a shared perception of speaking proficiency among raters from different English speaking countries. More specifically, this study examines whether there is a significant difference among English language learning (ELL) teachers, residing in Australia, Canada, the UK, and the USA when rating speech samples of…

  2. Proficiency test on incurred and spiked pesticide residues in cereals

    DEFF Research Database (Denmark)

    Poulsen, Mette Erecius; Christensen, Hanne Bjerre; Herrmann, Susan Strange

    2009-01-01

    A proficiency test on incurred and spiked pesticide residues in wheat was organised in 2008. The test material was grown in 2007 and treated in the field with 14 pesticides formulations containing the active substances, alpha-cypermethrin, bifentrin, carbendazim, chlormequat, chlorpyrifos...

  3. A high incidence of meiotic silencing of unsynapsed chromatin is not associated with substantial pachytene loss in heterozygous male mice carrying multiple simple robertsonian translocations.

    Directory of Open Access Journals (Sweden)

    Marcia Manterola

    2009-08-01

    Full Text Available Meiosis is a complex type of cell division that involves homologous chromosome pairing, synapsis, recombination, and segregation. When any of these processes is altered, cellular checkpoints arrest meiosis progression and induce cell elimination. Meiotic impairment is particularly frequent in organisms bearing chromosomal translocations. When chromosomal translocations appear in heterozygosis, the chromosomes involved may not correctly complete synapsis, recombination, and/or segregation, thus promoting the activation of checkpoints that lead to the death of the meiocytes. In mammals and other organisms, the unsynapsed chromosomal regions are subject to a process called meiotic silencing of unsynapsed chromatin (MSUC. Different degrees of asynapsis could contribute to disturb the normal loading of MSUC proteins, interfering with autosome and sex chromosome gene expression and triggering a massive pachytene cell death. We report that in mice that are heterozygous for eight multiple simple Robertsonian translocations, most pachytene spermatocytes bear trivalents with unsynapsed regions that incorporate, in a stage-dependent manner, proteins involved in MSUC (e.g., gammaH2AX, ATR, ubiquitinated-H2A, SUMO-1, and XMR. These spermatocytes have a correct MSUC response and are not eliminated during pachytene and most of them proceed into diplotene. However, we found a high incidence of apoptotic spermatocytes at the metaphase stage. These results suggest that in Robertsonian heterozygous mice synapsis defects on most pachytene cells do not trigger a prophase-I checkpoint. Instead, meiotic impairment seems to mainly rely on the action of a checkpoint acting at the metaphase stage. We propose that a low stringency of the pachytene checkpoint could help to increase the chances that spermatocytes with synaptic defects will complete meiotic divisions and differentiate into viable gametes. This scenario, despite a reduction of fertility, allows the spreading

  4. Assessment practices of third- and fifth-grade science teachers: A comparison to the style/format, process, and content of Ohio's proficiency tests

    Science.gov (United States)

    Janson, David C.

    This descriptive study is addressed to policy-makers, textbook publisher, teachers, principals, and curriculum directors. It compares the assessment practices of ten elementary teachers over a period of 11 weeks with Ohio's fourth and sixth grade science Proficiency Tests. Results show that the teachers' assessment practices were not aligned with Ohio's Proficiency Test. The tests used in the participants' classroom contained a disproportionate number of items characterized as low-level in terms of their cognitive function. Classroom test items generally fell into three categories---true/false, completion, and matching. The remaining items were predominantly low-level multiple-choice items requiring simple recall of information. The teachers in this study showed a heavy reliance on the packaged assessments that accompanied their adopted textbook series with little use of teacher-designed instruments. This differs from the findings of previous researchers who reported that most teacher assessments were done with teacher-made tests. The lack of alignment between classroom tests and Ohio's Proficiency Test is a concern because previous researchers and the teachers in this study believe that aligning classroom tests with high-stakes assessment improves student performance. Other research shows teachers teach what they test suggesting that the curriculum would be better aligned with State expectations if classroom tests were more in line with the proficiency tests. This study found that textbooks and their assessment packages are not aligned to most state standards and that teachers need help developing better assessments. The results of this study suggest directions school administrators might take to facilitate inservice training for current teachers and could be helpful to textbook publishers as well as educators serving on adoption committees. Since high-stakes testing of students in the nation's public schools and school accountability seem destined to remain a

  5. A Novel Antagonist of the Immune Checkpoint Protein Adenosine A2a Receptor Restores Tumor-Infiltrating Lymphocyte Activity in the Context of the Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Melanie Mediavilla-Varela

