Advances of Immune Checkpoint Inhibitors in Tumor Immunotherapy

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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.

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

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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

Checkpointing and Recovery in Distributed and Database Systems

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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…

Loss of yeast peroxiredoxin Tsa1p induces genome instability through activation of the DNA damage checkpoint and elevation of dNTP levels.

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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.

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

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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.

Role of the Checkpoint Clamp in DNA Damage Response

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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.

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

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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.

Checkpoint independence of most DNA replication origins in fission yeast.

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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

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

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

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

Template based parallel checkpointing in a massively parallel computer system

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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.

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...

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.

Prevention of DNA Rereplication Through a Meiotic Recombination Checkpoint Response

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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.

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

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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.

Newly Emerging Immune Checkpoints: Promises for Future Cancer Therapy

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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.

Radiotherapy and immune checkpoint blockades: a snapshot in 2016

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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.

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

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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.

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

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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

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

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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.

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.

Molecular Mechanisms of DNA Replication Checkpoint Activation

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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.

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.

Extinction antagonizes olfactory memory at the subcellular level.

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Schwaerzel, Martin; Heisenberg, Martin; Zars, Troy

2002-08-29

Memory loss occurs by diverse mechanisms, as different time constants of performance decrement and sensitivities to experimental manipulations suggest. While the phenomena of memory decay, interference, and extinction are well established behaviorally, little is known about them at the circuit or molecular level. In Drosophila, odorant memories lasting up to 3 hr can be localized to mushroom body Kenyon cells, a single neuronal level in the olfactory pathway. The plasticity underlying this memory trace can be induced without Kenyon cell synaptic output. Experimental extinction, i.e., presentation of the conditioned stimulus without the reinforcer, reduces memory performance and does so at the same circuit level as memory formation. Thus, unreinforced presentation of learned odorants antagonizes intracellularly the signaling cascade underlying memory formation.

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...

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...

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

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.

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.

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.

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

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.

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

EMODnet MedSea Checkpoint for sustainable Blue Growth

Science.gov (United States)

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

2016-04-01

Metadata standards for geographic information (ISO 19157 and ISO 19115 respectively). The fitness for use of the input datasets are assessed using 2 categories of criteria to determine how these datasets fits the user requirements which drive them to select a data source rather than another one and to show performance and gaps of the present monitoring systems : • Data appropriateness : what is made available to the user ?. • Data availability : how it is made available to the user? All information are stored in a GIS platform and made available with two types of interfaces: - Front-end interfaces with users, to present the input data used by all challenges, the innovative products generated by challenges and the assessment indicators. - Back-end interfaces to partners, to store the checkpoint descriptors of input data, specification to generate targeted products, catalogue information of products with associated checkpoint indicators linked to the input data The validation of the records is done at three levels, at technical level (GIS), at challenge level (use), and at sea basin level (synthesis of monitoring data adequacy including expert comments) to end with the production of a yearly Data Adequacy Report.

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.

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.

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.

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.

High estradiol levels improve false memory rates and meta-memory in highly schizotypal women.

Science.gov (United States)

Hodgetts, Sophie; Hausmann, Markus; Weis, Susanne

2015-10-30

Overconfidence in false memories is often found in patients with schizophrenia and healthy participants with high levels of schizotypy, indicating an impairment of meta-cognition within the memory domain. In general, cognitive control is suggested to be modulated by natural fluctuations in oestrogen. However, whether oestrogen exerts beneficial effects on meta-memory has not yet been investigated. The present study sought to provide evidence that high levels of schizotypy are associated with increased false memory rates and overconfidence in false memories, and that these processes may be modulated by natural differences in estradiol levels. Using the Deese-Roediger-McDermott paradigm, it was found that highly schizotypal participants with high estradiol produced significantly fewer false memories than those with low estradiol. No such difference was found within the low schizotypy participants. Highly schizotypal participants with high estradiol were also less confident in their false memories than those with low estradiol; low schizotypy participants with high estradiol were more confident. However, these differences only approached significance. These findings suggest that the beneficial effect of estradiol on memory and meta-memory observed in healthy participants is specific to highly schizotypal individuals and might be related to individual differences in baseline dopaminergic activity. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

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.

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...

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.

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.

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.

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.

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

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)

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.

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

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

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.

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.

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.

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.

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

GABA level, gamma oscillation, and working memory performance in schizophrenia.

Science.gov (United States)

Chen, Chi-Ming A; Stanford, Arielle D; Mao, Xiangling; Abi-Dargham, Anissa; Shungu, Dikoma C; Lisanby, Sarah H; Schroeder, Charles E; Kegeles, Lawrence S

2014-01-01

A relationship between working memory impairment, disordered neuronal oscillations, and abnormal prefrontal GABA function has been hypothesized in schizophrenia; however, in vivo GABA measurements and gamma band neural synchrony have not yet been compared in schizophrenia. This case-control pilot study (N = 24) compared baseline and working memory task-induced neuronal oscillations acquired with high-density electroencephalograms (EEGs) to GABA levels measured in vivo with magnetic resonance spectroscopy. Working memory performance, baseline GABA level in the left dorsolateral prefrontal cortex (DLPFC), and measures of gamma oscillations from EEGs at baseline and during a working memory task were obtained. A major limitation of this study is a relatively small sample size for several analyses due to the integration of diverse methodologies and participant compliance. Working memory performance was significantly lower for patients than for controls. During the working memory task, patients (n = 7) had significantly lower amplitudes in gamma oscillations than controls (n = 9). However, both at rest and across working memory stages, there were significant correlations between gamma oscillation amplitude and left DLPFC GABA level. Peak gamma frequency during the encoding stage of the working memory task (n = 16) significantly correlated with GABA level and working memory performance. Despite gamma band amplitude deficits in patients across working memory stages, both baseline and working memory-induced gamma oscillations showed strong dependence on baseline GABA levels in patients and controls. These findings suggest a critical role for GABA function in gamma band oscillations, even under conditions of system and cognitive impairments as seen in schizophrenia.

Low-level memory processes in vision.

Science.gov (United States)

Magnussen, S

2000-06-01

Psychophysical studies of the short-term memory for attributes or dimensions of the visual stimulus that are known to be important in early visual processing (spatial frequency, orientation, contrast, motion and color) identify a low-level perceptual memory mechanism. This proposed mechanism is located early in the visual processing stream, prior to the structural description system responsible for shape priming but beyond primary visual cortex (V1); it is composed of a series of parallel, special-purpose perceptual mechanisms with independent but limited processing resources. Each mechanism is devoted to the analysis of a single dimension and is coupled to a memory store.

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...

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.

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....

Impairment of memory and plasma flunitrazepam levels

NARCIS (Netherlands)

Bareggi, [No Value; Ferini-Strambi, L; Pirola, R; Smirne, S

Flunitrazepam was administered to volunteers in three different oral doses. The effects on psychomotor sedation, attention, working memory and explicit memory were then assessed at various intervals after dosing and compared with levels of the drug in the plasma. Three groups of 12 healthy males

Impairment of memory and plasma flunitrazepam levels

NARCIS (Netherlands)

Bareggi, [No Value; Ferini-Strambi, L; Pirola, R; Smirne, S

1998-01-01

Flunitrazepam was administered to volunteers in three different oral doses. The effects on psychomotor sedation, attention, working memory and explicit memory were then assessed at various intervals after dosing and compared with levels of the drug in the plasma. Three groups of 12 healthy males

GABA level, gamma oscillation, and working memory performance in schizophrenia

Directory of Open Access Journals (Sweden)

Chi-Ming A. Chen

2014-01-01

Full Text Available A relationship between working memory impairment, disordered neuronal oscillations, and abnormal prefrontal GABA function has been hypothesized in schizophrenia; however, in vivo GABA measurements and gamma band neural synchrony have not yet been compared in schizophrenia. This case–control pilot study (N = 24 compared baseline and working memory task-induced neuronal oscillations acquired with high-density electroencephalograms (EEGs to GABA levels measured in vivo with magnetic resonance spectroscopy. Working memory performance, baseline GABA level in the left dorsolateral prefrontal cortex (DLPFC, and measures of gamma oscillations from EEGs at baseline and during a working memory task were obtained. A major limitation of this study is a relatively small sample size for several analyses due to the integration of diverse methodologies and participant compliance. Working memory performance was significantly lower for patients than for controls. During the working memory task, patients (n = 7 had significantly lower amplitudes in gamma oscillations than controls (n = 9. However, both at rest and across working memory stages, there were significant correlations between gamma oscillation amplitude and left DLPFC GABA level. Peak gamma frequency during the encoding stage of the working memory task (n = 16 significantly correlated with GABA level and working memory performance. Despite gamma band amplitude deficits in patients across working memory stages, both baseline and working memory-induced gamma oscillations showed strong dependence on baseline GABA levels in patients and controls. These findings suggest a critical role for GABA function in gamma band oscillations, even under conditions of system and cognitive impairments as seen in schizophrenia.

The Level of Europium-154 Contaminating Samarium-153-EDTMP Activates the Radiation Alarm System at the US Homeland Security Checkpoints

Directory of Open Access Journals (Sweden)

Mohammed Najeeb Al Hallak

2009-08-01

Full Text Available 153Sm-EDTMP is a radiopharmaceutical composed of EDTMP (ethylenediamine-tetramethylenephosphonate and Samarium-153 [1]. 153Sm-EDTMP has an affinity for skeletal tissue and concentrates in areas with increased bone turnover; thus, it is successfully used in relieving pain related to diffuse bone metastases [1]. The manufacturing process of 153Sm-EDTMP leads to contamination with 154Eu (Europium-154 [2]. A previous study only alluded to the retention of 154Eu in the bones after receiving treatment with 153Sm-EDTMP [2]. Activation of the alarm at security checkpoints after 153Sm-EDTMP therapy has not been previously reported. Two out of 15 patients who received 153Sm-EDTMP at Roger Maris Cancer Center (Fargo, N. Dak., USA activated the radiation activity sensors while passing through checkpoints; one at a US airport and the other while crossing theAmerican-Canadian border. We assume that the 154Eu which remained in the patients’ bones activated the sensors. Methods: In order to investigate this hypothesis, we obtained the consent from 3 of our 15 patients who received 153Sm-EDTMP within the previous 4 months to 2 years, including the patient who had activated the radiation alarm at the airport. The patients were scanned with a handheld detector and a gamma camera for energies from 511 keV to 1.3 MeV. Results: All three patients exhibited identical spectral images, and further analysis showed that the observed spectra are the result of 154Eu emissions. Conclusion: Depending on the detection thresholds and windows used by local and federal authorities, the remaining activity of 154Eu retained in patients who received 153Sm-EDTMP could be sufficient enough to increase the count rates above background levels and activate the sensors. At Roger Maris Cancer Center, patients are now informed of the potential consequences of 153Sm-EDTMP therapy prior to initiating treatment. In addition, patients treated with 153Sm-EDTMP at Roger Maris Cancer Center

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.

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.

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.

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

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...

Genistein improves spatial learning and memory in male rats with elevated glucose level during memory consolidation.

Science.gov (United States)

Kohara, Yumi; Kawaguchi, Shinichiro; Kuwahara, Rika; Uchida, Yutaro; Oku, Yushi; Yamashita, Kimihiro

2015-03-01

Cognitive dysfunction due to higher blood glucose level has been reported previously. Genistein (GEN) is a phytoestrogen that we hypothesized might lead to improved memory, despite elevated blood glucose levels at the time of memory consolidation. To investigate this hypothesis, we compared the effects of orally administered GEN on the central nervous system in normal versus glucose-loaded adult male rats. A battery of behavioral assessments was carried out. In the MAZE test, which measured spatial learning and memory, the time of normal rats was shortened by GEN treatment compared to the vehicle group, but only in the early stages of testing. In the glucose-loaded group, GEN treatment improved performance as mazes were advanced. In the open-field test, GEN treatment delayed habituation to the new environment in normal rats, and increased the exploratory behaviors of glucose-loaded rats. There were no significant differences observed for emotionality or fear-motivated learning and memory. Together, these results indicate that GEN treatment improved spatial learning and memory only in the early stages of testing in the normal state, but improved spatial learning and memory when glucose levels increased during memory consolidation. Copyright © 2014 Elsevier Inc. All rights reserved.

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.

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

Strong homeostatic TCR signals induce formation of self-tolerant virtual memory CD8 T cells.

Science.gov (United States)

Drobek, Ales; Moudra, Alena; Mueller, Daniel; Huranova, Martina; Horkova, Veronika; Pribikova, Michaela; Ivanek, Robert; Oberle, Susanne; Zehn, Dietmar; McCoy, Kathy D; Draber, Peter; Stepanek, Ondrej

2018-05-11

Virtual memory T cells are foreign antigen-inexperienced T cells that have acquired memory-like phenotype and constitute 10-20% of all peripheral CD8 + T cells in mice. Their origin, biological roles, and relationship to naïve and foreign antigen-experienced memory T cells are incompletely understood. By analyzing T-cell receptor repertoires and using retrogenic monoclonal T-cell populations, we demonstrate that the virtual memory T-cell formation is a so far unappreciated cell fate decision checkpoint. We describe two molecular mechanisms driving the formation of virtual memory T cells. First, virtual memory T cells originate exclusively from strongly self-reactive T cells. Second, the stoichiometry of the CD8 interaction with Lck regulates the size of the virtual memory T-cell compartment via modulating the self-reactivity of individual T cells. Although virtual memory T cells descend from the highly self-reactive clones and acquire a partial memory program, they are not more potent in inducing experimental autoimmune diabetes than naïve T cells. These data underline the importance of the variable level of self-reactivity in polyclonal T cells for the generation of functional T-cell diversity. © 2018 The Authors. Published under the terms of the CC BY 4.0 license.

Associations between basal cortisol levels and memory retrieval in healthy young individuals

OpenAIRE

Ackermann, Sandra; Hartmann, Francina; Papassotiropoulos, Andreas; de Quervain, Dominique J-F; Rasch, Björn

2013-01-01

Cortisol is known to affect memory processes. On the one hand, stress-induced or pharmacologically induced elevations of cortisol levels enhance memory consolidation. On the other hand, such experimentally induced elevations of cortisol levels have been shown to impair memory retrieval. However, the effects of individual differences in basal cortisol levels on memory processes remain largely unknown. Here we tested whether individual differences in cortisol levels predict picture learning and...

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.

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....

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...

Memory-efficient dynamic programming backtrace and pairwise local sequence alignment.

Science.gov (United States)

Newberg, Lee A

2008-08-15

A backtrace through a dynamic programming algorithm's intermediate results in search of an optimal path, or to sample paths according to an implied probability distribution, or as the second stage of a forward-backward algorithm, is a task of fundamental importance in computational biology. When there is insufficient space to store all intermediate results in high-speed memory (e.g. cache) existing approaches store selected stages of the computation, and recompute missing values from these checkpoints on an as-needed basis. Here we present an optimal checkpointing strategy, and demonstrate its utility with pairwise local sequence alignment of sequences of length 10,000. Sample C++-code for optimal backtrace is available in the Supplementary Materials. Supplementary data is available at Bioinformatics online.

Low-level lead exposure effects on spatial reference memory and working memory in rats

Institute of Scientific and Technical Information of China (English)

Xinhua Yang; Ping Zhou; Yonghui Li

2009-01-01

BACKGROUND: Studies have demonstrated that lead exposure can result in cognitive dysfunction and behavior disorders. However, lead exposure impairments vary under different experimental conditions.OBJECTIVE: To detect changes in spatial learning and memory following low-level lead exposure in rats, in Morris water maze test under the same experimental condition used to analyze lead exposure effects on various memory types and learning processes.DESIGN AND SETTING: The experiment was conducted at the Animal Laboratory, Institute of Psychology, Chinese Academy of Science between February 2005 and March 2006. One-way analysis of variance (ANOVA) and behavioral observations were performed.MATERIALS: Sixteen male, healthy, adult, Sprague Dawley rats were randomized into normal control and lead exposure groups (n = 8).METHODS: Rats in the normal control group were fed distilled water, and those in the lead exposure group were fed 250 mL of 0.05% lead acetate once per day. At day 28, all rats performed the Morris water maze test, consisting of four phases: space navigation, probe test, working memory test, and visual cue test.MAIN OUTCOME MEASURES: Place navigation in the Morris water maze was used to evaluate spatial learning and memory, probe trials for spatial reference memory, working memory test for spatial working memory, and visual cue test for non-spatial cognitive function. Perkin-Elmer Model 300 Atomic Absorption Spectrometer was utilized to determine blood lead levels in rats.RESULTS: (1) In the working memory test, the time to reach the platform remained unchanged between the control and lead exposure groups (F(1,1) = 0.007, P = 0.935). A visible decrease in escape latencies was observed in each group (P = 0.028). However, there was no significant difference between the two groups (F(1,1) = 1.869, P = 0.193). The working memory probe test demonstrated no change between the two groups in the time spent in the target quadrant during the working memory probe test

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

Intermediate levels of hippocampal activity appear optimal for associative memory formation.

Directory of Open Access Journals (Sweden)

Xiao Liu

Full Text Available BACKGROUND: It is well established that hippocampal activity is positively related to effective associative memory formation. However, in biological systems often optimal levels of activity are contrasted by both sub- and supra-optimal levels. Sub-optimal levels of hippocampal activity are commonly attributed to unsuccessful memory formation, whereas the supra-optimal levels of hippocampal activity related to unsuccessful memory formation have been rarely studied. It is still unclear under what circumstances such supra-optimal levels of hippocampal activity occur. To clarify this issue, we aimed at creating a condition, in which supra-optimal hippocampal activity is associated with encoding failure. We assumed that such supra-optimal activity occurs when task-relevant information is embedded in task-irrelevant, distracting information, which can be considered as noise. METHODOLOGY/PRINCIPAL FINDINGS: In the present fMRI study, we probed neural correlates of associative memory formation in a full-factorial design with associative memory (subsequently remembered versus forgotten and noise (induced by high versus low distraction as factors. Results showed that encoding failure was associated with supra-optimal activity in the high-distraction condition and with sub-optimal activity in the low distraction condition. Thus, we revealed evidence for a bell-shape function relating hippocampal activity with associative encoding success. CONCLUSIONS/SIGNIFICANCE: Our findings indicate that intermediate levels of hippocampal activity are optimal while both too low and too high levels appear detrimental for associative memory formation. Supra-optimal levels of hippocampal activity seem to occur when task-irrelevant information is added to task-relevant signal. If such task-irrelevant noise is reduced adequately, hippocampal activity is lower and thus optimal for associative memory formation.

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.

Analysis of Drug Development Paradigms for Immune Checkpoint Inhibitors.

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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.

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

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

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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.

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)

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

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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

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

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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.

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...

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

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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.

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

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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.

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.

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.

Memory Effects in the Two-Level Model for Glasses

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Aquino, Gerardo; Allahverdyan, Armen; Nieuwenhuizen, Theo M.

2008-07-01

We study an ensemble of two-level systems interacting with a thermal bath. This is a well-known model for glasses. The origin of memory effects in this model is a quasistationary but nonequilibrium state of a single two-level system, which is realized due to a finite-rate cooling and slow thermally activated relaxation. We show that single-particle memory effects, such as negativity of the specific heat under reheating, vanish for a sufficiently disordered ensemble. In contrast, a disordered ensemble displays a collective memory effect [similar to the Kovacs effect], where nonequilibrium features of the ensemble are monitored via a macroscopic observable. An experimental realization of the effect can be used to further assess the consistency of the model.

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.

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...

Higher glucose levels associated with lower memory and reduced hippocampal microstructure.

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Kerti, Lucia; Witte, A Veronica; Winkler, Angela; Grittner, Ulrike; Rujescu, Dan; Flöel, Agnes

2013-11-12

For this cross-sectional study, we aimed to elucidate whether higher glycosylated hemoglobin (HbA1c) and glucose levels exert a negative impact on memory performance and hippocampal volume and microstructure in a cohort of healthy, older, nondiabetic individuals without dementia. In 141 individuals (72 women, mean age 63.1 years ± 6.9 SD), memory was tested using the Rey Auditory Verbal Learning Test. Peripheral levels of fasting HbA1c, glucose, and insulin and 3-tesla MRI scans were acquired to assess hippocampal volume and microstructure, as indicated by gray matter barrier density. Linear regression and simple mediation models were calculated to examine associations among memory, glucose metabolism, and hippocampal parameters. Lower HbA1c and glucose levels were significantly associated with better scores in delayed recall, learning ability, and memory consolidation. In multiple regression models, HbA1c remained strongly associated with memory performance. Moreover, mediation analyses indicated that beneficial effects of lower HbA1c on memory are in part mediated by hippocampal volume and microstructure. Our results indicate that even in the absence of manifest type 2 diabetes mellitus or impaired glucose tolerance, chronically higher blood glucose levels exert a negative influence on cognition, possibly mediated by structural changes in learning-relevant brain areas. Therefore, strategies aimed at lowering glucose levels even in the normal range may beneficially influence cognition in the older population, a hypothesis to be examined in future interventional trials.