    2017-07-01

    Full Text Available BACKGROUND: Therapeutic strategies targeting immune checkpoint proteins have led to significant responses in patients with various tumor types. The success of these studies has led to the development of various antibodies/inhibitors for the different checkpoint proteins involved in immune evasion of the tumor. Adenosine present in high concentrations in the tumor microenvironment activates the immune checkpoint adenosine A2a receptor (A2aR, leading to the suppression of antitumor responses. Inhibition of this checkpoint has the potential to enhance antitumor T-cell responsiveness. METHODS: We developed a novel A2aR antagonist (PBF-509 and tested its antitumor response in vitro, in a mouse model, and in non-small cell lung cancer patient samples. RESULTS: Our studies showed that PBF-509 is highly specific to the A2aR as well as inhibitory of A2aR function in an in vitro model. In a mouse model, we found that lung metastasis was decreased after treatment with PBF-509 compared with its control. Furthermore, freshly resected tumor-infiltrating lymphocytes from lung cancer patients showed increased A2aR expression in CD4+ cells and variable expression in CD8+ cells. Ex vivo studies showed an increased responsiveness of human tumor-infiltrating lymphocytes when PBF-509 was combined with anti-PD-1 or anti-PD-L1. CONCLUSIONS: Our studies demonstrate that inhibition of the A2aR using the novel inhibitor PBF-509 could lead to novel immunotherapeutic strategies in non-small cell lung cancer.

  6. ALDH1A1 maintains ovarian cancer stem cell-like properties by altered regulation of cell cycle checkpoint and DNA repair network signaling.

    Directory of Open Access Journals (Sweden)

    Erhong Meng

    Full Text Available OBJECTIVE: Aldehyde dehydrogenase (ALDH expressing cells have been characterized as possessing stem cell-like properties. We evaluated ALDH+ ovarian cancer stem cell-like properties and their role in platinum resistance. METHODS: Isogenic ovarian cancer cell lines for platinum sensitivity (A2780 and platinum resistant (A2780/CP70 as well as ascites from ovarian cancer patients were analyzed for ALDH+ by flow cytometry to determine its association to platinum resistance, recurrence and survival. A stable shRNA knockdown model for ALDH1A1 was utilized to determine its effect on cancer stem cell-like properties, cell cycle checkpoints, and DNA repair mediators. RESULTS: ALDH status directly correlated to platinum resistance in primary ovarian cancer samples obtained from ascites. Patients with ALDHHIGH displayed significantly lower progression free survival than the patients with ALDHLOW cells (9 vs. 3 months, respectively p<0.01. ALDH1A1-knockdown significantly attenuated clonogenic potential, PARP-1 protein levels, and reversed inherent platinum resistance. ALDH1A1-knockdown resulted in dramatic decrease of KLF4 and p21 protein levels thereby leading to S and G2 phase accumulation of cells. Increases in S and G2 cells demonstrated increased expression of replication stress associated Fanconi Anemia DNA repair proteins (FANCD2, FANCJ and replication checkpoint (pS317 Chk1 were affected. ALDH1A1-knockdown induced DNA damage, evidenced by robust induction of γ-H2AX and BAX mediated apoptosis, with significant increases in BRCA1 expression, suggesting ALDH1A1-dependent regulation of cell cycle checkpoints and DNA repair networks in ovarian cancer stem-like cells. CONCLUSION: This data suggests that ovarian cancer cells expressing ALDH1A1 may maintain platinum resistance by altered regulation of cell cycle checkpoint and DNA repair network signaling.

  7. The Unified Language Testing Plan: Speaking Proficiency Test. Spanish and English Pilot Validation Studies. Report Number 1.

    Science.gov (United States)

    Thornton, Julie A.

    This report describes one segment of the Federal Language Testing Board's Unified Language Testing Plan (ULTP), the validation of speaking proficiency tests in Spanish and English. The ULTP is a project to increase standardization of foreign language proficiency measurement and promote sharing of resources among testing programs in the federal…

  8. The English Proficiency Test of the Iranian Ministry of Science, Research, and Technology: A Review

    Directory of Open Access Journals (Sweden)

    Mahdieh Noori

    2017-08-01

    Full Text Available One of the serious decisions which every administrator may need to make during his/her professional career is to select or reject applicants based on their general language skills or competence. These significant decisions, which may be of serious consequences not only for the individuals but also for the society in general, are occasionally made based on norm-referenced proficiency tests. Out of internationally available proficiency tests such as the TOEFL test, those which fit the specific local cultural and academic contexts seem of greater prominence. One such test, which has been specifically designed for the Iranian EFL context by the Ministry of Science, Research, and Technology, is the MSRT proficiency test. While a few studies have been conducted on the analysis of the reliability and validity of the mentioned test, no study has yet reviewed the test and its component parts. Therefore, the current study aimed at considering the strengths and weaknesses of the test in general and its component items in particular. The results implicated that the MSRT benefits from more efficient general reliability and validity, well planned language items, practicality, ease of administration, objective scoring, ease of accessibility, as well as reasonable fees, while it needs to be more substantiated in terms of the inclusion of the speaking skill assessment, the computerized adaptive assessment procedures, and the correction factor for guessing. In addition, the use of the individual-based listening apparatus for testing listening comprehension as well as the consideration of the integrative communicative tests for its concurrent validity purposes can contribute to more appropriate distinction of proficient and non-proficient applicants.

  9. Worldwide open proficiency test IAEA-CU-2007-09/A: Determination of Po-210 in water

    International Nuclear Information System (INIS)

    2009-01-01

    The IAEA helps the Member States' laboratories to maintain their readiness by coordination activities, by development of standardized methods for sample collection and analysis, and by conducting interlaboratory comparisons and proficiency tests as a tool for external quality control. The Chemistry Unit of the Physics, Chemistry and Instrumentation Laboratory in the International Atomic Energy Agency's Seibersdorf Laboratories in Austria, has the programmatic responsibility to support global radionuclide measurement systems. To fulfil this obligation and ensure a reliable worldwide, rapid and consistent response, the Chemistry Unit organises interlaboratory studies and proficiency tests. The Po-210 poisoning event which occurred in November 2006 brought into focus a number of issues, including the capacity of laboratories to rapidly and accurately determine this radionuclide in environmental samples. A number of requests were received from Member States to address this issue. Responding to these requests, the Chemistry Unit of the Physics, Chemistry and Instrumentation Laboratory in the Agency's Laboratories, conducted a world wide proficiency test on the determination of Po-210 in water. The aim was to gather information on the current state of practice for Po-210 measurements at various levels in aqueous samples. This report describes the methodology employed and the results obtained in this proficiency test

  10. English Language Proficiency and Early School Attainment Among Children Learning English as an Additional Language.

    Science.gov (United States)

    Whiteside, Katie E; Gooch, Debbie; Norbury, Courtenay F

    2017-05-01

    Children learning English as an additional language (EAL) often experience lower academic attainment than monolingual peers. In this study, teachers provided ratings of English language proficiency and social, emotional, and behavioral functioning for 782 children with EAL and 6,485 monolingual children in reception year (ages 4-5). Academic attainment was assessed in reception and Year 2 (ages 6-7). Relative to monolingual peers with comparable English language proficiency, children with EAL displayed fewer social, emotional, and behavioral difficulties in reception, were equally likely to meet curriculum targets in reception, and were more likely to meet targets in Year 2. Academic attainment and social, emotional, and behavioral functioning in children with EAL are associated with English language proficiency at school entry. © 2016 The Authors. Child Development published by Wiley Periodicals, Inc. on behalf of Society for Research in Child Development.

  11. A new role of proficiency testing in nuclear analytical work

    DEFF Research Database (Denmark)

    Heydorn, Kaj

    2008-01-01

    The most recent definition of measurement result requires a statement of uncertainty whenever results obtained by nuclear or other quantitative methods of analysis are reported. Proficiency testing (PT) therefore must include the ability of laboratories to present not only unbiased quantity values...

  12. Histone dosage regulates DNA damage sensitivity in a checkpoint-independent manner by the homologous recombination pathway

    Science.gov (United States)

    Liang, Dun; Burkhart, Sarah Lyn; Singh, Rakesh Kumar; Kabbaj, Marie-Helene Miquel; Gunjan, Akash

    2012-01-01

    In eukaryotes, multiple genes encode histone proteins that package genomic deoxyribonucleic acid (DNA) and regulate its accessibility. Because of their positive charge, ‘free’ (non-chromatin associated) histones can bind non-specifically to the negatively charged DNA and affect its metabolism, including DNA repair. We have investigated the effect of altering histone dosage on DNA repair in budding yeast. An increase in histone gene dosage resulted in enhanced DNA damage sensitivity, whereas deletion of a H3–H4 gene pair resulted in reduced levels of free H3 and H4 concomitant with resistance to DNA damaging agents, even in mutants defective in the DNA damage checkpoint. Studies involving the repair of a HO endonuclease-mediated DNA double-strand break (DSB) at the MAT locus show enhanced repair efficiency by the homologous recombination (HR) pathway on a reduction in histone dosage. Cells with reduced histone dosage experience greater histone loss around a DSB, whereas the recruitment of HR factors is concomitantly enhanced. Further, free histones compete with the HR machinery for binding to DNA and associate with certain HR factors, potentially interfering with HR-mediated repair. Our findings may have important implications for DNA repair, genomic stability, carcinogenesis and aging in human cells that have dozens of histone genes. PMID:22850743