Associations between basal cortisol levels and memory retrieval in healthy young individuals.

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Ackermann, Sandra; Hartmann, Francina; Papassotiropoulos, Andreas; de Quervain, Dominique J F; Rasch, Björn

2013-11-01

Cortisol is known to affect memory processes. On the one hand, stress-induced or pharmacologically induced elevations of cortisol levels enhance memory consolidation. On the other hand, such experimentally induced elevations of cortisol levels have been shown to impair memory retrieval. However, the effects of individual differences in basal cortisol levels on memory processes remain largely unknown. Here we tested whether individual differences in cortisol levels predict picture learning and recall in a large sample. A total of 1225 healthy young women and men viewed two different sets of emotional and neutral pictures on two consecutive days. Both sets were recalled after a short delay (10 min). On Day 2, the pictures seen on Day 1 were additionally recalled, resulting in a long-delay (20 hr) recall condition. Cortisol levels were measured three times on Days 1 and 2 via saliva samples before encoding, between encoding and recall as well as after recall testing. We show that stronger decreases in cortisol levels during retrieval testing were associated with better recall performance of pictures, regardless of emotional valence of the pictures or length of the retention interval (i.e., 10 min vs. 20 hr). In contrast, average cortisol levels during retrieval were not related to picture recall. Remarkably during encoding, individual differences in average cortisol levels as well as changes in cortisol did not predict memory recall. Our results support previous findings indicating that higher cortisol levels during retrieval testing hinders recall of episodic memories and extend this view onto interindividual changes in basal cortisol levels.

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

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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.

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

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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.

PD-1 checkpoint inhibition: Toxicities and management.

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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.

Genistein improves spatial learning and memory in male rats with elevated glucose level during memory consolidation

OpenAIRE

Kohara, Yumi; Kawaguchi, Shinichiro; Kuwahara, Rika; Uchida, Yutaro; Oku, Yushi; Yamashita, Kimihiro

2015-01-01

Cognitive dysfunction due to higher blood glucose level has been reported previously. Genistein (GEN) is a phytoestrogen that we hypothesized might lead to improved memory, despite elevated blood glucose levels at the time of memory consolidation. To investigate this hypothesis, we compared the effects of orally administered GEN on the central nervous system in normal versus glucose-loaded adult male rats. A battery of behavioral assessments was carried out. In the MAZE test, which measured s...

The Levels of Processing Conceptualization of Human Memory: Some Empirical and Theoretical Issues,

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1984-12-01

levels -of- processing (LOP) framework was introduced by Craik and Lockhart in 1972...G. H. A multicomponent theory of the memory trace. In F. I. M. Craik and R. S. Lockhart , Levels of 6 processing : A framework for memory research... Lockhart , R. S. Levels of processing : A framework of memory research. Journal of Verbal Learning and Verbal Behavior, 1972, 11, 671-684. 25. Craik , F.

Level of Processing Modulates the Neural Correlates of Emotional Memory Formation

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Ritchey, Maureen; LaBar, Kevin S.; Cabeza, Roberto

2011-01-01

Emotion is known to influence multiple aspects of memory formation, including the initial encoding of the memory trace and its consolidation over time. However, the neural mechanisms whereby emotion impacts memory encoding remain largely unexplored. The present study used a levels-of-processing manipulation to characterize the impact of emotion on…

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

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

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

Levels of processing and language modality specificity in working memory.

Science.gov (United States)

Rudner, Mary; Karlsson, Thomas; Gunnarsson, Johan; Rönnberg, Jerker

2013-03-01

Neural networks underpinning working memory demonstrate sign language specific components possibly related to differences in temporary storage mechanisms. A processing approach to memory systems suggests that the organisation of memory storage is related to type of memory processing as well. In the present study, we investigated for the first time semantic, phonological and orthographic processing in working memory for sign- and speech-based language. During fMRI we administered a picture-based 2-back working memory task with Semantic, Phonological, Orthographic and Baseline conditions to 11 deaf signers and 20 hearing non-signers. Behavioural data showed poorer and slower performance for both groups in Phonological and Orthographic conditions than in the Semantic condition, in line with depth-of-processing theory. An exclusive masking procedure revealed distinct sign-specific neural networks supporting working memory components at all three levels of processing. The overall pattern of sign-specific activations may reflect a relative intermodality difference in the relationship between phonology and semantics influencing working memory storage and processing. Copyright © 2012 Elsevier Ltd. All rights reserved.

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

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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.

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...

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.

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

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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.

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.

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.

Room-Temperature Single-photon level Memory for Polarization States

Science.gov (United States)

Kupchak, Connor; Mittiga, Thomas; Jordaan, Bertus; Namazi, Mehdi; Nölleke, Christian; Figueroa, Eden

2015-01-01

An optical quantum memory is a stationary device that is capable of storing and recreating photonic qubits with a higher fidelity than any classical device. Thus far, these two requirements have been fulfilled for polarization qubits in systems based on cold atoms and cryogenically cooled crystals. Here, we report a room-temperature memory capable of storing arbitrary polarization qubits with a signal-to-background ratio higher than 1 and an average fidelity surpassing the classical benchmark for weak laser pulses containing 1.6 photons on average, without taking into account non-unitary operation. Our results demonstrate that a common vapor cell can reach the low background noise levels necessary for polarization qubit storage using single-photon level light, and propels atomic-vapor systems towards a level of functionality akin to other quantum information processing architectures.

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

GOTHIC memory management : a multiprocessor shared single level store

OpenAIRE

Michel , Béatrice

1990-01-01

Gothic purpose is to build an object-oriented fault-tolerant distributed operating system for a local area network of multiprocessor workstations. This paper describes Gothic memory manager. It realizes the sharing of the secondary memory space between any process running on the Gothic system. Processes on different processors can communicate by sharing permanent information. The manager implements a shared single level storage with an invalidation protocol working on disk-pages to maintain s...

Cenp-meta is required for sustained spindle checkpoint

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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.

Level of processing modulates the neural correlates of emotional memory formation

OpenAIRE

Ritchey, Maureen; LaBar, Kevin S.; Cabeza, Roberto

2010-01-01

Emotion is known to influence multiple aspects of memory formation, including the initial encoding of the memory trace and its consolidation over time. However, the neural mechanisms whereby emotion impacts memory encoding remain largely unexplored. The present study employed a levels-of-processing manipulation to characterize the impact of emotion on encoding with and without the influence of elaborative processes. Participants viewed emotionally negative, neutral, and positive scenes under ...

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.

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.

Attention, working memory, and phenomenal experience of WM content: memory levels determined by different types of top-down modulation.

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Jacob, Jane; Jacobs, Christianne; Silvanto, Juha

2015-01-01

What is the role of top-down attentional modulation in consciously accessing working memory (WM) content? In influential WM models, information can exist in different states, determined by allocation of attention; placing the original memory representation in the center of focused attention gives rise to conscious access. Here we discuss various lines of evidence indicating that such attentional modulation is not sufficient for memory content to be phenomenally experienced. We propose that, in addition to attentional modulation of the memory representation, another type of top-down modulation is required: suppression of all incoming visual information, via inhibition of early visual cortex. In this view, there are three distinct memory levels, as a function of the top-down control associated with them: (1) Nonattended, nonconscious associated with no attentional modulation; (2) attended, phenomenally nonconscious memory, associated with attentional enhancement of the actual memory trace; (3) attended, phenomenally conscious memory content, associated with enhancement of the memory trace and top-down suppression of all incoming visual input.

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

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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.

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

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.

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

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.

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.

Elevated lead levels from e-waste exposure are linked to decreased olfactory memory in children.

Science.gov (United States)

Zhang, Bo; Huo, Xia; Xu, Long; Cheng, Zhiheng; Cong, Xiaowei; Lu, Xueling; Xu, Xijin

2017-12-01

Lead (Pb) is a developmental neurotoxicant and can cause abnormal development of the nervous system in children. Hence, the aim of this study was to investigate the effect of Pb exposure on child olfactory memory by correlating the blood Pb levels of children in Guiyu with olfactory memory tests. We recruited 61 preschool children, 4- to 7-years of age, from Guiyu and 57 children from Haojiang. The mean blood Pb level of Guiyu children was 9.40 μg/dL, significantly higher than the 5.04 μg/dL mean blood Pb level of Haojiang children. In addition, approximately 23% of Guiyu children had blood Pb levels exceeding 10.00 μg/dL. The correlation analysis showed that blood Pb levels in children highly correlated with e-waste contact (r s  = 0.393). Moreover, the mean concentration of serum BDNF in Guiyu children (35.91 ng/ml) was higher than for Haojiang (28.10 ng/ml) and was positively correlated with blood Pb levels. Both item and source olfactory memory tests at 15 min, 5 h and 24 h after odor exposure showed that scores were lower in Guiyu children indicative of reduced olfactory memory in Guiyu children. Olfactory memory tests scores negatively correlated with blood Pb and serum BDNF levels, but were positively associated with parental education levels. At the same time, scores of both tests on children in the high blood Pb level group (blood Pb levels > 5.00 μg/dL) were lower than those in the low blood Pb level group (blood Pb levels ≤ 5.00 μg/dL), implying that Pb exposure decreases olfactory memory in children. Our findings suggest that Pb exposure in e-waste recycling and dismantling areas could result in an increase in serum BDNF level and a decrease in child olfactory memory, in addition, BDNF might be involved in olfactory memory impairment. Copyright © 2017 Elsevier Ltd. All rights reserved.

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)

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

Witnesses' memory for events and faces under elevated levels of intoxication.

Science.gov (United States)

Altman, Christopher M; Schreiber Compo, Nadja; McQuiston, Dawn; Hagsand, Angelica V; Cervera, Jiselle

2018-08-01

Research on alcohol and witness memory has burgeoned over the last decade. However, most studies have tested participants at relatively low breath alcohol concentration (BAC) levels, unrepresentative of those encountered by officers in the field. To examine how higher intoxication levels might impair witness memory for events and faces, the current research tested participants' ability to recall a mock crime at elevated BAC levels (>.08%). The BAC levels of bar patrons (N = 138) were recorded before witnessing a video-taped mock crime. Participants were then interviewed using free recall and cued questions and shown a six-person target-present or target-absent lineup. Results show that alcohol negatively affected both the quantity and quality of recall. Regardless of question format, alcohol also reduced the percentage of accurate information elicited from witnesses; however, only cued questions increased the percentage of inaccurate information reported. Intoxication had no effect on identification accuracy. These findings suggest that the encoding and storage systems for faces and events may be impacted differently by alcohol. Our results also highlight the importance of including higher BAC levels when examining the effects of alcohol on witness memory.

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.

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.

Similarities and Differences between Working Memory and Long-Term Memory: Evidence from the Levels-of-Processing Span Task

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Rose, Nathan S.; Myerson, Joel; Roediger, Henry L., III; Hale, Sandra

2010-01-01

Two experiments compared the effects of depth of processing on working memory (WM) and long-term memory (LTM) using a levels-of-processing (LOP) span task, a newly developed WM span procedure that involves processing to-be-remembered words based on their visual, phonological, or semantic characteristics. Depth of processing had minimal effect on…

GABA level, gamma oscillation, and working memory performance in schizophrenia

OpenAIRE

Chen, Chi-Ming A.; Stanford, Arielle D.; Mao, Xiangling; Abi-Dargham, Anissa; Shungu, Dikoma C.; Lisanby, Sarah H.; Schroeder, Charles E.; Kegeles, Lawrence S.

2014-01-01

A relationship between working memory impairment, disordered neuronal oscillations, and abnormal prefrontal GABA function has been hypothesized in schizophrenia; however, in vivo GABA measurements and gamma band neural synchrony have not yet been compared in schizophrenia. This case–control pilot study (N = 24) compared baseline and working memory task-induced neuronal oscillations acquired with high-density electroencephalograms (EEGs) to GABA levels measured in vivo with magnetic resonance ...

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...

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

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.

ALDH1A1 maintains ovarian cancer stem cell-like properties by altered regulation of cell cycle checkpoint and DNA repair network signaling.

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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.

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....

Selectivity in Postencoding Connectivity with High-Level Visual Cortex Is Associated with Reward-Motivated Memory.

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Murty, Vishnu P; Tompary, Alexa; Adcock, R Alison; Davachi, Lila

2017-01-18

Reward motivation has been demonstrated to enhance declarative memory by facilitating systems-level consolidation. Although high-reward information is often intermixed with lower reward information during an experience, memory for high value information is prioritized. How is this selectivity achieved? One possibility is that postencoding consolidation processes bias memory strengthening to those representations associated with higher reward. To test this hypothesis, we investigated the influence of differential reward motivation on the selectivity of postencoding markers of systems-level memory consolidation. Human participants encoded intermixed, trial-unique memoranda that were associated with either high or low-value during fMRI acquisition. Encoding was interleaved with periods of rest, allowing us to investigate experience-dependent changes in connectivity as they related to later memory. Behaviorally, we found that reward motivation enhanced 24 h associative memory. Analysis of patterns of postencoding connectivity showed that, even though learning trials were intermixed, there was significantly greater connectivity with regions of high-level, category-selective visual cortex associated with high-reward trials. Specifically, increased connectivity of category-selective visual cortex with both the VTA and the anterior hippocampus predicted associative memory for high- but not low-reward memories. Critically, these results were independent of encoding-related connectivity and univariate activity measures. Thus, these findings support a model by which the selective stabilization of memories for salient events is supported by postencoding interactions with sensory cortex associated with reward. Reward motivation is thought to promote memory by supporting memory consolidation. Yet, little is known as to how brain selects relevant information for subsequent consolidation based on reward. We show that experience-dependent changes in connectivity of both the

DESTINY: A Comprehensive Tool with 3D and Multi-Level Cell Memory Modeling Capability

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Sparsh Mittal

2017-09-01

Full Text Available To enable the design of large capacity memory structures, novel memory technologies such as non-volatile memory (NVM and novel fabrication approaches, e.g., 3D stacking and multi-level cell (MLC design have been explored. The existing modeling tools, however, cover only a few memory technologies, technology nodes and fabrication approaches. We present DESTINY, a tool for modeling 2D/3D memories designed using SRAM, resistive RAM (ReRAM, spin transfer torque RAM (STT-RAM, phase change RAM (PCM and embedded DRAM (eDRAM and 2D memories designed using spin orbit torque RAM (SOT-RAM, domain wall memory (DWM and Flash memory. In addition to single-level cell (SLC designs for all of these memories, DESTINY also supports modeling MLC designs for NVMs. We have extensively validated DESTINY against commercial and research prototypes of these memories. DESTINY is very useful for performing design-space exploration across several dimensions, such as optimizing for a target (e.g., latency, area or energy-delay product for a given memory technology, choosing the suitable memory technology or fabrication method (i.e., 2D v/s 3D for a given optimization target, etc. We believe that DESTINY will boost studies of next-generation memory architectures used in systems ranging from mobile devices to extreme-scale supercomputers. The latest source-code of DESTINY is available from the following git repository: https://bitbucket.org/sparshmittal/destinyv2.

[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

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.

Drosophila MOF controls Checkpoint protein2 and regulates genomic stability during early embryogenesis.

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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

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

Level of processing modulates the neural correlates of emotional memory formation.

Science.gov (United States)

Ritchey, Maureen; LaBar, Kevin S; Cabeza, Roberto

2011-04-01

Emotion is known to influence multiple aspects of memory formation, including the initial encoding of the memory trace and its consolidation over time. However, the neural mechanisms whereby emotion impacts memory encoding remain largely unexplored. The present study used a levels-of-processing manipulation to characterize the impact of emotion on encoding with and without the influence of elaborative processes. Participants viewed emotionally negative, neutral, and positive scenes under two conditions: a shallow condition focused on the perceptual features of the scenes and a deep condition that queried their semantic meaning. Recognition memory was tested 2 days later. Results showed that emotional memory enhancements were greatest in the shallow condition. fMRI analyses revealed that the right amygdala predicted subsequent emotional memory in the shallow more than deep condition, whereas the right ventrolateral PFC demonstrated the reverse pattern. Furthermore, the association of these regions with the hippocampus was modulated by valence: the amygdala-hippocampal link was strongest for negative stimuli, whereas the prefrontal-hippocampal link was strongest for positive stimuli. Taken together, these results suggest two distinct activation patterns underlying emotional memory formation: an amygdala component that promotes memory during shallow encoding, especially for negative information, and a prefrontal component that provides extra benefits during deep encoding, especially for positive information.

Level of processing modulates the neural correlates of emotional memory formation

Science.gov (United States)

Ritchey, Maureen; LaBar, Kevin S.; Cabeza, Roberto

2010-01-01

Emotion is known to influence multiple aspects of memory formation, including the initial encoding of the memory trace and its consolidation over time. However, the neural mechanisms whereby emotion impacts memory encoding remain largely unexplored. The present study employed a levels-of-processing manipulation to characterize the impact of emotion on encoding with and without the influence of elaborative processes. Participants viewed emotionally negative, neutral, and positive scenes under two conditions: a shallow condition focused on the perceptual features of the scenes and a deep condition that queried their semantic meaning. Recognition memory was tested 2 days later. Results showed that emotional memory enhancements were greatest in the shallow condition. FMRI analyses revealed that the right amygdala predicted subsequent emotional memory in the shallow more than deep condition, whereas the right ventrolateral prefrontal cortex demonstrated the reverse pattern. Furthermore, the association of these regions with the hippocampus was modulated by valence: the amygdala-hippocampal link was strongest for negative stimuli, whereas the prefrontal-hippocampal link was strongest for positive stimuli. Taken together, these results suggest two distinct activation patterns underlying emotional memory formation: an amygdala component that promotes memory during shallow encoding, especially for negative information, and a prefrontal component that provides extra benefits during deep encoding, especially for positive information. PMID:20350176

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.

A Processing Approach to the Working Memory/Long-Term Memory Distinction: Evidence from the Levels-of-Processing Span Task

Science.gov (United States)

Rose, Nathan S.; Craik, Fergus I. M.

2012-01-01

Recent theories suggest that performance on working memory (WM) tasks involves retrieval from long-term memory (LTM). To examine whether WM and LTM tests have common principles, Craik and Tulving's (1975) levels-of-processing paradigm, which is known to affect LTM, was administered as a WM task: Participants made uppercase, rhyme, or…

Intermediate levels of hippocampal activity appear optimal for associative memory formation.

NARCIS (Netherlands)

Liu, X.; Qin, S.; Rijpkema, M.J.P.; Luo, J.; Fernandez, G.S.E.

2010-01-01

BACKGROUND: It is well established that hippocampal activity is positively related to effective associative memory formation. However, in biological systems often optimal levels of activity are contrasted by both sub- and supra-optimal levels. Sub-optimal levels of hippocampal activity are commonly

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

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.

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

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

Abeta(1-42) injection causes memory impairment, lowered cortical and serum BDNF levels, and decreased hippocampal 5-HT(2A) levels

DEFF Research Database (Denmark)

Christensen, R; Marcussen, Anders Bue; Wörtwein, Gitta

2008-01-01

was used to monitor Abeta(1-42) induced memory impairment. Memory impairment was seen 22 days after injection of Abeta(1-42) in the experimental group and until termination of the experiments. In the Abeta(1-42) injected animals we saw an abolished increase in serum BDNF levels that was accompanied...... by significant lower BDNF levels in frontal cortex and by an 8.5% reduction in hippocampal 5-HT(2A) receptor levels. A tendency towards lowered cortical 5-HT(2A) was also observed. These results indicate that the Abeta(1-42) associated memory deficit is associated with an impaired BDNF regulation, which...

An integrative view of storage of low- and high-level visual dimensions in visual short-term memory.