  13. An Investigation of the Use of Listening Strategies and Listening Performance of Proficient and Nonproficient Language Learners

    Science.gov (United States)

    Piamsai, Chatraporn

    2014-01-01

    This study was an attempt to investigate how proficient and non-proficient learners used listening strategies to complete a listening task. 65 third-year Chulalongkorn University Commerce and Accountancy students participated in the first stage of the quantitative data collection. 18 students were randomly selected from the group for more in depth…

  14. 熟练和非熟练中英双语者不同认知控制成分的比较%A Comparison of Different Cognitive Control Components between Non-proficient and Proficient Chinese-English Bilinguals

    Institute of Scientific and Technical Information of China (English)

    范小月; 王瑞明; 吴际; 林哲婷

    2012-01-01

    A large number of studies have demonstrated the bilinguals' advantage in cognitive control, and some researchers have explored the components of cognitive control. However, there are four gaps. ( 1 ) Most studies only examined one or two components of cognitive control. Few studies clearly defined cognitive control and systematically compared these components between non-proficient bilinguals and proficient bilinguals. (2) Compared with non-proficient bilinguals, do proficient bilinguals 'also have advantages in some components of cognitive control? ( 3 ) Is the influence of bilingualism on some components of cognitive control in bilingual children consistent with that in bilingual adults? (4) Are existing results suitable for Chinese-English bilinguals? The present study aims at answering these questions. Thirty non-proficient Chinese-English bilinguals and thirty proficient Chinese-English bilinguals were asked to administer the "faces task". All the participants were adults. Before the task, they finished the Raven Intelligence Test, culture, ethnic background and social economic status (SES) survey to eliminate the influence of some irrelevant variables. In the face task, the colored eyes could be looking either straight ahead or towards one of the two boxes, creating the straight eyes task and the gaze shift task. The participants should press the key on the same side as the box containing the asterisk if the eyes turned green and the opposite side if the eyes turned red. Inhibitory control was assessed by the difference in RT between trials in which the eyes looked towards the target and those in which the eyes looked away from the target in the gaze shift task. The results showed that the non-proficient Chinese-English bilinguals produced a larger cost than the proficient Chinese-English bilinguals, t(57) = 2. 107, p = . 040. Cognitive flexibility was assessed by the difference between mixed and single block presentations. The results showed that the non

  15. Final report proficiency test on the determination of α, β and γ-emitting radionuclides

    International Nuclear Information System (INIS)

    Shakhashiro, A.; Trinkl, A.; Benesch, T.; Sansone, U.

    2005-06-01

    A proficiency test on the determination of α, β and γ-emitting radionuclides was organised within the frame of the Technical Cooperation project: RAS/9/024 'Environmental Radiation Monitoring and Regional Data Base' to evaluate the analytical performance of 14 laboratories from 12 Asian countries. This report summarises the performance evaluation of the participating laboratories. Analytical data evaluation of this proficiency test showed that 58% of all reported results obtained a 'Passed' final score for both the trueness and precision criteria applied to this exercise. (author)

  16. Child, family, and school characteristics related to English proficiency development among low-income, dual language learners.

    Science.gov (United States)

    Kim, Yoon Kyong; Curby, Timothy W; Winsler, Adam

    2014-12-01

    Little is known about 2nd language development among young, low-income, language-minority children. This article examined the longitudinal English development of low-income, dual language learners (DLLs) in Miami (n = 18,532) from kindergarten through 5th grade. Growth curve modeling indicated that social skills, good behavior, Spanish (L1) competence in preschool, having a mother born in the United States, and attending larger schools with fewer DLLs were associated with higher initial levels of English proficiency in kindergarten and/or steeper growth over time. Survival analyses indicated that it took about 2 years for half of the sample to become proficient in English according to the school district's criterion. Higher initial proficiency in kindergarten, not receiving free/reduced lunch, not being Hispanic or Black, strong cognitive, language, and socioemotional skills at age 4, and maternal education were associated with faster attainment of English proficiency. It is important for teachers, parents, researchers, and policy makers to understand that DLL students come from diverse backgrounds and that poverty and other factors influence the speed of English language development for DLLs. PsycINFO Database Record (c) 2014 APA, all rights reserved.