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Magen, Hagit

2017-03-01

Efficient performance in an environment filled with complex objects is often achieved through the temporal maintenance of conjunctions of features from multiple dimensions. The most striking finding in the study of binding in visual short-term memory (VSTM) is equal memory performance for single features and for integrated multi-feature objects, a finding that has been central to several theories of VSTM. Nevertheless, research on binding in VSTM focused almost exclusively on low-level features, and little is known about how items from low- and high-level visual dimensions (e.g., colored manmade objects) are maintained simultaneously in VSTM. The present study tested memory for combinations of low-level features and high-level representations. In agreement with previous findings, Experiments 1 and 2 showed decrements in memory performance when non-integrated low- and high-level stimuli were maintained simultaneously compared to maintaining each dimension in isolation. However, contrary to previous findings the results of Experiments 3 and 4 showed decrements in memory performance even when integrated objects of low- and high-level stimuli were maintained in memory, compared to maintaining single-dimension objects. Overall, the results demonstrate that low- and high-level visual dimensions compete for the same limited memory capacity, and offer a more comprehensive view of VSTM.

Multi-Level Bitmap Indexes for Flash Memory Storage

Energy Technology Data Exchange (ETDEWEB)

Wu, Kesheng; Madduri, Kamesh; Canon, Shane

2010-07-23

Due to their low access latency, high read speed, and power-efficient operation, flash memory storage devices are rapidly emerging as an attractive alternative to traditional magnetic storage devices. However, tests show that the most efficient indexing methods are not able to take advantage of the flash memory storage devices. In this paper, we present a set of multi-level bitmap indexes that can effectively take advantage of flash storage devices. These indexing methods use coarsely binned indexes to answer queries approximately, and then use finely binned indexes to refine the answers. Our new methods read significantly lower volumes of data at the expense of an increased disk access count, thus taking full advantage of the improved read speed and low access latency of flash devices. To demonstrate the advantage of these new indexes, we measure their performance on a number of storage systems using a standard data warehousing benchmark called the Set Query Benchmark. We observe that multi-level strategies on flash drives are up to 3 times faster than traditional indexing strategies on magnetic disk drives.

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

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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.

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

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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.

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

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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.

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

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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.

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

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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…

Levels of processing and picture memory: the physical superiority effect.

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Intraub, H; Nicklos, S

1985-04-01

Six experiments studied the effect of physical orienting questions (e.g., "Is this angular?") and semantic orienting questions (e.g., "Is this edible?") on memory for unrelated pictures at stimulus durations ranging from 125-2,000 ms. Results ran contrary to the semantic superiority "rule of thumb," which is based primarily on verbal memory experiments. Physical questions were associated with better free recall and cued recall of a diverse set of visual scenes (Experiments 1, 2, and 4). This occurred both when general and highly specific semantic questions were used (Experiments 1 and 2). Similar results were obtained when more simplistic visual stimuli--photographs of single objects--were used (Experiments 5 and 6). As in the case of the semantic superiority effect with words, the physical superiority effect for pictures was eliminated or reversed when the same physical questions were repeated throughout the session (Experiments 4 and 6). Conflicts with results of previous levels of processing experiments with words and nonverbal stimuli (e.g., faces) are explained in terms of the sensory-semantic model (Nelson, Reed, & McEvoy, 1977). Implications for picture memory research and the levels of processing viewpoint are discussed.

Prediction of changes in memory performance by plasma homovanillic acid levels in clozapine-treated patients with schizophrenia.

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Sumiyoshi, Tomiki; Roy, A; Kim, C-H; Jayathilake, K; Lee, M A; Sumiyoshi, C; Meltzer, H Y

2004-12-01

Cognitive dysfunction in schizophrenia has been demonstrated to be dependent, in part, on dopaminergic activity. Clozapine has been found to improve some domains of cognition, including verbal memory, in patients with schizophrenia. This study tested the hypothesis that plasma homovanillic acid (pHVA) levels, a peripheral measure of central dopaminergic activity, would predict the change in memory performance in patients with schizophrenia treated with clozapine. Twenty-seven male patients with schizophrenia received clozapine treatment for 6 weeks. Verbal list learning (VLL)-Delayed Recall (VLL-DR), a test of secondary verbal memory, was administered before and after clozapine treatment. Blood samples to measure pHVA levels were collected at baseline. Baseline pHVA levels were negatively correlated with change in performance on VLL-DR; the lower baseline pHVA level was associated with greater improvement in performance on VLL-DR during treatment with clozapine. Baseline pHVA levels in subjects who showed improvement in verbal memory during clozapine treatment ( n=13) were significantly lower than those in subjects whose memory performance did not improve ( n=14). The results of this study indicate that baseline pHVA levels predict the ability of clozapine to improve memory performance in patients with schizophrenia.

Chronic scream sound exposure alters memory and monoamine levels in female rat brain.

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Hu, Lili; Zhao, Xiaoge; Yang, Juan; Wang, Lumin; Yang, Yang; Song, Tusheng; Huang, Chen

2014-10-01

Chronic scream sound alters the cognitive performance of male rats and their brain monoamine levels, these stress-induced alterations are sexually dimorphic. To determine the effects of sound stress on female rats, we examined their serum corticosterone levels and their adrenal, splenic, and thymic weights, their cognitive performance and the levels of monoamine neurotransmitters and their metabolites in the brain. Adult female Sprague-Dawley rats, with and without exposure to scream sound (4h/day for 21 day) were tested for spatial learning and memory using a Morris water maze. Stress decreased serum corticosterone levels, as well as splenic and adrenal weight. It also impaired spatial memory but did not affect the learning ability. Monoamines and metabolites were measured in the prefrontal cortex (PFC), striatum, hypothalamus, and hippocampus. The dopamine (DA) levels in the PFC decreased but the homovanillic acid/DA ratio increased. The decreased DA and the increased 5-hydroxyindoleacetic acid (5-HIAA) levels were observed in the striatum. Only the 5-HIAA level increased in the hypothalamus. In the hippocampus, stress did not affect the levels of monoamines and metabolites. The results suggest that scream sound stress influences most physiologic parameters, memory, and the levels of monoamine neurotransmitter and their metabolites in female rats. Copyright © 2014. Published by Elsevier Inc.

Background Noise Analysis in a Few-Photon-Level Qubit Memory

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Mittiga, Thomas; Kupchak, Connor; Jordaan, Bertus; Namazi, Mehdi; Nolleke, Christian; Figeroa, Eden

2014-05-01

We have developed an Electromagnetically Induced Transparency based polarization qubit memory. The device is composed of a dual-rail probe field polarization setup colinear with an intense control field to store and retrieve any arbitrary polarization state by addressing a Λ-type energy level scheme in a 87Rb vapor cell. To achieve a signal-to-background ratio at the few photon level sufficient for polarization tomography of the retrieved state, the intense control field is filtered out through an etalon filtrating system. We have developed an analytical model predicting the influence of the signal-to-background ratio on the fidelities and compared it to experimental data. Experimentally measured global fidelities have been found to follow closely the theoretical prediction as signal-to-background decreases. These results suggest the plausibility of employing room temperature memories to store photonic qubits at the single photon level and for future applications in long distance quantum communication schemes.

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

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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.

Short-term visual memory properties sheet secondary school age with different levels of physical development

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E.E. Menshikh

2013-12-01

Full Text Available Purpose . The results presented properties of short-term visual memory with different levels of physical development. Materials and methods. The study included 405 boys and girls Cherkassy school 11 in age from 13 to 16 years. Study of short-term visual memory was carried out using tables with 10 characters ( numbers and ambiguous geometric shapes . Indicator memory was the higher, the more information was displayed. Measured the length and body weight was recorded cardiorespiratory indicators - heart rate at rest and after 20 squats, lung capacity, breath-hold inspiration and expiration. Physical development factor was calculated by taking into account actual and average population indices. Results . Found that the volume of short-term visual memory, the boys and girls high school age does not depend on the level of their physical development. Despite the fact that the trend towards higher performance memory in groups of persons with a high level of physical development compared to their same age with medium and low levels, significant differences between the mean values for the most part have been identified. No significant differences between the values of the investigated cognitive function in groups by sex. Conclusions . Growth pattern memory with age in this period of ontogenesis preserved that coincides with the data presented in the scientific works of scientists.

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

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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.

The influence of levels of processing on recall from working memory and delayed recall tasks.

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Loaiza, Vanessa M; McCabe, David P; Youngblood, Jessie L; Rose, Nathan S; Myerson, Joel

2011-09-01

Recent research in working memory has highlighted the similarities involved in retrieval from complex span tasks and episodic memory tasks, suggesting that these tasks are influenced by similar memory processes. In the present article, the authors manipulated the level of processing engaged when studying to-be-remembered words during a reading span task (Experiment 1) and an operation span task (Experiment 2) in order to assess the role of retrieval from secondary memory during complex span tasks. Immediate recall from both span tasks was greater for items studied under deep processing instructions compared with items studied under shallow processing instructions regardless of trial length. Recall was better for deep than for shallow levels of processing on delayed recall tests as well. These data are consistent with the primary-secondary memory framework, which suggests that to-be-remembered items are displaced from primary memory (i.e., the focus of attention) during the processing phases of complex span tasks and therefore must be retrieved from secondary memory. (c) 2011 APA, all rights reserved.

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

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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.

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.

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

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

The Influence of Levels of Processing on Recall from Working Memory and Delayed Recall Tasks

Science.gov (United States)

Loaiza, Vanessa M.; McCabe, David P.; Youngblood, Jessie L.; Rose, Nathan S.; Myerson, Joel

2011-01-01

Recent research in working memory has highlighted the similarities involved in retrieval from complex span tasks and episodic memory tasks, suggesting that these tasks are influenced by similar memory processes. In the present article, the authors manipulated the level of processing engaged when studying to-be-remembered words during a reading…

Modulation of memory with septal injections of morphine and glucose: effects on extracellular glucose levels in the hippocampus.

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McNay, Ewan C; Canal, Clinton E; Sherwin, Robert S; Gold, Paul E

2006-02-28

The concentration of glucose in the extracellular fluid (ECF) of the hippocampus decreases substantially during memory testing on a hippocampus-dependent memory task. Administration of exogenous glucose, which enhances task performance, prevents this decrease, suggesting a relationship between hippocampal glucose availability and memory performance. In the present experiment, spontaneous alternation performance and task-related changes in hippocampal ECF glucose were assessed in rats after intraseptal administration of morphine, which impairs memory on a spontaneous alternation task, and after co-administration of intraseptal glucose, which attenuates that impairment. Consistent with previous findings, spontaneous alternation testing resulted in a decrease in hippocampal ECF glucose levels in control rats. However, rats that received intraseptal morphine prior to testing showed memory impairments and an absence of the task-related decrease in hippocampal ECF glucose levels. Intraseptal co-administration of glucose with morphine attenuated the memory impairment, and ECF glucose levels in the hippocampus decreased in a manner comparable to that seen in control rats. These data suggest that fluctuations in hippocampal ECF glucose levels may be a marker of mnemonic processing and support the view that decreases in extracellular glucose during memory testing reflect increased glucose demand during memory processing.

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

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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.

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

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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.

mHealth and memory aids: levels of smartphone ownership in patients.

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Migo, Ellen M; Haynes, Becky I; Harris, Lara; Friedner, Kim; Humphreys, Kate; Kopelman, Michael D

2015-01-01

The use of mobile devices to deliver healthcare has not yet been exploited in neuropsychological rehabilitation. Smartphones have the potential to serve as multi-functional memory aids. To investigate whether patients attending a clinic for mixed memory problems own smartphones, to determine whether this could be a widely applicable medium to use as a memory aids device. A questionnaire on smartphone ownership was given to an opportunity sample of consecutive patients attending a neuropsychiatry and memory disorders outpatient clinic. Data were collected in 2012 and repeated 12 months later in 2013 to assess changes over time. Ownership of mobile phones was stable between 2012 (81%) and 2013 (85%), but ownership of smartphones showed a significant increase (from 26% to 40%). Age negatively predicted smartphone ownership. Despite cognitive or psychiatric problems, our patient group are as likely to own a mobile phone as a member of the general population. Ownership levels are at 40% and likely to increase in the future. Exploring how smartphones and their apps could function as memory aids is likely to be useful for a large enough number of patients to be clinically worthwhile.

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

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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.

Relationship of word- and sentence-level working memory to reading and writing in second, fourth, and sixth grade.

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Berninger, Virginia W; Abbott, Robert D; Swanson, H Lee; Lovitt, Dan; Trivedi, Pam; Lin, Shin-Ju Cindy; Gould, Laura; Youngstrom, Marci; Shimada, Shirley; Amtmann, Dagmar

2010-04-01

The purpose of this study was to evaluate the contribution of working memory at the word and sentence levels of language to reading and writing outcomes. Measures of working memory at the word and sentence levels, reading and writing, were administered to 2nd (N = 122), 4th (N = 222), and 6th (N = 105) graders. Structural equation modeling was used to evaluate whether the 2 predictor working memory factors contributed unique variance beyond their shared covariance to each of 5 outcome factors: handwriting, spelling, composing, word reading, and reading comprehension. At each grade level, except for handwriting and composing in 6th grade, the word-level working memory factor contributed unique variance to each reading and writing outcome. The text-level working memory factor contributed unique variance to reading comprehension in 4th and 6th grade. The clinical significance of these findings for assessment and intervention is discussed.

Levels of Phonological Awareness, Working Memory, and Lexical Knowledge in Elementary School Children

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Heloisa Helena Motta Bandini

2013-09-01

Full Text Available Relationships between oral language, phonological awareness, and working memory have been empirically demonstrated, however, phonological awareness encompasses different abilities, assessed at different levels. The present study investigated the possible associations between specific phonological awareness abilities and phonological working memory in first-grade students. In the initial phase ( n = 254, the study evaluated the abilities of phonological awareness and phonological working memory and found a high positive correlation between these abilities, thus confirming the findings of previous studies. The second phase ( n = 12 evaluated the vocabulary of individuals who, in the initial phase, showed low or high working memory and phonological awareness scores. Students with low working memory and low phonological awareness capacities had low scores in expressive language abilities, suggesting that phonological working memory may have direct effects on lexical knowledge. These results contribute to the understanding of the relationships investigated in this study and have important implications for planning teaching strategies.

Disruption of murine mp29/Syf2/Ntc31 gene results in embryonic lethality with aberrant checkpoint response.

Directory of Open Access Journals (Sweden)

Chia-Hsin Chen

Full Text Available Human p29 is a putative component of spliceosomes, but its role in pre-mRNA is elusive. By siRNA knockdown and stable overexpression, we demonstrated that human p29 is involved in DNA damage response and Fanconi anemia pathway in cultured cells. In this study, we generated p29 knockout mice (mp29(GT/GT using the mp29 gene trap embryonic stem cells to study the role of mp29 in DNA damage response in vivo. Interruption of mp29 at both alleles resulted in embryonic lethality. Embryonic abnormality occurred as early as E6.5 in mp29(GT/GT mice accompanied with decreased mRNA levels of α-tubulin and Chk1. The reduction of α-tubulin and Chk1 mRNAs is likely due to an impaired post-transcriptional event. An aberrant G2/M checkpoint was found in mp29 gene trap embryos when exposed to aphidicolin and UV light. This embryonic lethality was rescued by crossing with mp29 transgenic mice. Additionally, the knockdown of zfp29 in zebrafish resulted in embryonic death at 72 hours of development postfertilization (hpf. A lower level of acetylated α-tubulin was also observed in zfp29 morphants. Together, these results illustrate an indispensable role of mp29 in DNA checkpoint response during embryonic development.

A multi-level capacitor-less memory cell fabricated on a nano-scale strained silicon-on-insulator

International Nuclear Information System (INIS)

Park, Jea-Gun; Kim, Seong-Je; Shin, Mi-Hee; Song, Seung-Hyun; Shim, Tae-Hun; Chung, Sung-Woong; Enomoto, Hirofumi

2011-01-01

A multi-level capacitor-less memory cell was fabricated with a fully depleted n-metal-oxide-semiconductor field-effect transistor on a nano-scale strained silicon channel on insulator (FD sSOI n-MOSFET). The 0.73% biaxial tensile strain in the silicon channel of the FD sSOI n-MOSFET enhanced the effective electron mobility to ∼ 1.7 times that with an unstrained silicon channel. This thereby enables both front- and back-gate cell operations, demonstrating eight-level volatile memory-cell operation with a 1 ms retention time and 12 μA memory margin. This is a step toward achieving a terabit volatile memory cell.

HIV-Infected Children Have Elevated Levels of PD-1+ Memory CD4 T Cells With Low Proliferative Capacity and High Inflammatory Cytokine Effector Functions.

Science.gov (United States)

Foldi, Julia; Kozhaya, Lina; McCarty, Bret; Mwamzuka, Mussa; Marshed, Fatma; Ilmet, Tiina; Kilberg, Max; Kravietz, Adam; Ahmed, Aabid; Borkowsky, William; Unutmaz, Derya; Khaitan, Alka

2017-09-15

During human immunodeficiency virus (HIV) disease, chronic immune activation leads to T-cell exhaustion. PD-1 identifies "exhausted" CD8 T cells with impaired HIV-specific effector functions, but its role on CD4 T cells and in HIV-infected children is poorly understood. In a Kenyan cohort of vertically HIV-infected children, we measured PD-1+ CD4 T-cell frequencies and phenotype by flow cytometry and their correlation with HIV disease progression and immune activation. Second, in vitro CD4 T-cell proliferative and cytokine responses to HIV-specific and -nonspecific stimuli were assessed with and without PD-1 blockade. HIV-infected children have increased frequencies of PD-1+ memory CD4 T cells that fail to normalize with antiretroviral treatment. These cells are comprised of central and effector memory subsets and correlate with HIV disease progression, measured by viral load, CD4 percentage, CD4:CD8 T-cell ratio, and immune activation. Last, PD-1+ CD4 T cells predict impaired proliferative potential yet preferentially secrete the Th1 and Th17 cytokines interferon-γ and interleukin 17A, and are unresponsive to in vitro PD-1 blockade. This study highlights differences in PD-1+ CD4 T-cell memory phenotype and response to blockade between HIV-infected children and adults, with implications for potential immune checkpoint therapies. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

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

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

Multi-floor cascading ferroelectric nanostructures: multiple data writing-based multi-level non-volatile memory devices

Science.gov (United States)

Hyun, Seung; Kwon, Owoong; Lee, Bom-Yi; Seol, Daehee; Park, Beomjin; Lee, Jae Yong; Lee, Ju Hyun; Kim, Yunseok; Kim, Jin Kon

2016-01-01

Multiple data writing-based multi-level non-volatile memory has gained strong attention for next-generation memory devices to quickly accommodate an extremely large number of data bits because it is capable of storing multiple data bits in a single memory cell at once. However, all previously reported devices have failed to store a large number of data bits due to the macroscale cell size and have not allowed fast access to the stored data due to slow single data writing. Here, we introduce a novel three-dimensional multi-floor cascading polymeric ferroelectric nanostructure, successfully operating as an individual cell. In one cell, each floor has its own piezoresponse and the piezoresponse of one floor can be modulated by the bias voltage applied to the other floor, which means simultaneously written data bits in both floors can be identified. This could achieve multi-level memory through a multiple data writing process.Multiple data writing-based multi-level non-volatile memory has gained strong attention for next-generation memory devices to quickly accommodate an extremely large number of data bits because it is capable of storing multiple data bits in a single memory cell at once. However, all previously reported devices have failed to store a large number of data bits due to the macroscale cell size and have not allowed fast access to the stored data due to slow single data writing. Here, we introduce a novel three-dimensional multi-floor cascading polymeric ferroelectric nanostructure, successfully operating as an individual cell. In one cell, each floor has its own piezoresponse and the piezoresponse of one floor can be modulated by the bias voltage applied to the other floor, which means simultaneously written data bits in both floors can be identified. This could achieve multi-level memory through a multiple data writing process. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr07377d

The impact of level of education on age-related deficits in associative memory: Behavioral and neuropsychological perspectives.

Science.gov (United States)

Peterson, Dwight J; Gargya, Sanchita; Kopeikin, Ksenia S; Naveh-Benjamin, Moshe

2017-06-01

Older adults have difficulty forming associations and binding distinct item components despite mostly preserved item memory potentially because they rely on more automatic, rather than strategic, processing when attempting to form, store, and retrieve associations from memory. An intriguing possibility is that older adults with greater access to strategic processes (e.g., those with a high level of education) may be less susceptible to age-related associative memory deficits. Two experiments assessed the degree to which a high level of education provides an effective dose of cognitive reserve (CR), potentially preserving associative memory. Standard younger and older adults' item and associative memory performance was compared to older adults who had attained a high level of education (mostly doctoral degrees). In both experiments (Experiment 1: person-action pairs; Experiment 2: unrelated word pairs), consistent evidence was found that older adults, regardless of the level of education, exhibited an age-related associative memory deficit relative to younger adults. Interestingly, neuropsychological assessment of both older adult groups revealed greater frontal lobe, but not enhanced medial temporal lobe, functioning in the highly educated. As such, although the highly educated older adults exhibited greater frontal lobe functioning than the standard older adults, this did not aid in the reduction of the age-related associative memory deficit. Copyright © 2017 Elsevier Ltd. All rights reserved.

Are subjective memory problems related to suggestibility, compliance, false memories, and objective memory performance?

Science.gov (United States)

Van Bergen, Saskia; Jelicic, Marko; Merckelbach, Harald

2009-01-01

The relationship between subjective memory beliefs and suggestibility, compliance, false memories, and objective memory performance was studied in a community sample of young and middle-aged people (N = 142). We hypothesized that people with subjective memory problems would exhibit higher suggestibility and compliance levels and would be more susceptible to false recollections than those who are optimistic about their memory. In addition, we expected a discrepancy between subjective memory judgments and objective memory performance. We found that subjective memory judgments correlated significantly with compliance, with more negative memory judgments accompanying higher levels of compliance. Contrary to our expectation, subjective memory problems did not correlate with suggestibility or false recollections. Furthermore, participants were accurate in estimating their objective memory performance.

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...

False memory and level of processing effect: an event-related potential study.

Science.gov (United States)

Beato, Maria Soledad; Boldini, Angela; Cadavid, Sara

2012-09-12

Event-related potentials (ERPs) were used to determine the effects of level of processing on true and false memory, using the Deese-Roediger-McDermott (DRM) paradigm. In the DRM paradigm, lists of words highly associated to a single nonpresented word (the 'critical lure') are studied and, in a subsequent memory test, critical lures are often falsely remembered. Lists with three critical lures per list were auditorily presented here to participants who studied them with either a shallow (saying whether the word contained the letter 'o') or a deep (creating a mental image of the word) processing task. Visual presentation modality was used on a final recognition test. True recognition of studied words was significantly higher after deep encoding, whereas false recognition of nonpresented critical lures was similar in both experimental groups. At the ERP level, true and false recognition showed similar patterns: no FN400 effect was found, whereas comparable left parietal and late right frontal old/new effects were found for true and false recognition in both experimental conditions. Items studied under shallow encoding conditions elicited more positive ERP than items studied under deep encoding conditions at a 1000-1500 ms interval. These ERP results suggest that true and false recognition share some common underlying processes. Differential effects of level of processing on true and false memory were found only at the behavioral level but not at the ERP level.

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.

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.

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.

Complex multicellular functions at a unicellular eukaryote level: Learning, memory, and immunity.

Science.gov (United States)

Csaba, György

2017-06-01

According to experimental data, eukaryote unicellulars are able to learn, have immunity and memory. Learning is carried out in a very primitive form, and the memory is not neural but an epigenetic one. However, this epigenetic memory, which is well justified by the presence and manifestation of hormonal imprinting, is strong and permanent in the life of cell and also in its progenies. This memory is epigenetically executed by the alteration and fixation of methylation pattern of genes without changes in base sequences. The immunity of unicellulars is based on self/non-self discrimination, which leads to the destruction of non-self invaders and utilization of them as nourishment (by phagocytosis). The tools of learning, memory, and immunity of unicellulars are uniformly found in plasma membrane receptors, which formed under the effect of dynamic receptor pattern generation, suggested by Koch et al., and this is the basis of hormonal imprinting, by which the encounter between a chemical substance and the cell is specifically memorized. The receptors and imprinting are also used in the later steps of evolution up to mammals (including man) in each mentioned functions. This means that learning, memory, and immunity can be deduced to a unicellular eukaryote level.

Selectivity in Postencoding Connectivity with High-Level Visual Cortex Is Associated with Reward-Motivated Memory

OpenAIRE

Murty, Vishnu P.; Tompary, Alexa; Adcock, R. Alison; Davachi, Lila

2017-01-01

Reward motivation has been demonstrated to enhance declarative memory by facilitating systems-level consolidation. Although high-reward information is often intermixed with lower reward information during an experience, memory for high value information is prioritized. How is this selectivity achieved? One possibility is that postencoding consolidation processes bias memory strengthening to those representations associated with higher reward. To test this hypothesis, we investigated the influ...

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...

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.

Monitoring of scrap loads at Gorzia border checkpoints: A thirty months experience and some suggestions

International Nuclear Information System (INIS)

Fabretto, M.

1999-01-01

The following topics are highlighted: personnel training, assistance from foreign scrap suppliers, and computerized database. It is suggested that when selecting personnel for this job, major attention should be paid to their attitudes; the personnel should be given very good training, teaching them also how to make controls manually; expert physicist' support should be available within a very short time; each monitoring checkpoint should have its local electronic database; periodical exchange and updating of information should be practised on the standardization of methods of detection, of levels of attention and alarm, of statistics among the people in charge of EU and non-EU countries. (P.A.)

Does Controlling for Temporal Parameters Change the Levels-of-Processing Effect in Working Memory?

OpenAIRE

Loaiza, Vanessa M.; Camos, Val?rie

2016-01-01

The distinguishability between working memory (WM) and long-term memory has been a frequent and long-lasting source of debate in the literature. One recent method of identifying the relationship between the two systems has been to consider the influence of long-term memory effects, such as the levels-of-processing (LoP) effect, in WM. However, the few studies that have examined the LoP effect in WM have shown divergent results. This study examined the LoP effect in WM by considering a theoret...

Effects of Attention and Levels of Processing on Explicit and Implicit Memory Function with Interesting and Uninteresting Tasks in University Students

Science.gov (United States)

Mahdavian, Alireza; Kormi-Nouri, Reza

This study aims to investigate the effect of attention and levels of processing on memory function and recalling words in two situations when students are interested in the subject and when they are not. This is an experimental study of 160 students conducted individually using a computer software. Results reveal focused attention, interest in the subject and deep processing caused the explicit memory to be at its highest level of functionality. On the contrary, shallow processing, divided attention and lack of interest in the subject plunged memory function into its lowest levels. Variables have different effects on attention, explicit and implicit memory. That is, interesting tasks with focused attention and deep processing have the highest effect on explicit memory in order. Also, interesting tasks, focused attention, respectively affect implicit memory. But level of processing does not affect implicit memory significantly.

Sympathetic arousal increases a negative memory bias in young women with low sex hormone levels

Science.gov (United States)

Nielsen, Shawn E.; Barber, Sarah J.; Chai, Audrey; Clewett, David V.; Mather, Mara

2015-01-01

Emotionally arousing events are typically better attended to and remembered than neutral ones. Current theories propose that arousal-induced increases in norepinephrine during encoding bias attention and memory in favor of affectively salient stimuli. Here, we tested this hypothesis by manipulating levels of physiological arousal prior to encoding and examining how it influenced memory for emotionally salient images, particularly those that are negative rather than positive in valence. We also tested whether sex steroid hormones interact with noradrenergic activity to influence these emotional memory biases in women. Healthy naturally cycling women and women on hormonal contraception completed one of the following physiological arousal manipulations prior to viewing a series of negative, positive and neutral images: 1) Immediate handgrip arousal – isometric handgrip immediately prior to encoding, 2) Residual handgrip arousal – isometric handgrip 15 min prior to encoding, or 3) No handgrip. Sympathetic arousal was measured throughout the session via pupil diameter changes. Levels of 17β-estradiol and progesterone were measured via salivary samples. Memory performance was assessed approximately 10 minutes after encoding using a surprise free recall test. The results indicated that handgrip successfully increased sympathetic arousal compared to the control task. Under immediate handgrip arousal, women showed enhanced memory for negative images over positive images; this pattern was not observed in women assigned to the residual and no-handgrip arousal conditions. Additionally, under immediate handgrip arousal, both high estradiol and progesterone levels attenuated the memory bias for negative over positive images. Follow-up hierarchical linear models revealed consistent effects when accounting for trial-by-trial variability in normative International Affective Picture System valence and arousal ratings. These findings suggest that heightened sympathetic arousal

Organization of the two-level memory in the image processing system on scanning measuring projectors

International Nuclear Information System (INIS)

Sychev, A.Yu.

1977-01-01

Discussed are the problems of improving the efficiency of the system for processing pictures taken in bubble chambers with the use of scanning measuring projectors. The system comprises 20 to 30 pro ectors linked with the ICL-1903A computer provided with a mainframe memory, 64 kilobytes in size. Because of the insufficient size of a mainframe memory, a part of the programs and data is located in a second-level memory, i.e. in an external memory. The analytical model described herein is used to analyze the effect of the memory organization on the characteristics of the system. It is shown that organization of pure procedures and introduction of the centralized control of the tWo-leVel memory result in substantial improvement of the efficiency of the picture processing system

Homogeneous-oxide stack in IGZO thin-film transistors for multi-level-cell NAND memory application

Science.gov (United States)

Ji, Hao; Wei, Yehui; Zhang, Xinlei; Jiang, Ran

2017-11-01

A nonvolatile charge-trap-flash memory that is based on amorphous indium-gallium-zinc-oxide thin film transistors was fabricated with a homogeneous-oxide structure for a multi-level-cell application. All oxide layers, i.e., tunneling layer, charge trapping layer, and blocking layer, were fabricated with Al2O3 films. The fabrication condition (including temperature and deposition method) of the charge trapping layer was different from those of the other oxide layers. This device demonstrated a considerable large memory window of 4 V between the states fully erased and programmed with the operation voltage less than 14 V. This kind of device shows a good prospect for multi-level-cell memory applications.

Neural Network with Local Memory for Nuclear Reactor Power Level Control

International Nuclear Information System (INIS)

Uluyol, Oender; Ragheb, Magdi; Tsoukalas, Lefteri

2001-01-01

A methodology is introduced for a neural network with local memory called a multilayered local output gamma feedback (LOGF) neural network within the paradigm of locally-recurrent globally-feedforward neural networks. It appears to be well-suited for the identification, prediction, and control tasks in highly dynamic systems; it allows for the presentation of different timescales through incorporation of a gamma memory. A learning algorithm based on the backpropagation-through-time approach is derived. The spatial and temporal weights of the network are iteratively optimized for a given problem using the derived learning algorithm. As a demonstration of the methodology, it is applied to the task of power level control of a nuclear reactor at different fuel cycle conditions. The results demonstrate that the LOGF neural network controller outperforms the classical as well as the state feedback-assisted classical controllers for reactor power level control by showing a better tracking of the demand power, improving the fuel and exit temperature responses, and by performing robustly in different fuel cycle and power level conditions

Glycemia and Levels of Cerebrospinal Fluid Amyloid and Tau in Patients Attending a Memory Clinic

NARCIS (Netherlands)

Exalto, L.G.; van der Flier, W.M.; Scheltens, P.; Biessels, G.J.

2010-01-01

OBJECTIVES: To determine the association between markers of glycemia and cerebrospinal fluid (CSF) amyloid β 1-42 (Aβ42) and tau levels in patients attending a memory clinic. DESIGN: Cross-sectional study. SETTING: Memory clinic. PARTICIPANTS: Two hundred forty-five consecutive patients attending a

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

between tumors even within the same molecular subtype. These data indicate that assessing the levels of immune checkpoint molecule expression in an individual patient has important implications for the success of therapeutically targeting them in BC.

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.

The Trouble with Levels: A Reexamination of Craik and Lockhart's Framework for Memory Research

Science.gov (United States)

Baddeley, Alan D.

1978-01-01

Begins by discussing a number of problems in applying a levels-of-processing approach to memory as proposed in the late 1960s and then revised in 1972 by Craik and Lockhart, suggests that some of the basic assumptions are false, and argues for information-processing models devised to study working memory and reading, which aim to explore the…

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...

High levels of glucose induce "metabolic memory" in cardiomyocyte via epigenetic histone H3 lysine 9 methylation.

Science.gov (United States)

Yu, Xi-Yong; Geng, Yong-Jian; Liang, Jia-Liang; Zhang, Saidan; Lei, He-Ping; Zhong, Shi-Long; Lin, Qiu-Xiong; Shan, Zhi-Xin; Lin, Shu-Guang; Li, Yangxin

2012-09-01

Diabetic patients continue to develop inflammation and cardiovascular complication even after achieving glycemic control, suggesting a "metabolic memory". Metabolic memory is a major challenge in the treatment of diabetic complication, and the mechanisms underlying metabolic memory are not clear. Recent studies suggest a link between chromatin histone methylation and metabolic memory. In this study, we tested whether histone 3 lysine-9 tri-methylation (H3K9me3), a key epigenetic chromatin marker, was involved in high glucose (HG)-induced inflammation and metabolic memory. Incubating cardiomyocyte cells in HG resulted in increased levels of inflammatory cytokine IL-6 mRNA when compared with myocytes incubated in normal culture media, whereas mannitol (osmotic control) has no effect. Chromatin immunoprecipitation (ChIP) assays showed that H3K9me3 levels were significantly decreased at the promoters of IL-6. Immunoblotting demonstrated that protein levels of the H3K9me3 methyltransferase, Suv39h1, were also reduced after HG treatment. HG-induced apoptosis, mitochondrial dysfunction and cytochrome-c release were reversible. However, the effects of HG on the expression of IL-6 and the levels of H3K9me3 were irreversible after the removal of HG from the culture. These results suggest that HG-induced sustained inflammatory phenotype and epigenetic histone modification, rather than HG-induced mitochondrial dysfunction and apoptosis, are main mechanisms responsible for metabolic memory. In conclusion, our data demonstrate that HG increases expression of inflammatory cytokine and decreases the levels of histone-3 methylation at the cytokine promoter, and suggest that modulating histone 3 methylation and inflammatory cytokine expression may be a useful strategy to prevent metabolic memory and cardiomyopathy in diabetic patients.

Levels of processing and the coding of position cues in motor short-term memory.

Science.gov (United States)

Ho, L; Shea, J B

1978-06-01

The present study investigated the appropriateness of the levels-of-processing framework of memory for explaining retention of information in motor short-term memory. Subjects were given labels descriptive of the positions to be remembered by the experimenter (EL), were given no labels (NL), or provided their own labels (SL). A control group (CONT) was required to count backwards during the presentation of the criterion positions. The inclusion of a 30-sec filled retention interval as well as 0-sec and 30-sec unfilled retention intervals tested a prediction by Craik and Lockhart (1972), when attention is diverted from an item, information will be lost at a rate appropriate to its level of processing - that is, slower rates for deeper levels. Groups EL and SL had greater accuracy at recall for all three retention intervals than groups CONT and NL. In addition, there was no significant increase in error between 30-sec unfilled and 30-sec filled intervals for groups EL and SL, while there was a significant increase in error for groups CONT and NL. The data were interpreted in terms of Craik and Lockhart's (1972) levels-of-processing approach to memory.

dNTP pool levels modulate mutator phenotypes of error-prone DNA polymerase ε variants.

Science.gov (United States)

Williams, Lindsey N; Marjavaara, Lisette; Knowels, Gary M; Schultz, Eric M; Fox, Edward J; Chabes, Andrei; Herr, Alan J

2015-05-12

Mutator phenotypes create genetic diversity that fuels tumor evolution. DNA polymerase (Pol) ε mediates leading strand DNA replication. Proofreading defects in this enzyme drive a number of human malignancies. Here, using budding yeast, we show that mutator variants of Pol ε depend on damage uninducible (Dun)1, an S-phase checkpoint kinase that maintains dNTP levels during a normal cell cycle and up-regulates dNTP synthesis upon checkpoint activation. Deletion of DUN1 (dun1Δ) suppresses the mutator phenotype of pol2-4 (encoding Pol ε proofreading deficiency) and is synthetically lethal with pol2-M644G (encoding altered Pol ε base selectivity). Although pol2-4 cells cycle normally, pol2-M644G cells progress slowly through S-phase. The pol2-M644G cells tolerate deletions of mediator of the replication checkpoint (MRC) 1 (mrc1Δ) and radiation sensitive (Rad) 9 (rad9Δ), which encode mediators of checkpoint responses to replication stress and DNA damage, respectively. The pol2-M644G mutator phenotype is partially suppressed by mrc1Δ but not rad9Δ; neither deletion suppresses the pol2-4 mutator phenotype. Thus, checkpoint activation augments the Dun1 effect on replication fidelity but is not required for it. Deletions of genes encoding key Dun1 targets that negatively regulate dNTP synthesis, suppress the dun1Δ pol2-M644G synthetic lethality and restore the mutator phenotype of pol2-4 in dun1Δ cells. DUN1 pol2-M644G cells have constitutively high dNTP levels, consistent with checkpoint activation. In contrast, pol2-4 and POL2 cells have similar dNTP levels, which decline in the absence of Dun1 and rise in the absence of the negative regulators of dNTP synthesis. Thus, dNTP pool levels correlate with Pol ε mutator severity, suggesting that treatments targeting dNTP pools could modulate mutator phenotypes for therapy.

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

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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.

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

Increased glucose levels are associated with episodic memory in nondiabetic women.

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Rolandsson, Olov; Backeström, Anna; Eriksson, Sture; Hallmans, Göran; Nilsson, Lars-Göran

2008-02-01

Patients with type 2 diabetes have an increased risk of a reduction in cognitive function. We investigated the hypothesis that plasma glucose is associated with a reduction in episodic and/or semantic memory already in nondiabetic subjects. We linked two large population-based datasets in Sweden: the Betula study, in which a random sample from the population aged 35-85 years was investigated for cognitive function, including episodic and semantic memory; and the Västerbotten Intervention Program, a health survey with subjects aged 40, 50, and 60 years, that includes measuring of fasting and 2-h plasma glucose, along with other risk factors for diabetes and cardiovascular disease. We identified 411 (179 men and 232 women, mean age 50.6 +/- 8.0 years) nondiabetic subjects, free from dementia, who had participated in the two surveys within 6 months. Women had better episodic (score 7.37 +/- 1.42) and semantic memory (score 16.05 +/- 2.76) than men (score 6.59 +/- 1.29 and 15.15 +/- 2.92, respectively, P glucose (fPG) and 2-h plasma glucose (2hPG) were significantly negatively associated with episodic memory (fPG: B -0.198, SE 0.068, beta -0.209, P = 0.004; and 2hPG: B -0.061, SE 0.031, beta -0.148, P = 0.048, respectively) in women but not in men. The association was not found in relation to semantic memory. We conclude that an increase in plasma glucose is associated with impairment in episodic memory in women. This could be explained by a negative effect on the hippocampus caused by raised plasma glucose levels.

Long-memory and the sea level-temperature relationship: a fractional cointegration approach.

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Ventosa-Santaulària, Daniel; Heres, David R; Martínez-Hernández, L Catalina

2014-01-01

Through thermal expansion of oceans and melting of land-based ice, global warming is very likely contributing to the sea level rise observed during the 20th century. The amount by which further increases in global average temperature could affect sea level is only known with large uncertainties due to the limited capacity of physics-based models to predict sea levels from global surface temperatures. Semi-empirical approaches have been implemented to estimate the statistical relationship between these two variables providing an alternative measure on which to base potentially disrupting impacts on coastal communities and ecosystems. However, only a few of these semi-empirical applications had addressed the spurious inference that is likely to be drawn when one nonstationary process is regressed on another. Furthermore, it has been shown that spurious effects are not eliminated by stationary processes when these possess strong long memory. Our results indicate that both global temperature and sea level indeed present the characteristics of long memory processes. Nevertheless, we find that these variables are fractionally cointegrated when sea-ice extent is incorporated as an instrumental variable for temperature which in our estimations has a statistically significant positive impact on global sea level.

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...