  17. The correlation between motor proficiency and physical activity in Senior Phase learners in the Potchefstroom area

    Directory of Open Access Journals (Sweden)

    Lizl-Louise van Niekerk

    2016-10-01

    Objectives: To determine the relationship between motor proficiency and physical activity levels in adolescent Senior Phase learners in Potchefstroom, South Africa. No literature exists on the relationship between motor proficiency and physical activity levels among South African adolescents. Method: A total of 239 13- to 14-year-old learners were assessed using the Bruininkse Oseretsky Test of Motor Proficiency 2 (BOT-2 for motor proficiency, and the International Physical Activity Questionnaire (IPAQ for physical activity levels. Data analysis included descriptive statistics, Spearman correlation coefficients and effect sizes. Results: Statistically and practically significant correlations were found between the total BOT-2 score and the physical activity levels of the total group, as well as the boys and the girls respectively. Fine motor coordination correlated with physical activity levels in the girls, while manipulation coordination correlated with the physical activity levels of the total group and the boys. The body coordination skill of jumping in place and the strength test items showed strong correlations with physical activity in all the groups. Conclusion: The motor skills of Senior Phase learners, especially coordination and strength skills, should be developed and maintained in the Physical Education curriculum to enhance physical activity levels.

  18. Characterization of a cancer cell line that expresses a splicing variant form of 53BP1: Separation of checkpoint and repair functions in 53BP1

    International Nuclear Information System (INIS)

    Iwabuchi, Kuniyoshi; Matsui, Tadashi; Hashimoto, Mitsumasa; Matsumoto, Yoshihisa; Kurihara, Takayuki; Date, Takayasu

    2008-01-01

    53BP1 plays important roles in checkpoint signaling and repair for DNA double-strand breaks. We found that a colon cancer cell line, SW48, expressed a splicing variant form of 53BP1, which lacks the residues corresponding to exons 10 and 11. Activation of ATM and phosphorylation of ATM and ATR targets occurred in SW48 cells in response to X-irradiation, and these X-ray-induced responses were not enhanced by expression of full-length 53BP1 in SW48 cells, indicating that this splicing variant fully activates the major checkpoint signaling in SW48 cells. In contrast, the expression of full-length 53BP1 in SW48 cells promoted the repair of X-ray-induced DNA damage, evidenced by faster disappearance of X-ray-induced γ-H2AX foci, a marker for DNA damage, and less residual chromosomal aberrations after X-irradiation. We conclude that the two major roles of 53BP1, the checkpoint signaling and repair for DNA damage, can be functionally separated

  19. Does Wechsler Intelligence Scale administration and scoring proficiency improve during assessment training?

    Science.gov (United States)

    Platt, Tyson L; Zachar, Peter; Ray, Glen E; Lobello, Steven G; Underhill, Andrea T

    2007-04-01

    Studies have found that Wechsler scale administration and scoring proficiency is not easily attained during graduate training. These findings may be related to methodological issues. Using a single-group repeated measures design, this study documents statistically significant, though modest, error reduction on the WAIS-III and WISC-III during a graduate course in assessment. The study design does not permit the isolation of training factors related to error reduction, or assessment of whether error reduction is a function of mere practice. However, the results do indicate that previous study findings of no or inconsistent improvement in scoring proficiency may have been the result of methodological factors. Implications for teaching individual intelligence testing and further research are discussed.

  20. Comparing the Effects of Two Facets of Multiple Intelligences Theory on Developing EFL Learners' Listening

    Science.gov (United States)

    Bemani Naeini, Ma'ssoumeh

    2015-01-01

    Gardner's Multiple Intelligences Theory (MIT), however having been embraced in the field of language acquisition, has apparently failed to play a role in research on learning styles as an alternative construct. This study aims at examining the potential effects of MI-based activities, as learning styles, on the listening proficiency of Iranian…

  1. Education in the World System: The Demand for Language and International Proficiencies in Economic Development and National Security.

    Science.gov (United States)

    Hoegl, Juergen K.

    1986-01-01

    Discusses the role of second-language proficiency from international, national, and state perspectives, including consideration of the need for such proficiency in science, technology, and research for economic development. Trends indicate that a more internationalized curricula in higher education and a greater demand for second-language…

  2. Mad2 binding to Mad1 and Cdc20, rather than oligomerization, is required for the spindle checkpoint

    DEFF Research Database (Denmark)

    Sironi, L; Melixetian, M; Faretta, M

    2001-01-01

    Mad2 is a key component of the spindle checkpoint, a device that controls the fidelity of chromosome segregation in mitosis. The ability of Mad2 to form oligomers in vitro has been correlated with its ability to block the cell cycle upon injection into Xenopus embryos. Here we show that Mad2 forms...