Optimized ONO thickness for multi-level and 2-bit/cell operation for wrapped-select-gate (WSG) SONOS memory

International Nuclear Information System (INIS)

Wu, Woei-Cherng; Chao, Tien-Sheng; Yang, Tsung-Yu; Peng, Wu-Chin; Yang, Wen-Luh; Chen, Jian-Hao; Ma, Ming Wen; Lai, Chao-Sung; Lee, Chien-Hsing; Hsieh, Tsung-Min; Liou, Jhyy Cheng; Chen, Tzu Ping; Chen, Chien Hung; Lin, Chih Hung; Chen, Hwi Huang; Ko, Joe

2008-01-01

In this paper, highly reliable wrapped-select-gate (WSG) silicon–oxide–nitride–oxide–silicon (SONOS) memory cells with multi-level and 2-bit/cell operation have been successfully demonstrated. The source-side injection mechanism for WSG-SONOS memory with different ONO thickness was thoroughly investigated. The different programming efficiencies of the WSG-SONOS memory under different ONO thicknesses are explained by the lateral electrical field extracted from the simulation results. Furthermore, multi-level storage is easily obtained, and good V TH distribution presented, for the WSG-SONOS memory with optimized ONO thickness. High program/erase speed (10 µs/5 ms) and low programming current (3.5 µA) are used to achieve the multi-level operation with tolerable gate and drain disturbance, negligible second-bit effect, excellent data retention and good endurance performance

Inconsistent-handed advantage in episodic memory extends to paragraph-level materials.

Science.gov (United States)

Prichard, Eric C; Christman, Stephen D

2017-09-01

Past research using handedness as a proxy for functional access to the right hemisphere demonstrates that individuals who are mixed/inconsistently handed outperform strong/consistently handed individuals when performing episodic recall tasks. However, research has generally been restricted to stimuli presented in a list format. In the present paper, we present two studies in which participants were presented with paragraph-level material and then asked to recall material from the passages. The first study was based on a classic study looking at retroactive interference with prose materials. The second was modelled on a classic experiment looking at perspective taking and the content of memory. In both studies, the classic effects were replicated and the general finding that mixed/inconsistent-handers outperform strong/consistent-handers was replicated. This suggests that considering degree of handedness may be an empirically useful means of reducing error variance in paradigms looking at memory for prose level material.

Estradiol replacement enhances fear memory formation, impairs extinction and reduces COMT expression levels in the hippocampus of ovariectomized female mice.

Science.gov (United States)

McDermott, Carmel M; Liu, Dan; Ade, Catherine; Schrader, Laura A

2015-02-01

Females experience depression, posttraumatic stress disorder (PTSD), and anxiety disorders at approximately twice the rate of males, but the mechanisms underlying this difference remain undefined. The effect of sex hormones on neural substrates presents a possible mechanism. We investigated the effect of ovariectomy at two ages, before puberty and in adulthood, and 17β-estradiol (E2) replacement administered chronically in drinking water on anxiety level, fear memory formation, and extinction. Based on previous studies, we hypothesized that estradiol replacement would impair fear memory formation and enhance extinction rate. Females, age 4 weeks and 10 weeks, were divided randomly into 4 groups; sham surgery, OVX, OVX+low E2 (200nM), and OVX+high E2 (1000nM). Chronic treatment with high levels of E2 significantly increased anxiety levels measured in the elevated plus maze. In both age groups, high levels of E2 significantly increased contextual fear memory but had no effect on cued fear memory. In addition, high E2 decreased the rate of extinction in both ages. Finally, catechol-O-methyltransferase (COMT) is important for regulation of catecholamine levels, which play a role in fear memory formation and extinction. COMT expression in the hippocampus was significantly reduced by high E2 replacement, implying increased catecholamine levels in the hippocampus of high E2 mice. These results suggest that estradiol enhanced fear memory formation, and inhibited fear memory extinction, possibly stabilizing the fear memory in female mice. This study has implications for a neurobiological mechanism for PTSD and anxiety disorders. Copyright © 2014 Elsevier Inc. All rights reserved.

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

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.

Specifying the Mechanisms in a Levels-of-Processing Approach to Memory

Science.gov (United States)

Klein, Kitty; Saltz, Eli

1976-01-01

Craik and Lockhart's (1972) levels-of-processing theory has spurred new interest in semantic processing as a factor in memory, particularly with regard to free recall following incidental learning. However, their formulation lacks a clear description of the operations and structures involved in semantic processing. This research outlines a…

Fission yeast strains with circular chromosomes require the 9-1-1 checkpoint complex for the viability in response to the anti-cancer drug 5-fluorodeoxyuridine.

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Hossain Mohammad Shamim

Full Text Available Thymidine kinase converts 5-fluorodeoxyuridine to 5-fluorodeoxyuridine monophosphate, which causes disruption of deoxynucleotide triphosphate ratios. The fission yeast Schizosaccharomyces pombe does not express endogenous thymidine kinase but 5-fluorodeoxyuridine inhibits growth when exogenous thymidine kinase is expressed. Unexpectedly, we found that 5-fluorodeoxyuridine causes S phase arrest even without thymidine kinase expression. DNA damage checkpoint proteins such as the 9-1-1 complex were required for viability in the presence of 5-fluorodeoxyuridine. We also found that strains with circular chromosomes, due to loss of pot1+, which have higher levels of replication stress, were more sensitive to loss of the 9-1-1 complex in the presence of 5-fluorodeoxyuridine. Thus, our results suggest that strains carrying circular chromosomes exhibit a greater dependence on DNA damage checkpoints to ensure viability in the presence of 5-fluorodeoxyuridine compared to stains that have linear chromosomes.

Fission yeast strains with circular chromosomes require the 9-1-1 checkpoint complex for the viability in response to the anti-cancer drug 5-fluorodeoxyuridine.

Science.gov (United States)

Shamim, Hossain Mohammad; Minami, Yukako; Tanaka, Daiki; Ukimori, Shinobu; Murray, Johanne M; Ueno, Masaru

2017-01-01

Thymidine kinase converts 5-fluorodeoxyuridine to 5-fluorodeoxyuridine monophosphate, which causes disruption of deoxynucleotide triphosphate ratios. The fission yeast Schizosaccharomyces pombe does not express endogenous thymidine kinase but 5-fluorodeoxyuridine inhibits growth when exogenous thymidine kinase is expressed. Unexpectedly, we found that 5-fluorodeoxyuridine causes S phase arrest even without thymidine kinase expression. DNA damage checkpoint proteins such as the 9-1-1 complex were required for viability in the presence of 5-fluorodeoxyuridine. We also found that strains with circular chromosomes, due to loss of pot1+, which have higher levels of replication stress, were more sensitive to loss of the 9-1-1 complex in the presence of 5-fluorodeoxyuridine. Thus, our results suggest that strains carrying circular chromosomes exhibit a greater dependence on DNA damage checkpoints to ensure viability in the presence of 5-fluorodeoxyuridine compared to stains that have linear chromosomes.

Overgeneral autobiographical memory predicts higher prospective levels of depressive symptoms and intrusions in borderline patients.

Science.gov (United States)

Van den Broeck, Kris; Pieters, Guido; Claes, Laurence; Berens, Ann; Raes, Filip

2016-11-01

Overgeneral memory (OGM), the tendency to retrieve categories of events from autobiographical memory instead of single events, is found to be a reliable predictor for future mood disturbances and post-traumatic symptom severity. Patients with borderline personality disorder (BPD) often report co-morbid episodes of major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). Therefore, we investigated whether OGM would predict depression severity and (post-traumatic) stress symptoms in BPD patients. At admission (N = 54) and at six-month follow-up (N ≥ 31), BPD patients completed the Structured Clinical Interview for DSM-IV Disorders, the Assessment of DSM-IV Personality Disorders, the Autobiographical Memory Test, the Beck Depression Inventory-2nd edition (BDI-II), and the Impact of Event Scale. OGM at baseline predicted (a) higher levels of depressive symptoms at follow-up and (b) more intrusions related to a stressful event over and above baseline levels of borderline symptoms, depressive symptoms, and intrusions, respectively. No association was found between memory specificity and event-related avoidance at follow-up. Despite previous findings suggesting that OGM in BPD is less robust than in MDD and PTSD, our results suggest that memory specificity in BPD patients may have some relevance for the course of depressive and stress symptomatology in BPD.

Identifying long-term memory B-cells in vaccinated children despite waning antibody levels specific for Bordetella pertussis proteins.

Science.gov (United States)

Hendrikx, Lotte H; Oztürk, Kemal; de Rond, Lia G H; Veenhoven, Reinier H; Sanders, Elisabeth A M; Berbers, Guy A M; Buisman, Anne-Marie

2011-02-04

Whooping cough is a respiratory disease caused by Bordetella pertussis. Since the 1950s in developed countries pertussis vaccinations are included in the national immunization program. However, antibody levels rapidly wane after both whole cell and acellular pertussis vaccination. Therefore protection against pertussis may depend largely on long-term B- and T-cell immunities. We investigated long-term pertussis-specific memory B-cell responses in children who were primed at infant age with the Dutch wP-vaccine (ISRCTN65428640). Purified B-cells were characterized by FACS-analysis and after polyclonal stimulation memory B-cells were detected by ELISPOT-assays specific for pertussis toxin, filamentous haemagglutinin, pertactin and tetanus. In addition, plasma IgG levels directed to the same antigens were measured by a fluorescent bead-based multiplex immunoassay. Two and 3 years after wP priming as well as 2 and 5 years after the aP booster at the age of 4, low plasma IgG levels to the pertussis proteins were found. At the same time, however pertussis protein-specific memory B-cells could be detected and their number increased with age. The number of tetanus-specific memory B-cells was similar in all age groups, whereas IgG-tetanus levels were high 2 years after tetanus booster compared to pre- and 5 years post-booster levels. This study shows the presence of long-term pertussis protein-specific memory B-cells in children despite waning antibody levels after vaccination, which suggests that memory B-cells in addition to antibodies may contribute to protection against pertussis. Copyright © 2010 Elsevier Ltd. All rights reserved.

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...

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

Working Memory Modulates Glutamate Levels in the Dorsolateral Prefrontal Cortex during 1H fMRS

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Eric A. Woodcock

2018-03-01

Full Text Available Glutamate is involved in excitatory neurotransmission and metabolic processes related to brain function. Previous studies using proton functional magnetic resonance spectroscopy (1H fMRS have demonstrated elevated cortical glutamate levels by 2–4% during visual and motor stimulation, relative to periods of no stimulation. Here, we extended this approach to working memory cognitive task performance, which has been consistently associated with dorsolateral prefrontal cortex (dlPFC activation. Sixteen healthy adult volunteers completed a continuous visual fixation “rest” task followed by a letter 2-back working memory task during 1H fMRS acquisition of the left dlPFC, which encompassed Brodmann areas 45 and 46 over a 4.5-cm3 volume. Using a 100% automated fitting procedure integrated with LCModel, raw spectra were eddy current-, phase-, and shift-corrected prior to quantification resulting in a 32s temporal resolution or 8 averages per spectra. Task compliance was high (95 ± 11% correct and the mean Cramer-Rao Lower Bound of glutamate was 6.9 ± 0.9%. Relative to continuous passive visual fixation, left dlPFC glutamate levels were significantly higher by 2.7% (0.32 mmol/kg wet weight during letter 2-back performance. Elevated dlPFC glutamate levels reflect increased metabolic activity and excitatory neurotransmission driven by working memory-related cognitive demands. These results provide the first in vivo demonstration of elevated dlPFC glutamate levels during working memory.

A Survey of Rollback-Recovery Protocols in Message-Passing Systems

Science.gov (United States)

1999-06-01

and M.A. Castillo. "Checkpointing through garbage collection." Technical report. Departamento de Ciencia de la Computation, Escuela de Ingenieria ...between consecutive checkpoints. It can be implemented by using the dirty-bit of the memory protection hardware or by emulating a dirty-bit in software [4...compare the program’s state with the previous checkpoint in software , and writing the difference in a new checkpoint [46]. The required storage and

Immune checkpoint inhibitors and targeted therapies for metastatic melanoma: A network meta-analysis.

Science.gov (United States)

Pasquali, Sandro; Chiarion-Sileni, Vanna; Rossi, Carlo Riccardo; Mocellin, Simone

2017-03-01

Immune checkpoint inhibitors and targeted therapies, two new class of drugs for treatment of metastatic melanoma, have not been compared in randomized controlled trials (RCT). We quantitatively summarized the evidence and compared immune and targeted therapies in terms of both efficacy and toxicity. A comprehensive search for RCTs of immune checkpoint inhibitors and targeted therapies was conducted to August 2016. Using a network meta-analysis approach, treatments were compared with each other and ranked based on their effectiveness (as measured by the impact on progression-free survival [PFS]) and acceptability (the inverse of high grade toxicity). Twelve RCTs enrolling 6207 patients were included. Network meta-analysis generated 15 comparisons. Combined BRAF and MEK inhibitors were associated with longer PFS as compared to anti-CTLA4 (HR: 0.22; 95% confidence interval [CI]: 0.12-0.41) and anti-PD1 antibodies alone (HR: 0.38; CI: 0.20-0.72). However, anti-PD1 monoclonal antibodies were less toxic than anti-CTLA4 monoclonal antibodies (RR: 0.65; CI: 0.40-0.78) and their combination significantly increased toxicity compared to either single agent anti-CTLA4 (RR: 2.06; CI: 1.45-2.93) or anti-PD1 monoclonal antibodies (RR: 3.67; CI: 2.27-5.96). Consistently, ranking analysis suggested that the combination of targeted therapies is the most effective strategy, whereas single agent anti-PD1 antibodies have the best acceptability. The GRADE level of evidence quality for these findings was moderate to low. The simultaneous inhibition of BRAF and MEK appears the most effective treatment for melanomas harboring BRAF V600 mutation, although anti-PD1 antibodies appear to be less toxic. Further research is needed to increase the quality of evidence. Copyright © 2017 Elsevier Ltd. All rights reserved.

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.)

Running wheel training does not change neurogenesis levels or alter working memory tasks in adult rats

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Cesar A. Acevedo-Triana

2017-05-01

Full Text Available Background Exercise can change cellular structure and connectivity (neurogenesis or synaptogenesis, causing alterations in both behavior and working memory. The aim of this study was to evaluate the effect of exercise on working memory and hippocampal neurogenesis in adult male Wistar rats using a T-maze test. Methods An experimental design with two groups was developed: the experimental group (n = 12 was subject to a forced exercise program for five days, whereas the control group (n = 9 stayed in the home cage. Six to eight weeks after training, the rats’ working memory was evaluated in a T-maze test and four choice days were analyzed, taking into account alternation as a working memory indicator. Hippocampal neurogenesis was evaluated by means of immunohistochemistry of BrdU positive cells. Results No differences between groups were found in the behavioral variables (alternation, preference index, time of response, time of trial or feeding, or in the levels of BrdU positive cells. Discussion Results suggest that although exercise may have effects on brain structure, a construct such as working memory may require more complex changes in networks or connections to demonstrate a change at behavioral level.

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...

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

Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade

Science.gov (United States)

McGranahan, Nicholas; Furness, Andrew J. S.; Rosenthal, Rachel; Ramskov, Sofie; Lyngaa, Rikke; Saini, Sunil Kumar; Jamal-Hanjani, Mariam; Wilson, Gareth A.; Birkbak, Nicolai J.; Hiley, Crispin T.; Watkins, Thomas B. K.; Shafi, Seema; Murugaesu, Nirupa; Mitter, Richard; Akarca, Ayse U.; Linares, Joseph; Marafioti, Teresa; Henry, Jake Y.; Van Allen, Eliezer M.; Miao, Diana; Schilling, Bastian; Schadendorf, Dirk; Garraway, Levi A.; Makarov, Vladimir; Rizvi, Naiyer A.; Snyder, Alexandra; Hellmann, Matthew D.; Merghoub, Taha; Wolchok, Jedd D.; Shukla, Sachet A.; Wu, Catherine J.; Peggs, Karl S.; Chan, Timothy A.; Hadrup, Sine R.; Quezada, Sergio A.; Swanton, Charles

2016-01-01

As tumors grow, they acquire mutations, some of which create neoantigens that influence the response of patients to immune checkpoint inhibitors. We explored the impact of neoantigen intratumor heterogeneity (ITH) on antitumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas. CD8+ tumor-infiltrating lymphocytes reactive to clonal neoantigens were identified in early-stage non–small cell lung cancer and expressed high levels of PD-1. Sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. T cells recognizing clonal neoantigens were detectable in patients with durable clinical benefit. Cytotoxic chemotherapy–induced subclonal neoantigens, contributing to an increased mutational load, were enriched in certain poor responders. These data suggest that neoantigen heterogeneity may influence immune surveillance and support therapeutic developments targeting clonal neoantigens. PMID:26940869

Delayed Dopamine Signaling of Energy Level Builds Appetitive Long-Term Memory in Drosophila

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Pierre-Yves Musso

2015-02-01

Full Text Available Sensory cues relevant to a food source, such as odors, can be associated with post-ingestion signals related either to food energetic value or toxicity. Despite numerous behavioral studies, a global understanding of the mechanisms underlying these long delay associations remains out of reach. Here, we demonstrate in Drosophila that the long-term association between an odor and a nutritious sugar depends on delayed post-ingestion signaling of energy level. We show at the neural circuit level that the activity of two pairs of dopaminergic neurons is necessary and sufficient to signal energy level to the olfactory memory center. Accordingly, we have identified in these dopaminergic neurons a delayed calcium trace that correlates with appetitive long-term memory formation. Altogether, these findings demonstrate that the Drosophila brain remembers food quality through a two-step mechanism that consists of the integration of olfactory and gustatory sensory information and then post-ingestion energetic value.

Delayed dopamine signaling of energy level builds appetitive long-term memory in Drosophila.

Science.gov (United States)

Musso, Pierre-Yves; Tchenio, Paul; Preat, Thomas

2015-02-24

Sensory cues relevant to a food source, such as odors, can be associated with post-ingestion signals related either to food energetic value or toxicity. Despite numerous behavioral studies, a global understanding of the mechanisms underlying these long delay associations remains out of reach. Here, we demonstrate in Drosophila that the long-term association between an odor and a nutritious sugar depends on delayed post-ingestion signaling of energy level. We show at the neural circuit level that the activity of two pairs of dopaminergic neurons is necessary and sufficient to signal energy level to the olfactory memory center. Accordingly, we have identified in these dopaminergic neurons a delayed calcium trace that correlates with appetitive long-term memory formation. Altogether, these findings demonstrate that the Drosophila brain remembers food quality through a two-step mechanism that consists of the integration of olfactory and gustatory sensory information and then post-ingestion energetic value. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Cognitive load privileges memory-based over data-driven processing, not group-level over person-level processing.

Science.gov (United States)

Skorich, Daniel P; Mavor, Kenneth I

2013-09-01

In the current paper, we argue that categorization and individuation, as traditionally discussed and as experimentally operationalized, are defined in terms of two confounded underlying dimensions: a person/group dimension and a memory-based/data-driven dimension. In a series of three experiments, we unconfound these dimensions and impose a cognitive load. Across the three experiments, two with laboratory-created targets and one with participants' friends as the target, we demonstrate that cognitive load privileges memory-based over data-driven processing, not group- over person-level processing. We discuss the results in terms of their implications for conceptualizations of the categorization/individuation distinction, for the equivalence of person and group processes, for the ultimate 'purpose' and meaningfulness of group-based perception and, fundamentally, for the process of categorization, broadly defined. © 2012 The British Psychological Society.

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...

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.

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

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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.

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

Addiction memory as a specific, individually learned memory imprint.

Science.gov (United States)

Böning, J

2009-05-01

The construct of "addiction memory" (AM) and its importance for relapse occurrence has been the subject of discussion for the past 30 years. Neurobiological findings from "social neuroscience" and biopsychological learning theory, in conjunction with construct-valid behavioral pharmacological animal models, can now also provide general confirmation of addiction memory as a pathomorphological correlate of addiction disorders. Under multifactorial influences, experience-driven neuronal learning and memory processes of emotional and cognitive processing patterns in the specific individual "set" and "setting" play an especially pivotal role in this connection. From a neuropsychological perspective, the episodic (biographical) memory, located at the highest hierarchical level, is of central importance for the formation of the AM in certain structural and functional areas of the brain and neuronal networks. Within this context, neuronal learning and conditioning processes take place more or less unconsciously and automatically in the preceding long-term-memory systems (in particular priming and perceptual memory). They then regulate the individually programmed addiction behavior implicitly and thus subsequently stand for facilitated recollection of corresponding, previously stored cues or context situations. This explains why it is so difficult to treat an addiction memory, which is embedded above all in the episodic memory, from the molecular carrier level via the neuronal pattern level through to the psychological meaning level, and has thus meanwhile become a component of personality.

Upregulated ATM gene expression and activated DNA crosslink-induced damage response checkpoint in Fanconi anemia: implications for carcinogenesis.

Science.gov (United States)

Yamamoto, Kazuhiko; Nihrane, Abdallah; Aglipay, Jason; Sironi, Juan; Arkin, Steven; Lipton, Jeffrey M; Ouchi, Toru; Liu, Johnson M

2008-01-01

Fanconi anemia (FA) predisposes to hematopoietic failure, birth defects, leukemia, and squamous cell carcinoma of the head and neck (HNSCC) and cervix. The FA/BRCA pathway includes 8 members of a core complex and 5 downstream gene products closely linked with BRCA1 or BRCA2. Precancerous lesions are believed to trigger the DNA damage response (DDR), and we focused on the DDR in FA and its putative role as a checkpoint barrier to cancer. In primary fibroblasts with mutations in the core complex FANCA protein, we discovered that basal expression and phosphorylation of ATM (ataxia telangiectasia mutated) and p53 induced by irradiation (IR) or mitomycin C (MMC) were upregulated. This heightened response appeared to be due to increased basal levels of ATM in cultured FANCA-mutant cells, highlighting the new observation that ATM can be regulated at the transcriptional level in addition to its well-established activation by autophosphorylation. Functional analysis of this response using gamma-H2AX foci as markers of DNA double-stranded breaks (DSBs) demonstrated abnormal persistence of only MMC- and not IR-induced foci. Thus, we describe a processing defect that leads to general DDR upregulation but specific persistence of DNA crosslinker-induced damage response foci. Underscoring the significance of these findings, we found resistance to DNA crosslinker-induced cell cycle arrest and apoptosis in a TP53-mutant, patient-derived HNSCC cell line, whereas a lymphoblastoid cell line derived from this same individual was not mutated at TP53 and retained DNA crosslinker sensitivity. Our results suggest that cancer in FA may arise from selection for cells that escape from a chronically activated DDR checkpoint.

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.

Characterization of a putative spindle assembly checkpoint kinase Mps1, suggests its involvement in cell division, morphogenesis and oxidative stress tolerance in Candida albicans.

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Mohan Kamthan

Full Text Available In Saccharomyces cerevisiae MPS1 is one of the major protein kinase that governs the spindle checkpoint pathway. The S. cerevisiae structural homolog of opportunistic pathogen Candida albicans CaMPS1, is indispensable for the cell viability. The essentiality of Mps1 was confirmed by Homozygote Trisome test. To determine its biological function in this pathogen conditional mutant was generated through regulatable MET3 promoter. Examination of heterozygous and conditional (+Met/Cys mps1 mutants revealed a mitosis specific arrest phenotype, where mutants showed large buds with undivided nuclei. Flowcytometry analysis revealed abnormal ploidy levels in mps1 mutant. In presence of anti-microtubule drug Nocodazole, mps1 mutant showed a dramatic loss of viability suggesting a role of Mps1 in Spindle Assembly Checkpoint (SAC activation. These mutants were also defective in microtubule organization. Moreover, heterozygous mutant showed defective in-vitro yeast to hyphae morphological transition. Growth defect in heterozygous mutant suggest haploinsufficiency of this gene. qRT PCR analysis showed around 3 fold upregulation of MPS1 in presence of serum. This expression of MPS1 is dependent on Efg1 and is independent of other hyphal regulators like Ras1 and Tpk2. Furthermore, mps1 mutants were also sensitive to oxidative stress. Heterozygous mps1 mutant did not undergo morphological transition and showed 5-Fold reduction in colony forming units in response to macrophage. Thus, the vital checkpoint kinase, Mps1 besides cell division also has a role in morphogenesis and oxidative stress tolerance, in this pathogenic fungus.

Mik1 levels accumulate in S phase and may mediate an intrinsic link between S phase and mitosis

DEFF Research Database (Denmark)

Christensen, P U; Bentley, N J; Martinho, R G

2000-01-01

is independent of the Rad3- and Cds1-dependent checkpoint controls. In response to perturbed S phase, Rad3-Cds1 checkpoint controls are required to maintain high levels of Mik1, probably indirectly by extending the S phase period, where Mik1 is stable. In addition, we find that Mik1 protein can be moderately...

Impurity levels and fatigue lives of pseudoelastic NiTi shape memory alloys

International Nuclear Information System (INIS)

Rahim, M.; Frenzel, J.; Frotscher, M.; Pfetzing-Micklich, J.; Steegmüller, R.; Wohlschlögel, M.; Mughrabi, H.; Eggeler, G.

2013-01-01

In the present work we show how different oxygen (O) and carbon (C) levels affect fatigue lives of pseudoelastic NiTi shape memory alloys. We compare three alloys, one with an ultrahigh purity and two which contain the maximum accepted levels of C and O. We use bending rotation fatigue (up to cycle numbers >10 8 ) and scanning electron microscopy (for investigating microstructural details of crack initiation and growth) to study fatigue behavior. High cycle fatigue (HCF) life is governed by the number of cycles required for crack initiation. In the low cycle fatigue (LCF) regime, the high-purity alloy outperforms the materials with higher number densities of carbides and oxides. In the HCF regime, on the other hand, the high-purity and C-containing alloys show higher fatigue lives than the alloy with oxide particles. There is high experimental scatter in the HCF regime where fatigue cracks preferentially nucleate at particle/void assemblies (PVAs) which form during processing. Cyclic crack growth follows the Paris law and does not depend on impurity levels. The results presented in the present work contribute to a better understanding of structural fatigue of pseudoelastic NiTi shape memory alloys

Alterations of the spindle checkpoint pathway in clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas.

Science.gov (United States)

Arai, Eri; Gotoh, Masahiro; Tian, Ying; Sakamoto, Hiromi; Ono, Masaya; Matsuda, Akio; Takahashi, Yoriko; Miyata, Sayaka; Totsuka, Hirohiko; Chiku, Suenori; Komiyama, Motokiyo; Fujimoto, Hiroyuki; Matsumoto, Kenji; Yamada, Tesshi; Yoshida, Teruhiko; Kanai, Yae

2015-12-01

CpG-island methylator phenotype (CIMP)-positive clear cell renal cell carcinomas (RCCs) are characterized by accumulation of DNA hypermethylation of CpG islands, clinicopathological aggressiveness and poor patient outcome. The aim of this study was to clarify the molecular pathways participating in CIMP-positive renal carcinogenesis. Genome (whole-exome and copy number), transcriptome and proteome (two-dimensional image converted analysis of liquid chromatography-mass spectrometry) analyses were performed using tissue specimens of 87 CIMP-negative and 14 CIMP-positive clear cell RCCs and corresponding specimens of non-cancerous renal cortex. Genes encoding microtubule-associated proteins, such as DNAH2, DNAH5, DNAH10, RP1 and HAUS8, showed a 10% or higher incidence of genetic aberrations (non-synonymous single-nucleotide mutations and insertions/deletions) in CIMP-positive RCCs, whereas CIMP-negative RCCs lacked distinct genetic characteristics. MetaCore pathway analysis of CIMP-positive RCCs revealed that alterations of mRNA or protein expression were significantly accumulated in six pathways, all participating in the spindle checkpoint, including the "The metaphase checkpoint (p = 1.427 × 10(-6))," "Role of Anaphase Promoting Complex in cell cycle regulation (p = 7.444 × 10(-6))" and "Spindle assembly and chromosome separation (p = 9.260 × 10(-6))" pathways. Quantitative RT-PCR analysis revealed that mRNA expression levels for genes included in such pathways, i.e., AURKA, AURKB, BIRC5, BUB1, CDC20, NEK2 and SPC25, were significantly higher in CIMP-positive than in CIMP-negative RCCs. All CIMP-positive RCCs showed overexpression of Aurora kinases, AURKA and AURKB, and this overexpression was mainly attributable to increased copy number. These data suggest that abnormalities of the spindle checkpoint pathway participate in CIMP-positive renal carcinogenesis, and that AURKA and AURKB may be potential therapeutic targets in more aggressive CIMP-positive RCCs. �

Iron Loading Selectively Increases Hippocampal Levels of Ubiquitinated Proteins and Impairs Hippocampus-Dependent Memory.

Science.gov (United States)

Figueiredo, Luciana Silva; de Freitas, Betânia Souza; Garcia, Vanessa Athaíde; Dargél, Vinícius Ayub; Köbe, Luiza Machado; Kist, Luiza Wilges; Bogo, Maurício Reis; Schröder, Nadja

2016-11-01

Alterations of brain iron levels have been observed in a number of neurodegenerative disorders. We have previously demonstrated that iron overload in the neonatal period results in severe and persistent memory deficits in the adulthood. Protein degradation mediated by the ubiquitin-proteasome system (UPS) plays a central regulatory role in several cellular processes. Impairment of the UPS has been implicated in the pathogenesis of neurodegenerative disorders. Here, we examined the effects of iron exposure in the neonatal period (12th-14th day of postnatal life) on the expression of proteasome β-1, β-2, and β-5 subunits, and ubiquitinated proteins in brains of 15-day-old rats, to evaluate the immediate effect of the treatment, and in adulthood to assess long-lasting effects. Two different memory types, emotionally motivated conditioning and object recognition were assessed in adult animals. We found that iron administered in the neonatal period impairs both emotionally motivated and recognition memory. Polyubiquitinated protein levels were increased in the hippocampus, but not in the cortex, of adult animals treated with iron. Gene expression of subunits β1 and β5 was affected by age, being higher in the early stages of development in the hippocampus, accompanied by an age-related increase in polyubiquitinated protein levels in adults. In the cortex, gene expression of the three proteasome subunits was significantly higher in adulthood than in the neonatal period. These findings suggest that expression of proteasome subunits and activity are age-dependently regulated. Iron exposure in the neonatal period produces long-lasting harmful effects on the UPS functioning, which may be related with iron-induced memory impairment.

The sensory components of high-capacity iconic memory and visual working memory

OpenAIRE

Claire eBradley; Claire eBradley; Joel ePearson

2012-01-01

Early visual memory can be split into two primary components: a high-capacity, short-lived iconic memory followed by a limited-capacity visual working memory that can last many seconds. Whereas a large number of studies have investigated visual working memory for low-level sensory features, much research on iconic memory has used more high-level alphanumeric stimuli such as letters or numbers. These two forms of memory are typically examined separately, despite an intrinsic overlap in their c...

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.

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

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

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

Attenuation of G2 cell cycle checkpoint control in human tumor cells is associated with increased frequencies of unrejoined chromosome breaks but not increased cytotoxicity following radiation exposure

International Nuclear Information System (INIS)

Schwartz, J.L.; Cowan, J.; Grdina, D.J.

1997-01-01

The contribution of G 2 cell cycle checkpoint control to ionizing radiation responses was examined in ten human tumor cell lines. Most of the delay in cell cycle progression seen in the first cell cycle following radiation exposure was due to blocks in G 2 and there were large cell line-to-cell line variations in the length of the G 2 block. Longer delays were seen in cell lines that had mutations in p53. There was a highly significant inverse correlation between the length of G 2 delay and the frequency of unrejoined chromosome breaks seen as chromosome terminal deletions in mitosis, and observation that supports the hypothesis that the signal for G 2 delay in mammalian cells is an unrejoined chromosome break. There were also an inverse correlation between the length of G 2 delay and the level of chromosome aneuploidy in each cell line, suggesting that the G 2 and mitotic spindel checkpoints may be linked to each other. Attenuation in G 2 checkpoint control was not associated with alterations in either the frequency of induced chromosome rearrangements or cell survival following radiation exposure suggesting that chromosome rearrangements, the major radiation-induced lethal lesion in tumor cells, form before cells enters G 2 . Thus, agents that act solely to override G 2 arrest should produce little radiosensitization in human tumor cells

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.

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

Lacosamide reduces HDAC levels in the brain and improves memory: Potential for treatment of Alzheimer's disease.

Science.gov (United States)

Bang, Shraddha R; Ambavade, Shirishkumar D; Jagdale, Priti G; Adkar, Prafulla P; Waghmare, Arun B; Ambavade, Prashant D

2015-07-01

Lacosamide, a histone deacetylase (HDAC) inhibitor, has been approved for the treatment of epilepsy. Some HDAC inhibitors have been proven effective for the treatment of memory disorders. The present investigation was designed to evaluate the effect of lacosamide on memory and brain HDAC levels. The effect on memory was evaluated in animals with scopolamine-induced amnesia using the elevated plus maze, object recognition test, and radial arm maze. The levels of acetylcholinesterase and HDAC in the cerebral cortex were evaluated. Lacosamide at doses of 10 and 30mg/kg significantly reduced the transfer latency in the elevated plus maze. Lacosamide at a dose of 30mg/kg significantly increased the time spent with a familiar object in the object recognition test at the 24h interval and decreased the time spent in the baited arm. Moreover, at this dose, the number of errors in the radial arm maze at 3 and 24h intervals was minimized and a reduction in the level of HDAC1, but not acetylcholinesterase, was observed in the cerebral cortex. These effects of lacosamide are equivalent to those of piracetam at a dose of 300mg/kg. These results suggest that lacosamide at a 30mg/kg dose improves disrupted memory, possibly by inhibiting HDAC, and could be used to treat amnesic symptoms of Alzheimer's disease. Copyright © 2015 Elsevier Inc. All rights reserved.

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.

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.

Protective Role of Educational Level on Episodic Memory Aging: An Event-Related Potential Study

Science.gov (United States)

Angel, Lucie; Fay, Severine; Bouazzaoui, Badiaa; Baudouin, Alexia; Isingrini, Michel

2010-01-01

The aim of the present experiment was to investigate whether educational level could modulate the effect of aging on episodic memory and on the electrophysiological correlates of retrieval success. Participants were divided into four groups based on age (young vs. older) and educational level (high vs. low), with 14 participants in each group.…

A comparison of the effects of propofol and midazolam on memory during two levels of sedation by using target-controlled infusion.

Science.gov (United States)

de Roode, A; van Gerven, J M; Schoemaker, R C; Engbers, F H; Olieman, W; Kroon, J R; Cohen, A F; Bovill, J G

2000-11-01

We examined memory during sedation with target-controlled infusions of propofol and midazolam in a double-blinded five-way, cross-over study in 10 volunteers. Each active drug infusion was targeted to sedation level 1 (asleep) and level 4 (lethargic) as determined with the Observer Assessment of Alertness/Sedation scale. At the target level of sedation, drug concentration was clamped for 30 min, during which time neutral words were presented. After 2 h, explicit memory was assessed by recall, and implicit memory by using a wordstem completion test. Venous drug concentrations (mean +/- SD) were 1350 ng/mL (+/-332 ng/mL) for propofol and 208 ng/mL (+/-112 ng/mL) for midazolam during Observer Assessment of Alertness/Sedation scale level 4; and 1620 ng/mL (+/-357 ng/mL) and 249 ng/mL (+/-82 ng/mL) respectively during level 1. The wordstem completion test frequencies at low level sedation were significantly higher than spontaneous frequencies (8.7% + 2.4%; P: sedation were accompanied by small differences in venous propofol or midazolam concentrations. This indicates steep concentration-effect relationships. Neutral information is still memorized during low-level sedation with both drugs. The memory effect of propofol and midazolam did not differ significantly. Implicit memory can occur during different states of consciousness and might lead to psychological damage. In 10 volunteers, implicit memory was investigated during sedation with propofol and midazolam in a double-blinded, placebo-controlled study. To compare the effects of both drugs, they were titrated using a computer-controlled infusion system to produce similar high and low levels of sedation.

Dietary levels of pure flavonoids improve spatial memory performance and increase hippocampal brain-derived neurotrophic factor.

Directory of Open Access Journals (Sweden)

Catarina Rendeiro

Full Text Available Evidence suggests that flavonoid-rich foods are capable of inducing improvements in memory and cognition in animals and humans. However, there is a lack of clarity concerning whether flavonoids are the causal agents in inducing such behavioral responses. Here we show that supplementation with pure anthocyanins or pure flavanols for 6 weeks, at levels similar to that found in blueberry (2% w/w, results in an enhancement of spatial memory in 18 month old rats. Pure flavanols and pure anthocyanins were observed to induce significant improvements in spatial working memory (p = 0.002 and p = 0.006 respectively, to a similar extent to that following blueberry supplementation (p = 0.002. These behavioral changes were paralleled by increases in hippocampal brain-derived neurotrophic factor (R = 0.46, p<0.01, suggesting a common mechanism for the enhancement of memory. However, unlike protein levels of BDNF, the regional enhancement of BDNF mRNA expression in the hippocampus appeared to be predominantly enhanced by anthocyanins. Our data support the claim that flavonoids are likely causal agents in mediating the cognitive effects of flavonoid-rich foods.

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.

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.

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.

The relationship between level of processing and hippocampal-cortical functional connectivity during episodic memory formation in humans.

Science.gov (United States)

Schott, Björn H; Wüstenberg, Torsten; Wimber, Maria; Fenker, Daniela B; Zierhut, Kathrin C; Seidenbecher, Constanze I; Heinze, Hans-Jochen; Walter, Henrik; Düzel, Emrah; Richardson-Klavehn, Alan

2013-02-01

New episodic memory traces represent a record of the ongoing neocortical processing engaged during memory formation (encoding). Thus, during encoding, deep (semantic) processing typically establishes more distinctive and retrievable memory traces than does shallow (perceptual) processing, as assessed by later episodic memory tests. By contrast, the hippocampus appears to play a processing-independent role in encoding, because hippocampal lesions impair encoding regardless of level of processing. Here, we clarified the neural relationship between processing and encoding by examining hippocampal-cortical connectivity during deep and shallow encoding. Participants studied words during functional magnetic resonance imaging and freely recalled these words after distraction. Deep study processing led to better recall than shallow study processing. For both levels of processing, successful encoding elicited activations of bilateral hippocampus and left prefrontal cortex, and increased functional connectivity between left hippocampus and bilateral medial prefrontal, cingulate and extrastriate cortices. Successful encoding during deep processing was additionally associated with increased functional connectivity between left hippocampus and bilateral ventrolateral prefrontal cortex and right temporoparietal junction. In the shallow encoding condition, on the other hand, pronounced functional connectivity increases were observed between the right hippocampus and the frontoparietal attention network activated during shallow study processing. Our results further specify how the hippocampus coordinates recording of ongoing neocortical activity into long-term memory, and begin to provide a neural explanation for the typical advantage of deep over shallow study processing for later episodic memory. Copyright © 2011 Wiley Periodicals, Inc.

Making Memories Matter

OpenAIRE

Gold, Paul E.; Korol, Donna L.

2012-01-01

This article reviews some of the neuroendocrine bases by which emotional events regulate brain mechanisms of learning and memory. In laboratory rodents, there is extensive evidence that epinephrine influences memory processing through an inverted-U relationship, at which moderate levels enhance and high levels impair memory. These effects are, in large part, mediated by increases in blood glucose levels subsequent to epinephrine release, which then provide support for the brain processes en...

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

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.

Understanding the Relative Contributions of Lower-Level Word Processes, Higher-Level Processes, and Working Memory to Reading Comprehension Performance in Proficient Adult Readers

Science.gov (United States)

Hannon, Brenda

2012-01-01

Although a considerable amount of evidence has been amassed regarding the contributions of lower-level word processes, higher-level processes, and working memory to reading comprehension, little is known about the relationships among these sources of individual differences or their relative contributions to reading comprehension performance. This…

Drosophila Polo regulates the spindle assembly checkpoint through Mps1-dependent BubR1 phosphorylation.

Science.gov (United States)

Conde, Carlos; Osswald, Mariana; Barbosa, João; Moutinho-Santos, Tatiana; Pinheiro, Diana; Guimarães, Sofia; Matos, Irina; Maiato, Helder; Sunkel, Claudio E

2013-06-12

Maintenance of genomic stability during eukaryotic cell division relies on the spindle assembly checkpoint (SAC) that prevents mitotic exit until all chromosomes are properly attached to the spindle. Polo is a mitotic kinase proposed to be involved in SAC function, but its role has remained elusive. We demonstrate that Polo and Aurora B functional interdependency comprises a positive feedback loop that promotes Mps1 kinetochore localization and activity. Expression of constitutively active Polo restores normal Mps1 kinetochore levels even after Aurora B inhibition, highlighting a role for Polo in Mps1 recruitment to unattached kinetochores downstream of Aurora B. We also show that Mps1 kinetochore localization is required for BubR1 hyperphosphorylation and formation of the 3F3/2 phosphoepitope. This is essential to allow recruitment of Cdc20 to unattached kinetochores and the assembly of anaphase-promoting complex/cyclosome-inhibitory complexes to levels that ensure long-term SAC activity. We propose a model in which Polo controls Mps1-dependent BubR1 phosphorylation to promote Cdc20 kinetochore recruitment and sustained SAC function.