  3. Pemodelan Molekul Turunan p-Metoksi sinnamoil Hidrazida Sebagai Inhibitor Checkpoint Kinase 1 dan Inhibitor Aromatase secara In silico

    Directory of Open Access Journals (Sweden)

    Galih Satrio Putra

    2017-08-01

    Full Text Available The development of anticancer drugs from ethyl p-methoxycinnamate (EPMC derivatives continues to obtain compounds that have high ability of cancer cells apoptosis and minimal side effects. p-Methoxycinnamoyl hydrazide derivate compounds from EPMC structure modification were docked into the ligand-binding pocket of Check point kinase 1 enzymes (2YWP and the aromatase enzyme (3S7S using software Molegro Virtual Docker (MVD Ver.5.5. We compared the Rerank score of native ligand with derivate compounds of p-Methoxycinnamoyl hydrazide. Rerank scores of compounds 4b and 4c (-99.98 Kcal/mol and -99.80 Kcal/mol were lower than the native ligand A42 in inhibiting the enzyme checkpoint kinase 1. Rerank values of p-Methoxycinnamoyl hydrazide derivate compounds were greater than the native ligand EXM in inhibiting the enzyme aromatase. p-Methoxycinnamoyl hydrazide derivate compounds, especially compounds 4b and 4c, had anticancer mechanism by inhibiting the enzyme pathway checkpoint kinase 1 and had not activity in inhibiting the aromatase enzyme.

  4. The human papillomavirus type 58 E7 oncoprotein modulates cell cycle regulatory proteins and abrogates cell cycle checkpoints

    International Nuclear Information System (INIS)

    Zhang Weifang; Li Jing; Kanginakudru, Sriramana; Zhao Weiming; Yu Xiuping; Chen, Jason J.

    2010-01-01

    HPV type 58 (HPV-58) is the third most common HPV type in cervical cancer from Eastern Asia, yet little is known about how it promotes carcinogenesis. In this study, we demonstrate that HPV-58 E7 significantly promoted the proliferation and extended the lifespan of primary human keratinocytes (PHKs). HPV-58 E7 abrogated the G1 and the postmitotic checkpoints, although less efficiently than HPV-16 E7. Consistent with these observations, HPV-58 E7 down-regulated the cellular tumor suppressor pRb to a lesser extent than HPV-16 E7. Similar to HPV-16 E7 expressing PHKs, Cdk2 remained active in HPV-58 E7 expressing PHKs despite the presence of elevated levels of p53 and p21. Interestingly, HPV-58 E7 down-regulated p130 more efficiently than HPV-16 E7. Our study demonstrates a correlation between the ability of down-regulating pRb/p130 and abrogating cell cycle checkpoints by HPV-58 E7, which also correlates with the biological risks of cervical cancer progression associated with HPV-58 infection.

  5. Determinants of second language proficiency among refugees in the Netherlands

    NARCIS (Netherlands)

    Tubergen, F.A. van

    2010-01-01

    Little is known about the language acquisition of refugees in Western countries. This study examines how pre- and post-migration characteristics of refugees are related to their second language proficiency. Data are from a survey of 3,500 refugees, who were born in Afghanistan, Iran, Iraq, former

  6. Advances in immunotherapeutic strategies for colorectal cancer commentary on: tumoral immune cell exploitation in colorectal cancer metastases can be targeted effectively by anti-CCR5 therapy in cancer patients by Halama et al.

    Science.gov (United States)

    Deming, Dustin A

    2016-01-01

    Colorectal cancer is a leading cause of cancer-related death in the United States, despite recent advances in treatment strategies. The immune system has been implicated in the pathogenesis of colorectal cancer, with numerous studies identifying either antagonistic or pro-tumorigenic effects of infiltrating immune cells. Therapeutic strategies harnessing the immune system to target cancers have evolved expediently over the last 5 years, especially the use of checkpoint inhibitors. Recently, a subset of patients whose colorectal cancers harbor a deficiency in mismatch repair proteins have demonstrated dramatic and durable response to checkpoint blockade. Unfortunately, the vast majority of colorectal cancers are mismatch repair proficient and resistant to these inhibitors. The tumor microenvironment has been implicated in the resistance to checkpoint block and ways to overcome these resistance mechanisms would be a major advance for the treatment of colorectal cancer. Here we provide commentary on a manuscript from Halama et al. examining CCL5/CCR5 as an immune biomarker and the potential role of anti-CCR5 agents for the treatment of patients with colorectal cancer.

  7. The relationship between English language learning strategies and proficiency of pre-university students: A study case of UMS

    Science.gov (United States)

    Kiram, Johannah Jamalul; Sulaiman, Jumat; Swanto, Suyansah; Din, Wardatul Akmam

    2014-07-01

    This paper seeks to investigate the relationship between language learning strategies and proficiency in English. Fifty-six pre-university students (22 males, 34 females) of University Malaysia Sabah participated in this study. Oxford's Strategy Inventory for Language Learning (SILL) self-report questionnaire was adopted to identify the students' language learning strategies, whereas their proficiencies were judged based on their Malaysian University English Test (MUET) Results. Pearson's correlation coefficient, Spearman's rank correlation coefficient and the t-test were utilized to make statistical interpretation about the relationship. The knowledge obtained from this study will be helpful for future studies on how to improve the quality of learning and proficiency in English.

  8. Measuring Second Language Proficiency with EEG Synchronization: How Functional Cortical Networks and Hemispheric Involvement Differ as a Function of Proficiency Level in Second Language Speakers

    Science.gov (United States)

    Reiterer, Susanne; Pereda, Ernesto; Bhattacharya, Joydeep

    2009-01-01

    This article examines the question of whether university-based high-level foreign language and linguistic training can influence brain activation and whether different L2 proficiency groups have different brain activation in terms of lateralization and hemispheric involvement. The traditional and prevailing theory of hemispheric involvement in…

  9. Online Assessment of Oral Proficiency for Intercultural Professional Communication: An introduction

    NARCIS (Netherlands)

    Rusman, Ellen; Stoyanov, Slavi

    2012-01-01

    Rusman, E., & Stoyanov, S. (2011). Online Assessment of Oral Proficiency for Intercultural Professional Communication: An introduction. Presentation about the CEFcult project (www.cefcult.eu) as an introduction to various personal interviews held with stakeholders, Heerlen, The Netherlands: Open

  10. Operating Room Performance Improves after Proficiency-Based Virtual Reality Cataract Surgery Training

    DEFF Research Database (Denmark)

    Thomsen, Ann Sofia Skou; Bach-Holm, Daniella; Kjærbo, Hadi

    2017-01-01

    PURPOSE: To investigate the effect of virtual reality proficiency-based training on actual cataract surgery performance. The secondary purpose of the study was to define which surgeons benefit from virtual reality training. DESIGN: Multicenter masked clinical trial. PARTICIPANTS: Eighteen cataract...... surgeons with different levels of experience. METHODS: Cataract surgical training on a virtual reality simulator (EyeSi) until a proficiency-based test was passed. MAIN OUTCOME MEASURES: Technical performance in the operating room (OR) assessed by 3 independent, masked raters using a previously validated...... task-specific assessment tool for cataract surgery (Objective Structured Assessment of Cataract Surgical Skill). Three surgeries before and 3 surgeries after the virtual reality training were video-recorded, anonymized, and presented to the raters in random order. RESULTS: Novices (non...

  11. Beyond Host Language Proficiency: Coping Resources Predicting International Students' Satisfaction

    Science.gov (United States)

    Mak, Anita S.; Bodycott, Peter; Ramburuth, Prem

    2015-01-01

    As international students navigate in a foreign educational environment, having higher levels of coping or stress-resistance resources--both internal and external--could be related to increased satisfaction with personal and university life. The internal coping resources examined in this study were host language proficiency, self-esteem,…

  12. Teaching Mathematical Problem Solving to Students with Limited English Proficiency.

    Science.gov (United States)

    Kaplan, Rochelle G.; Patino, Rodrigo A.

    Many mainstreamed students with limited English proficiency continue to face the difficulty of learning English as a second language (ESL) while studying mathematics and other content areas framed in the language of native speakers. The difficulty these students often encounter in mathematics classes and their poor performance on subsequent…

  13. Foreign Language Teachers' Language Proficiency and Their Language Teaching Practice

    Science.gov (United States)

    Richards, Heather; Conway, Clare; Roskvist, Annelies; Harvey, Sharon

    2013-01-01

    Teachers' subject knowledge is recognized as an essential component of effective teaching. In the foreign language context, teachers' subject knowledge includes language proficiency. In New Zealand high schools, foreign languages (e.g. Chinese, French, German, Japanese and Spanish) have recently been offered to learners earlier in their schooling,…

  14. A retrospective evaluation of proficiency testing, and rapid HIV test ...

    African Journals Online (AJOL)

    Background: Proficiency testing (PT) has been implemented as a form of External Quality Assurance (EQA) by the National HIV Reference Laboratory in Kenya since 2007 in order to monitor and improve on the quality of HIV testing and counselling HTC services. Objective: To compare concordance between National HIV ...

  15. Assessing students' English language proficiency during clinical placement: A qualitative evaluation of a language framework.