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.

Report for the ASC CSSE L2 Milestone (4873) - Demonstration of Local Failure Local Recovery Resilient Programming Model.

Energy Technology Data Exchange (ETDEWEB)

Heroux, Michael Allen; Teranishi, Keita

2014-06-01

Recovery from process loss during the execution of a distributed memory parallel application is presently achieved by restarting the program, typically from a checkpoint file. Future computer system trends indicate that the size of data to checkpoint, the lack of improvement in parallel file system performance and the increase in process failure rates will lead to situations where checkpoint restart becomes infeasible. In this report we describe and prototype the use of a new application level resilient computing model that manages persistent storage of local state for each process such that, if a process fails, recovery can be performed locally without requiring access to a global checkpoint file. LFLR provides application developers with an ability to recover locally and continue application execution when a process is lost. This report discusses what features are required from the hardware, OS and runtime layers, and what approaches application developers might use in the design of future codes, including a demonstration of LFLR-enabled MiniFE code from the Matenvo mini-application suite.

ATTENTION IN ADVERTISERS BRAND PROCESSING: An analysis of explicit and implicit memories of individuals receptors in the light of directed attention level

Directory of Open Access Journals (Sweden)

Taís Pasquotto Andreoli

2016-07-01

Full Text Available The most of exposure of individuals to brand ads happens on mere exposure condition, when the stimuli are available in the context, but aren´t necessarily actively processed, but yet unconsiously, at the preattentive level. Despite the lack of individual intention and conscious, it emphasizes the ability of preattentive processing on influencing memory and judgement on stimuli receiving. In the light of the above, the study has with aim to analize the influency diferences in the individual receiver according with the level of attention used on the brand ad processing. To that, the study adopted a concepctual base with the attention process under a complex perspective, subdivided into preattention and attention, and the influency of attention in the memory of individual receiver. Using a hipothteical-dedutivo method, the explicit and implicit memory and the brand valuation were analysed and compared between three different attention levels (preattention, divided attention and drived attention. As contribution, the study support three of the four traced hypotheses: implicit memory independent of the level of attention; explicit memory in larger levels of attention; brand valuation on preattetinve processing higher than those expected by chance, but without diferences between the three attention levels.

High-bandwidth memory interface

CERN Document Server

Kim, Chulwoo; Song, Junyoung

2014-01-01

This book provides an overview of recent advances in memory interface design at both the architecture and circuit levels. Coverage includes signal integrity and testing, TSV interface, high-speed serial interface including equalization, ODT, pre-emphasis, wide I/O interface including crosstalk, skew cancellation, and clock generation and distribution. Trends for further bandwidth enhancement are also covered.   • Enables readers with minimal background in memory design to understand the basics of high-bandwidth memory interface design; • Presents state-of-the-art techniques for memory interface design; • Covers memory interface design at both the circuit level and system architecture level.

Exploring memory hierarchy design with emerging memory technologies

CERN Document Server

Sun, Guangyu

2014-01-01

This book equips readers with tools for computer architecture of high performance, low power, and high reliability memory hierarchy in computer systems based on emerging memory technologies, such as STTRAM, PCM, FBDRAM, etc.  The techniques described offer advantages of high density, near-zero static power, and immunity to soft errors, which have the potential of overcoming the “memory wall.”  The authors discuss memory design from various perspectives: emerging memory technologies are employed in the memory hierarchy with novel architecture modification;  hybrid memory structure is introduced to leverage advantages from multiple memory technologies; an analytical model named “Moguls” is introduced to explore quantitatively the optimization design of a memory hierarchy; finally, the vulnerability of the CMPs to radiation-based soft errors is improved by replacing different levels of on-chip memory with STT-RAMs.   ·         Provides a holistic study of using emerging memory technologies i...

Alpha spectral power and coherence in the patients with mild cognitive impairment during a three-level working memory task

Institute of Scientific and Technical Information of China (English)

无

2007-01-01

Objective: The functional relationship between calculated alpha band spectral power and inter-/intra-hemispheric coherence during a three-level working memory task of patients with mild cognitive impairment (MCI) was investigated. Methods:Subjects included 35 MCI patients according to the DSM-Ⅳ criteria (mean age: 62.3, SD: 6.5) and 34 healthy controls (mean age:57.4, SD: 4.0) were selected from the community at large. All subjects performed a simple calculation and recall task with three levels of working memory load while electroencephalograph (EEG) signal was recorded. The spectral EEG power was computed over alphal (8.0～10.0 Hz) and alpha2 (10.5～13.0 Hz) frequency bands and was compared between rest stage and working memory processing stage by two-way ANOVA. Post hoc testing analyzed the differences between each two levels of working memory load during task processing. The inter-hemisphere EEG coherence of frontal (F3-F4), central (C3-C4), parietal (P3-P4), temporal (T5-T6) as well as occipital (O1-O2) was compared between MCI patients and normal controls. The EEG signals from F3-C3,F4-C4, C3-P3, C4-P4, P3-O1, P4-O2, T5-C3, T6-C4, T5-P3 and T6-P4 electrode pairs resulted from the intra-hemispheric action for alphal and alpha2 frequency bands. Result: There was significantly higher EEG power from MCI patients than from normal controls both at rest and during working memory processing. Significant differences existed between rest condition and three-level working memory tasks (P＜0.001). The inter- and intra-hemispheric coherence during working memory tasks showed a "drop to rise" tendency compared to that at rest condition. There was significantly higher coherence in MCI patients than in the controls.When task difficulties increased, the cortical connectivity of intra-hemispheric diminished while the inter-hemispheric connectivity dominantly maintained the cognitive processing in MCI patients. Conclusion: The results of the present study indicate that the

Elevated levels of serum cholesterol are associated with better performance on tasks of episodic memory.

Science.gov (United States)

Leritz, Elizabeth C; McGlinchey, Regina E; Salat, David H; Milberg, William P

2016-04-01

We examined how serum cholesterol, an established risk factor for cerebrovascular disease (CVD), relates to cognitive function in healthy middle-older aged individuals with no neurologic or CVD history. A complete lipid panel was obtained from a cohort of one hundred twenty individuals, ages 43-85, who also underwent a comprehensive neuropsychological examination. In order to reduce the number of variables and empirically identify broad cognitive domains, scores from neuropsychological tests were submitted into a factor analysis. This analysis revealed three explainable factors: Memory, Executive Function and Memory/Language. Three separate hierarchical multiple regression analyses were conducted using individual cholesterol metrics (total cholesterol, low density lipoprotein; LDL, high density lipoprotein; HDL, and triglycerides), as well as age, education, medication status (lipid lowering agents), ApoE status, and additional risk factors for CVD to predict neuropsychological function. The Memory Factor was predicted by a combination of age, LDL, and triglyceride levels; both age and triglycerides were negatively associated with factor score, while LDL levels revealed a positive relationship. Both the Executive and Memory/Language factor were only explained by education, whereby more years were associated with better performance. These results provide evidence that individual cholesterol lipoproteins and triglycerides may differentially impact cognitive function, over and above other common CVD risk factors and ApoE status. Our findings demonstrate the importance of consideration of vascular risk factors, such as cholesterol, in studies of cognitive aging.

Neural population-level memory traces in the mouse hippocampus.

Science.gov (United States)

Chen, Guifen; Wang, L Phillip; Tsien, Joe Z

2009-12-16

One of the fundamental goals in neurosciences is to elucidate the formation and retrieval of brain's associative memory traces in real-time. Here, we describe real-time neural ensemble transient dynamics in the mouse hippocampal CA1 region and demonstrate their relationships with behavioral performances during both learning and recall. We employed the classic trace fear conditioning paradigm involving a neutral tone followed by a mild foot-shock 20 seconds later. Our large-scale recording and decoding methods revealed that conditioned tone responses and tone-shock association patterns were not present in CA1 during the first pairing, but emerged quickly after multiple pairings. These encoding patterns showed increased immediate-replay, correlating tightly with increased immediate-freezing during learning. Moreover, during contextual recall, these patterns reappeared in tandem six-to-fourteen times per minute, again correlating tightly with behavioral recall. Upon traced tone recall, while various fear memories were retrieved, the shock traces exhibited a unique recall-peak around the 20-second trace interval, further signifying the memory of time for the expected shock. Therefore, our study has revealed various real-time associative memory traces during learning and recall in CA1, and demonstrates that real-time memory traces can be decoded on a moment-to-moment basis over any single trial.

Neural population-level memory traces in the mouse hippocampus.

Directory of Open Access Journals (Sweden)

Guifen Chen

2009-12-01

Full Text Available One of the fundamental goals in neurosciences is to elucidate the formation and retrieval of brain's associative memory traces in real-time. Here, we describe real-time neural ensemble transient dynamics in the mouse hippocampal CA1 region and demonstrate their relationships with behavioral performances during both learning and recall. We employed the classic trace fear conditioning paradigm involving a neutral tone followed by a mild foot-shock 20 seconds later. Our large-scale recording and decoding methods revealed that conditioned tone responses and tone-shock association patterns were not present in CA1 during the first pairing, but emerged quickly after multiple pairings. These encoding patterns showed increased immediate-replay, correlating tightly with increased immediate-freezing during learning. Moreover, during contextual recall, these patterns reappeared in tandem six-to-fourteen times per minute, again correlating tightly with behavioral recall. Upon traced tone recall, while various fear memories were retrieved, the shock traces exhibited a unique recall-peak around the 20-second trace interval, further signifying the memory of time for the expected shock. Therefore, our study has revealed various real-time associative memory traces during learning and recall in CA1, and demonstrates that real-time memory traces can be decoded on a moment-to-moment basis over any single trial.

Attenuation of G{sub 2} cell cycle checkpoint control in human tumor cells is associated with increased frequencies of unrejoined chromosome breaks but not increased cytotoxicity following radiation exposure

Energy Technology Data Exchange (ETDEWEB)

Schwartz, J.L.; Cowan, J.; Grdina, D.J. [and others

1997-08-01

The contribution of G{sub 2} cell cycle checkpoint control to ionizing radiation responses was examined in ten human tumor cell lines. Most of the delay in cell cycle progression seen in the first cell cycle following radiation exposure was due to blocks in G{sub 2} and there were large cell line-to-cell line variations in the length of the G{sub 2} block. Longer delays were seen in cell lines that had mutations in p53. There was a highly significant inverse correlation between the length of G{sub 2} delay and the frequency of unrejoined chromosome breaks seen as chromosome terminal deletions in mitosis, and observation that supports the hypothesis that the signal for G{sub 2} delay in mammalian cells is an unrejoined chromosome break. There were also an inverse correlation between the length of G{sub 2} delay and the level of chromosome aneuploidy in each cell line, suggesting that the G{sub 2} and mitotic spindel checkpoints may be linked to each other. Attenuation in G{sub 2} checkpoint control was not associated with alterations in either the frequency of induced chromosome rearrangements or cell survival following radiation exposure suggesting that chromosome rearrangements, the major radiation-induced lethal lesion in tumor cells, form before cells enters G{sub 2}. Thus, agents that act solely to override G{sub 2} arrest should produce little radiosensitization in human tumor cells.

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

Hippocampal Cortactin Levels are Reduced Following Spatial Working Memory Formation, an Effect Blocked by Chronic Calpain Inhibition.

Science.gov (United States)

Olson, Mikel L; Ingebretson, Anna E; Harmelink, Katherine M

2015-06-19

The mechanism by which the hippocampus facilitates declarative memory formation appears to involve, among other things, restructuring of the actin cytoskeleton within neuronal dendrites. One protein involved in this process is cortactin, which is an important link between extracellular signaling and cytoskeletal reorganization. In this paper, we demonstrate that total hippocampal cortactin, as well as Y421-phosphorylated cortactin are transiently reduced following spatial working memory formation in the radial arm maze (RAM). Because cortactin is a substrate of the cysteine protease calpain, we also assessed the effect of chronic calpain inhibition on RAM performance and cortactin expression. Calpain inhibition impaired spatial working memory and blocked the reduction in hippocampal cortactin levels following RAM training. These findings add to a growing body of research implicating cortactin and calpain in hippocampus-dependent memory formation.

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.

[Evaluation of Significant Autobiographical Memories Scale: Design and structural validation at an exploratory level].

Science.gov (United States)

Lolich, María; Azzollini, Susana

2016-11-01

Personal memories are multimodal cognitive representations. Nowadays, psychometric instruments which aim to assess signifcant memories phenomenological features are scarce. Consequently, the Evaluation of Signifcant Autobiographical Memories Scale was constructed and structural validated at an exploratory level. A total of 404 individuals from Buenos Aires city (Argentina) participated in the research. Initially, an expert judgment and a pilot study administration were carried out. Next, a homogeneity and a principal components analysis were implemented. To assess the scale reliability, Cronbach's alphas coefficients were analyzed. The fnal version has 30 Likert response items gathered in 8 dimensions. Satisfactory psychometric proprieties were obtained - internal consistency of .892 and a total explained variance of 65.78%. The scale provides two main scores regarding the total quantity and intensity of the phenomenological components as well as a partial score per each dimension. It is stated that the test will prove to be useful in the research feld as well as in the clinical area.

The sensory components of high-capacity iconic memory and visual working memory.

Science.gov (United States)

Bradley, Claire; Pearson, Joel

2012-01-01

EARLY VISUAL MEMORY CAN BE SPLIT INTO TWO PRIMARY COMPONENTS: a high-capacity, short-lived iconic memory followed by a limited-capacity visual working memory that can last many seconds. Whereas a large number of studies have investigated visual working memory for low-level sensory features, much research on iconic memory has used more "high-level" alphanumeric stimuli such as letters or numbers. These two forms of memory are typically examined separately, despite an intrinsic overlap in their characteristics. Here, we used a purely sensory paradigm to examine visual short-term memory for 10 homogeneous items of three different visual features (color, orientation and motion) across a range of durations from 0 to 6 s. We found that the amount of information stored in iconic memory is smaller for motion than for color or orientation. Performance declined exponentially with longer storage durations and reached chance levels after ∼2 s. Further experiments showed that performance for the 10 items at 1 s was contingent on unperturbed attentional resources. In addition, for orientation stimuli, performance was contingent on the location of stimuli in the visual field, especially for short cue delays. Overall, our results suggest a smooth transition between an automatic, high-capacity, feature-specific sensory-iconic memory, and an effortful "lower-capacity" visual working memory.

The sensory components of high-capacity iconic memory and visual working memory

Directory of Open Access Journals (Sweden)

Claire eBradley

2012-09-01

Full Text Available Early visual memory can be split into two primary components: a high-capacity, short-lived iconic memory followed by a limited-capacity visual working memory that can last many seconds. Whereas a large number of studies have investigated visual working memory for low-level sensory features, much research on iconic memory has used more high-level alphanumeric stimuli such as letters or numbers. These two forms of memory are typically examined separately, despite an intrinsic overlap in their characteristics. Here, we used a purely sensory paradigm to examine visual short-term memory for 10 homogeneous items of 3 different visual features (colour, orientation and motion across a range of durations from 0 to 6 seconds. We found that the amount of information stored in iconic memory is smaller for motion than for colour or orientation. Performance declined exponentially with longer storage durations and reached chance levels after ~2 seconds. Further experiments showed that performance for the 10 items at 1 second was contingent on unperturbed attentional resources. In addition, for orientation stimuli, performance was contingent on the location of stimuli in the visual field, especially for short cue delays. Overall, our results suggest a smooth transition between an automatic, high-capacity, feature-specific sensory-iconic memory and an effortful ‘lower-capacity’ visual working memory.

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.

Effects of level of processing but not of task enactment on recognition memory in a case of developmental amnesia.

Science.gov (United States)

Gardiner, John M; Brandt, Karen R; Vargha-Khadem, Faraneh; Baddeley, Alan; Mishkin, Mortimer

2006-09-01

We report the performance in four recognition memory experiments of Jon, a young adult with early-onset developmental amnesia whose episodic memory is gravely impaired in tests of recall, but seems relatively preserved in tests of recognition, and who has developed normal levels of performance in tests of intelligence and general knowledge. Jon's recognition performance was enhanced by deeper levels of processing in comparing a more meaningful study task with a less meaningful one, but not by task enactment in comparing performance of an action with reading an action phrase. Both of these variables normally enhance episodic remembering, which Jon claimed to experience. But Jon was unable to support that claim by recollecting what it was that he remembered. Taken altogether, the findings strongly imply that Jon's recognition performance entailed little genuine episodic remembering and that the levels-of-processing effects in Jon reflected semantic, not episodic, memory.

Phenotypic characterization of autoreactive B cells--checkpoints of B cell tolerance in patients with systemic lupus erythematosus.

Directory of Open Access Journals (Sweden)

Annett M Jacobi

Full Text Available DNA-reactive B cells play a central role in systemic lupus erythematosus (SLE; DNA antibodies precede clinical disease and in established disease correlate with renal inflammation and contribute to dendritic cell activation and high levels of type 1 interferon. A number of central and peripheral B cell tolerance mechanisms designed to control the survival, differentiation and activation of autoreactive B cells are thought to be disturbed in patients with SLE. The characterization of DNA-reactive B cells has, however, been limited by their low frequency in peripheral blood. Using a tetrameric configuration of a peptide mimetope of DNA bound by pathogenic anti-DNA antibodies, we can identify B cells producing potentially pathogenic DNA-reactive antibodies. We, therefore, characterized the maturation and differentiation states of peptide, (ds double stranded DNA cross-reactive B cells in the peripheral blood of lupus patients and correlated these with clinical disease activity. Flow cytometric analysis demonstrated a significantly higher frequency of tetramer-binding B cells in SLE patients compared to healthy controls. We demonstrated the existence of a novel tolerance checkpoint at the transition of antigen-naïve to antigen-experienced. We further demonstrate that patients with moderately active disease have more autoreactive B cells in both the antigen-naïve and antigen-experienced compartments consistent with greater impairment in B cell tolerance in both early and late checkpoints in these patients than in patients with quiescent disease. This methodology enables us to gain insight into the development and fate of DNA-reactive B cells in individual patients with SLE and paves the way ultimately to permit better and more customized therapies.

Spindle assembly checkpoint protein expression correlates with cellular proliferation and shorter time to recurrence in ovarian cancer.

LENUS (Irish Health Repository)

McGrogan, Barbara

2014-07-01

Ovarian carcinoma (OC) is the most lethal of the gynecological malignancies, often presenting at an advanced stage. Treatment is hampered by high levels of drug resistance. The taxanes are microtubule stabilizing agents, used as first-line agents in the treatment of OC that exert their apoptotic effects through the spindle assembly checkpoint. BUB1-related protein kinase (BUBR1) and mitotic arrest deficient 2 (MAD2), essential spindle assembly checkpoint components, play a key role in response to taxanes. BUBR1, MAD2, and Ki-67 were assessed on an OC tissue microarray platform representing 72 OC tumors of varying histologic subtypes. Sixty-one of these patients received paclitaxel and platinum agents combined; 11 received platinum alone. Overall survival was available for all 72 patients, whereas recurrence-free survival (RFS) was available for 66 patients. Increased BUBR1 expression was seen in serous carcinomas, compared with other histologies (P = .03). Increased BUBR1 was significantly associated with tumors of advanced stage (P = .05). Increased MAD2 and BUBR1 expression also correlated with increased cellular proliferation (P < .0002 and P = .02, respectively). Reduced MAD2 nuclear intensity was associated with a shorter RFS (P = .03), in ovarian tumors of differing histologic subtype (n = 66). In this subgroup, for those women who received paclitaxel and platinum agents combined (n = 57), reduced MAD2 intensity also identified women with a shorter RFS (P < .007). For the entire cohort of patients, irrespective of histologic subtype or treatment, MAD2 nuclear intensity retained independent significance in a multivariate model, with tumors showing reduced nuclear MAD2 intensity identifying patients with a poorer RFS (P = .05).