    Science.gov (United States)

    San Miguel, Caroline; Rogan, Fran

    2015-06-01

    The increase in nursing students for whom English is an additional language requires clinical facilitators to assess students' performance regarding clinical skills, nursing communication and English language. However, assessing language proficiency is a complex process that is often conflated with cultural norms and clinical skills, and facilitators may lack confidence in assessing English language. This paper discusses an evaluation of a set of guidelines developed in a large metropolitan Australian university to help clinical facilitators make decisions about students' English language proficiency. The study found that the guidelines were useful in helping facilitators assess English language. However, strategies to address identified language problems needed to be incorporated to enable the guidelines to also be used as a teaching tool. The study concludes that to be effective, such guidelines need embedding within a systematic approach that identifies and responds to students who may be underperforming due to a low level of English language proficiency. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Proficiency Test Program Involvement as a Tool for External Quality Control for Radiochemistry and Environmental Laboratory, Malaysian Nuclear Agency

    International Nuclear Information System (INIS)

    Nurrul Assyikeen Mohd Jaffary; Wo, Y.M.; Zal U'yun Wan Mahmood; Norfaizal Mohamed; Abdul Kadir Ishak; Noor Fadzilah Yusof; Jalal Sharib

    2016-01-01

    As the only Laboratory in Malaysia under the IAEA Analytical Laboratories for the Measurement of Environmental Radioactivity (ALMERA) Network, the Radiochemistry and Environmental Laboratory (RAS), Malaysian Nuclear Agency participates in the proficiency test programmes organised by ALMERA to achieve mutual acceptance of analytical data. The ALMERA has been providing quality support of proficiency tests using sets of different samples matrices and radionuclide levels typically encountered in environmental and food monitoring laboratories. The involvement of RAS laboratory in the IAEA proficiency tests gives opportunity to improve the laboratory capability and personnel skills in the field of radioactivity testing. (author)

  17. Loss of yeast peroxiredoxin Tsa1p induces genome instability through activation of the DNA damage checkpoint and elevation of dNTP levels.

    Directory of Open Access Journals (Sweden)

    Hei-Man Vincent Tang

    2009-10-01

    Full Text Available Peroxiredoxins are a family of antioxidant enzymes critically involved in cellular defense and signaling. Particularly, yeast peroxiredoxin Tsa1p is thought to play a role in the maintenance of genome integrity, but the underlying mechanism is not understood. In this study, we took a genetic approach to investigate the cause of genome instability in tsa1Delta cells. Strong genetic interactions of TSA1 with DNA damage checkpoint components DUN1, SML1, and CRT1 were found when mutant cells were analyzed for either sensitivity to DNA damage or rate of spontaneous base substitutions. An elevation in intracellular dNTP production was observed in tsa1Delta cells. This was associated with constitutive activation of the DNA damage checkpoint as indicated by phosphorylation of Rad9/Rad53p, reduced steady-state amount of Sml1p, and induction of RNR and HUG1 genes. In addition, defects in the DNA damage checkpoint did not modulate intracellular level of reactive oxygen species, but suppressed the mutator phenotype of tsa1Delta cells. On the contrary, overexpression of RNR1 exacerbated this phenotype by increasing dNTP levels. Taken together, our findings uncover a new role of TSA1 in preventing the overproduction of dNTPs, which is a root cause of genome instability.

  18. [Japanese learners' processing time for reading English relative clauses analyzed in relation to their English listening proficiency].

    Science.gov (United States)

    Oyama, Yoshinori

    2011-06-01

    The present study examined Japanese university students' processing time for English subject and object relative clauses in relation to their English listening proficiency. In Analysis 1, the relation between English listening proficiency and reading span test scores was analyzed. The results showed that the high and low listening comprehension groups' reading span test scores do not differ. Analysis 2 investigated English listening proficiency and processing time for sentences with subject and object relative clauses. The results showed that reading the relative clause ending and the main verb section of a sentence with an object relative clause (such as "attacked" and "admitted" in the sentence "The reporter that the senator attacked admitted the error") takes less time for learners with high English listening scores than for learners with low English listening scores. In Analysis 3, English listening proficiency and comprehension accuracy for sentences with subject and object relative clauses were examined. The results showed no significant difference in comprehension accuracy between the high and low listening-comprehension groups. These results indicate that processing time for English relative clauses is related to the cognitive processes involved in listening comprehension, which requires immediate processing of syntactically complex audio information.

  19. Music Teachers in Turkey: Their Proficiency, Working Environments and Problems

    Science.gov (United States)

    Otacioglu, Sena Gursen

    2008-01-01

    The aim of this study was the collection of data concerning Turkish music teachers' proficiency and their place in the primary and secondary education system. In addition, information was collected regarding the teachers' working environment and professional complications. A total of 200 music teachers' opinions were compiled for the determination…

  20. Reading Processing Skills among EFL Learners in Different Proficiency Levels

    Science.gov (United States)

    Dhanapala, Kusumi Vasantha; Yamada, Jun

    2015-01-01

    This study aims to understand how EFL learners in different reading proficiency levels comprehend L2 texts, using five-component skills involving measures of (1) vocabulary knowledge, (2) drawing inferences and predictions, (3) knowledge of text structure and discourse organization, (4) identifying the main idea and summarizing skills, and (5)…