Working Memory Influences on Long-Term Memory and Comprehension

National Research Council Canada - National Science Library

Radvansky, Gabriel

2004-01-01

.... This study looked at how comprehension and memory processing at the mental model level is related to traditional measures of working memory capacity, including the word span, reading span, operation...

Making memories matter

Directory of Open Access Journals (Sweden)

Paul E. Gold

2012-12-01

Full Text Available This article reviews some of the neuroendocrine bases by which emotional events regulate brain mechanisms of learning and memory. In laboratory rodents, there is extensive evidence that epinephrine influences memory processing through an inverted-U relationship, at which moderate levels enhance and high levels impair memory. These effects are, in large part, mediated by increases in blood glucose levels subsequent to epinephrine release, which then provide support for the brain processes engaged by learning and memory. These brain processes include augmentation of neurotransmitter release and of energy metabolism, the latter apparently including a key role for astrocytic glycogen. In addition to up- and down-regulation of learning and memory in general, physiological concomitants of emotion and arousal can also switch the neural system that controls learning at a particular time, at once improving some attributes of learning and impairing others in a manner that results in a change in the strategy used to solve a problem.

Making Memories Matter

Science.gov (United States)

Gold, Paul E.; Korol, Donna L.

2012-01-01

This article reviews some of the neuroendocrine bases by which emotional events regulate brain mechanisms of learning and memory. In laboratory rodents, there is extensive evidence that epinephrine influences memory processing through an inverted-U relationship, at which moderate levels enhance and high levels impair memory. These effects are, in large part, mediated by increases in blood glucose levels subsequent to epinephrine release, which then provide support for the brain processes engaged by learning and memory. These brain processes include augmentation of neurotransmitter release and of energy metabolism, the latter apparently including a key role for astrocytic glycogen. In addition to up- and down-regulation of learning and memory in general, physiological concomitants of emotion and arousal can also switch the neural system that controls learning at a particular time, at once improving some attributes of learning and impairing others in a manner that results in a change in the strategy used to solve a problem. PMID:23264764

Assessing the Driver's Current Level of Working Memory Load with High Density Functional Near-infrared Spectroscopy: A Realistic Driving Simulator Study.

Science.gov (United States)

Unni, Anirudh; Ihme, Klas; Jipp, Meike; Rieger, Jochem W

2017-01-01

Cognitive overload or underload results in a decrease in human performance which may result in fatal incidents while driving. We envision that driver assistive systems which adapt their functionality to the driver's cognitive state could be a promising approach to reduce road accidents due to human errors. This research attempts to predict variations of cognitive working memory load levels in a natural driving scenario with multiple parallel tasks and to reveal predictive brain areas. We used a modified version of the n-back task to induce five different working memory load levels (from 0-back up to 4-back) forcing the participants to continuously update, memorize, and recall the previous 'n' speed sequences and adjust their speed accordingly while they drove for approximately 60 min on a highway with concurrent traffic in a virtual reality driving simulator. We measured brain activation using multichannel whole head, high density functional near-infrared spectroscopy (fNIRS) and predicted working memory load level from the fNIRS data by combining multivariate lasso regression and cross-validation. This allowed us to predict variations in working memory load in a continuous time-resolved manner with mean Pearson correlations between induced and predicted working memory load over 15 participants of 0.61 [standard error (SE) 0.04] and a maximum of 0.8. Restricting the analysis to prefrontal sensors placed over the forehead reduced the mean correlation to 0.38 (SE 0.04), indicating additional information gained through whole head coverage. Moreover, working memory load predictions derived from peripheral heart rate parameters achieved much lower correlations (mean 0.21, SE 0.1). Importantly, whole head fNIRS sampling revealed increasing brain activation in bilateral inferior frontal and bilateral temporo-occipital brain areas with increasing working memory load levels suggesting that these areas are specifically involved in workload-related processing.

Hippocampal Cortactin Levels are Reduced Following Spatial Working Memory Formation, an Effect Blocked by Chronic Calpain Inhibition

Directory of Open Access Journals (Sweden)

Mikel L. Olson

2015-06-01

Full Text Available The mechanism by which the hippocampus facilitates declarative memory formation appears to involve, among other things, restructuring of the actin cytoskeleton within neuronal dendrites. One protein involved in this process is cortactin, which is an important link between extracellular signaling and cytoskeletal reorganization. In this paper, we demonstrate that total hippocampal cortactin, as well as Y421-phosphorylated cortactin are transiently reduced following spatial working memory formation in the radial arm maze (RAM. Because cortactin is a substrate of the cysteine protease calpain, we also assessed the effect of chronic calpain inhibition on RAM performance and cortactin expression. Calpain inhibition impaired spatial working memory and blocked the reduction in hippocampal cortactin levels following RAM training. These findings add to a growing body of research implicating cortactin and calpain in hippocampus-dependent memory formation.

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

When Delays Improve Memory: Stabilizing Memory in Children May Require Time

OpenAIRE

Darby, Kevin P.; Sloutsky, Vladimir M.

2015-01-01

Memory is critical for learning, cognition and cognitive development. Recent work has suggested that preschool-aged children are vulnerable to catastrophic levels of memory interference, in which new learning dramatically attenuates memory for previously acquired knowledge. Work reported here investigates the effects of consolidation on children’s memory by introducing a 48- hours-long delay between learning and testing. In Experiment 1, the delay improved children’s memory and eliminated int...

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.

The effects of nongenetic memory on population level sensitivity to stress

Science.gov (United States)

Adams, Rhys; Nevozhay, Dmitry; van Itallie, Elizabeth; Bennett, Matthew; Balazsi, Gabor

2011-03-01

While gene expression is often thought of as a unidirectional determinant of cellular fitness, recent studies have shown how growth retardation due to protein expression can affect gene expression levels in single cells. We developed two yeast strains carrying a drug resistance protein under the control of different synthetic gene constructs, one of which was monostable, while the other was bistable. The gene expression of these cell populations was tuned using a molecular inducer so that their respective means and noises were identical, while their nongenetic memory properties were different. We tested the sensitivity of these two cell population distributions to the antibiotic zeocin. We found that the gene expression distributions of bistable cell populations were sensitive to stressful environments, while the gene expression distribution of monostable cells were nearly unchanged by stress. We conclude that cell populations with high nongenetic memory are more adaptable to their environment. This work was funded by the National Institutes of Health through the NIH Director's New Innovator Award Program, 1-DP2- OD006481-01.

False memories and memory confidence in borderline patients.

Science.gov (United States)

Schilling, Lisa; Wingenfeld, Katja; Spitzer, Carsten; Nagel, Matthias; Moritz, Steffen

2013-12-01

Mixed results have been obtained regarding memory in patients with borderline personality disorder (BPD). Prior reports and anecdotal evidence suggests that patients with BPD are prone to false memories but this assumption has to been put to firm empirical test, yet. Memory accuracy and confidence was assessed in 20 BPD patients and 22 healthy controls using a visual variant of the false memory (Deese-Roediger-McDermott) paradigm which involved a negative and a positive-valenced picture. Groups did not differ regarding veridical item recognition. Importantly, patients did not display more false memories than controls. At trend level, borderline patients rated more items as new with high confidence compared to healthy controls. The results tentatively suggest that borderline patients show uncompromised visual memory functions and display no increased susceptibility for distorted memories. Copyright © 2013 Elsevier Ltd. All rights reserved.

The effect of different levels of dietary restriction on glucose homeostasis and metabolic memory.

Science.gov (United States)

Matyi, Stephanie; Jackson, Jordan; Garrett, Karla; Deepa, Sathyaseelan S; Unnikrishnan, Archana

2018-02-17

Over the past 50 years, dietary restriction (DR) has been shown to extend the life span of a wide variety of organisms. A hallmark feature of DR is improved glucose homeostasis resulting in increased glucose tolerance and insulin sensitivity of animals ranging from rodents to humans. In this study, we demonstrate the early effects of varying levels of DR on glucose tolerance. Within 10 days of 40% DR, glucose tolerance was significantly improved and by 120 days; 10 and 20% DR also showed enhanced glucose tolerance. All three levels of DR showed reduced adiposity, increased expression of genes involved in fat turnover, and a reduction in the expression for markers of inflammation. Studies have shown that mice fed a DR diet retained metabolic memory in terms of improved glucose tolerance even after DR is discontinued. We show that 40% DR not only has an early effect on glucose tolerance but also maintained it after DR was discontinued for 2 months. Therefore, improvement in glucose tolerance is brought about by all three levels of DR but the metabolic memory is not dose responsive.

A content addressable memory for use in CEBAF's CLAS detector level 2 triggering system

International Nuclear Information System (INIS)

Hodson, R.F.; Doughty, D.C. Jr.; Allgood, D.C.; Campbell, S.A.; Wilson, W.C.; Bickley, M.H.

1996-01-01

A collaboration of researchers from CEBAF, CNU and NASA is designing a 256-32 specialized Content Addressable Memory (CAM) for the level 2 triggering system in CEBAF's CLAS detector. These integrated circuits will find tracks and the momentum and angle of each track within 2 microseconds of an event. The custom CAM can operate as conventional memory, performing read and write operations, and can additionally perform independent byte compare operations across all words simultaneously. It is this compare feature which makes these CAMs attractive for identifying tracks passing through drift chambers by linking together segment number triplets within the CAM. Simulations have indicated that less than 16 k triplets need to be stored for each sector of the detector. This implies the level 2 triggering can be performed with 64 CAM chips per sector, or 384 total. Each data channel into a sector CAM array is buffered in a FIFO and is designed to handle aggregate data rates up to 750 Mbs for three channels (one channel/superlayer). The architecture of the level 2 trigger and details of the CAM chip design are discussed along with a performance report on our prototype CAMs

Psychosocial stress impairs working memory at high loads: An association with cortisol levels and memory retrieval

NARCIS (Netherlands)

Oei, N.Y.L.; Everaerd, W.T.A.M.; Elzinga, B.M.; van Well, S.; Bermond, B.

2006-01-01

Stress and cortisol are known to impair memory retrieval of well-consolidated declarative material. The effects of cortisol on memory retrieval may in particular be due to glucocorticoid (GC) receptors in the hippocampus and prefrontal cortex (PFC). Therefore, effects of stress and cortisol should

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.

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....

Angiotensin IV and LVV-haemorphin 7 enhance spatial working memory in rats: effects on hippocampal glucose levels and blood flow.

Science.gov (United States)

De Bundel, Dimitri; Smolders, Ilse; Yang, Rui; Albiston, Anthony L; Michotte, Yvette; Chai, Siew Yeen

2009-07-01

The IRAP ligands Angiotensin IV (Ang IV) and LVV-haemorphin 7 (LVV-H7) enhance performance in a range of memory paradigms in normal rats and ameliorate memory deficits in rat models for amnesia. The mechanism by which these peptides facilitate memory remains to be elucidated. In recent in vitro experiments, we demonstrated that Ang IV and LVV-H7 potentiate activity-evoked glucose uptake into hippocampal neurons. This raises the possibility that IRAP ligands may facilitate memory in hippocampus-dependent tasks through enhancement of hippocampal glucose uptake. Acute intracerebroventricular (i.c.v.) administration of 1nmol Ang IV or 0.1nmol LVV-H7 in 3 months-old Sprague-Dawley rats enhanced spatial working memory in the plus maze spontaneous alternation task. Extracellular hippocampal glucose levels were monitored before, during and after behavioral testing using in vivo microdialysis. Extracellular hippocampal glucose levels decreased significantly to about 70% of baseline when the animals explored the plus maze, but remained constant when the animals were placed into a novel control chamber. Ang IV and LVV-H7 did not significantly alter hippocampal glucose levels compared to control animals in the plus maze or control chamber. Both peptides had no effect on hippocampal blood flow as determined by laser Doppler flowmetry, excluding that either peptide increased the hippocampal supply of glucose. We demonstrated for the first time that Ang IV and LVV-H7 enhance spatial working memory in the plus maze spontaneous alternation task but no in vivo evidence was found for enhanced hippocampal glucose uptake or blood flow.

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.

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

Disentangling multi-level systems: averaging, correlations and memory

International Nuclear Information System (INIS)

Wouters, Jeroen; Lucarini, Valerio

2012-01-01

We consider two weakly coupled systems and adopt a perturbative approach based on the Ruelle response theory to study their interaction. We propose a systematic way of parameterizing the effect of the coupling as a function of only the variables of a system of interest. Our focus is on describing the impacts of the coupling on the long term statistics rather than on the finite-time behavior. By direct calculation, we find that, at first order, the coupling can be surrogated by adding a deterministic perturbation to the autonomous dynamics of the system of interest. At second order, there are additionally two separate and very different contributions. One is a term taking into account the second-order contributions of the fluctuations in the coupling, which can be parameterized as a stochastic forcing with given spectral properties. The other one is a memory term, coupling the system of interest to its previous history, through the correlations of the second system. If these correlations are known, this effect can be implemented as a perturbation with memory on the single system. In order to treat this case, we present an extension to Ruelle's response theory able to deal with integral operators. We discuss our results in the context of other methods previously proposed for disentangling the dynamics of two coupled systems. We emphasize that our results do not rely on assuming a time scale separation, and, if such a separation exists, can be used equally well to study the statistics of the slow variables and that of the fast variables. By recursively applying the technique proposed here, we can treat the general case of multi-level systems

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

Inactivation of basolateral amygdala prevents chronic immobilization stress-induced memory impairment and associated changes in corticosterone levels.

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Tripathi, Sunil Jamuna; Chakraborty, Suwarna; Srikumar, B N; Raju, T R; Shankaranarayana Rao, B S

2017-07-01

Chronic stress causes detrimental effects on various forms of learning and memory. The basolateral amygdala (BLA) not only plays a crucial role in mediating certain forms of memory, but also in the modulation of the effects of stress. Chronic immobilization stress (CIS) results in hypertrophy of the BLA, which is believed to be one of the underlying causes for stress' effects on learning. Thus, it is plausible that preventing the effects of CIS on amygdala would preclude its deleterious cognitive effects. Accordingly, in the first part, we evaluated the effect of excitotoxic lesion of the BLA on chronic stress-induced hippocampal-dependent spatial learning using a partially baited radial arm maze task. The BLA was ablated bilaterally using ibotenic acid prior to CIS. Chronically stressed rats showed impairment in spatial learning with decreased percentage correct choice and increased reference memory errors. Excitotoxic lesion of the BLA prevented the impairment in spatial learning and reference memory. In the retention test, lesion of the BLA was able to rescue the chronic stress-induced impairment. Interestingly, stress-induced enhanced plasma corticosterone levels were partially prevented by the lesion of BLA. These results motivated us to evaluate if the same effects can be observed with temporary inactivation of BLA, only during stress. We found that chronic stress-induced spatial learning deficits were also prevented by temporary inactivation of the BLA. Additionally, temporary inactivation of BLA partially precluded the stress-induced increase in plasma corticosterone levels. Thus, inactivation of BLA precludes stress-induced spatial learning deficits, and enhanced plasma corticosterone levels. It is speculated that BLA inactivation-induced reduction in corticosterone levels during stress, might be crucial in restoring spatial learning impairments. Our study provides evidence that amygdalar modulation during stress might be beneficial for strategic

Chess knowledge predicts chess memory even after controlling for chess experience: Evidence for the role of high-level processes.

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Lane, David M; Chang, Yu-Hsuan A

2018-04-01

The expertise effect in memory for chess positions is one of the most robust effects in cognitive psychology. One explanation of this effect is that chess recall is based on the recognition of familiar patterns and that experts have learned more and larger patterns. Template theory and its instantiation as a computational model are based on this explanation. An alternative explanation is that the expertise effect is due, in part, to stronger players having better and more conceptual knowledge, with this knowledge facilitating memory performance. Our literature review supports the latter view. In our experiment, a sample of 79 chess players were given a test of memory for chess positions, a test of declarative chess knowledge, a test of fluid intelligence, and a questionnaire concerning the amount of time they had played nontournament chess and the amount of time they had studied chess. We determined the numbers of tournament games the players had played from chess databases. Chess knowledge correlated .67 with chess memory and accounted for 16% of the variance after controlling for chess experience. Fluid intelligence accounted for an additional 13% of the variance. These results support the conclusion that both high-level conceptual processing and low-level recognition of familiar patterns play important roles in memory for chess positions.

The Sensory Components of High-Capacity Iconic Memory and Visual Working Memory

OpenAIRE

Bradley, Claire; Pearson, Joel

2012-01-01

Early visual memory can be split into two primary components: a high-capacity, short-lived iconic memory followed by a limited-capacity visual working memory that can last many seconds. Whereas a large number of studies have investigated visual working memory for low-level sensory features, much research on iconic memory has used more “high-level” alphanumeric stimuli such as letters or numbers. These two forms of memory are typically examined separately, despite an intrinsic overlap in their...

Acute inflammatory thyromegaly following checkpoint inhibition: A new imaging entity?

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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.

The Effect of Scalp Point Cluster-Needling on Learning and Memory Function and Neurotransmitter Levels in Rats with Vascular Dementia

OpenAIRE

Yang, Junli; Litscher, Gerhard; Li, Haitao; Guo, Wenhai; Liang, Zhang; Zhang, Ting; Wang, Weihua; Li, Xiaoyan; Zhou, Yao; Zhao, Bing; Rong, Qi; Sheng, Zemin; Gaischek, Ingrid; Litscher, Daniela; Wang, Lu

2014-01-01

We observed the effect of scalp point cluster-needling treatment on learning and memory function and neurotransmitter levels in rats with vascular dementia (VD). Permanent ligation of the bilateral carotid arteries was used to create the VD rat model. A Morris water maze was used to measure the rats' learning and memory function, and the changes in neurotransmitter levels in the rats' hippocampus were analyzed. The results show that scalp point cluster-needling can increase the VD rat model's...

Novel memory architecture for video signal processor

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Hung, Jen-Sheng; Lin, Chia-Hsing; Jen, Chein-Wei

1993-11-01

An on-chip memory architecture for video signal processor (VSP) is proposed. This memory structure is a two-level design for the different data locality in video applications. The upper level--Memory A provides enough storage capacity to reduce the impact on the limitation of chip I/O bandwidth, and the lower level--Memory B provides enough data parallelism and flexibility to meet the requirements of multiple reconfigurable pipeline function units in a single VSP chip. The needed memory size is decided by the memory usage analysis for video algorithms and the number of function units. Both levels of memory adopted a dual-port memory scheme to sustain the simultaneous read and write operations. Especially, Memory B uses multiple one-read-one-write memory banks to emulate the real multiport memory. Therefore, one can change the configuration of Memory B to several sets of memories with variable read/write ports by adjusting the bus switches. Then the numbers of read ports and write ports in proposed memory can meet requirement of data flow patterns in different video coding algorithms. We have finished the design of a prototype memory design using 1.2- micrometers SPDM SRAM technology and will fabricated it through TSMC, in Taiwan.

Levels of word processing and incidental memory: dissociable mechanisms in the temporal lobe.

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Castillo, E M; Simos, P G; Davis, R N; Breier, J; Fitzgerald, M E; Papanicolaou, A C

2001-11-16

Word recall is facilitated when deep (e.g. semantic) processing is applied during encoding. This fact raises the question of the existence of specific brain mechanisms supporting different levels of information processing that can modulate incidental memory performance. In this study we obtained spatiotemporal brain activation profiles, using magnetic source imaging, from 10 adult volunteers as they performed a shallow (phonological) processing task and a deep (semantic) processing task. When phonological analysis of the word stimuli into their constituent phonemes was required, activation was largely restricted to the posterior portion of the left superior temporal gyrus (area 22). Conversely, when access to lexical/semantic representations was required, activation was found predominantly in the left middle temporal gyrus and medial temporal cortex. The differential engagement of each mechanism during word encoding was associated with dramatic changes in subsequent incidental memory performance.

Assessing the Driver’s Current Level of Working Memory Load with High Density Functional Near-infrared Spectroscopy: A Realistic Driving Simulator Study

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Unni, Anirudh; Ihme, Klas; Jipp, Meike; Rieger, Jochem W.

2017-01-01

Cognitive overload or underload results in a decrease in human performance which may result in fatal incidents while driving. We envision that driver assistive systems which adapt their functionality to the driver’s cognitive state could be a promising approach to reduce road accidents due to human errors. This research attempts to predict variations of cognitive working memory load levels in a natural driving scenario with multiple parallel tasks and to reveal predictive brain areas. We used a modified version of the n-back task to induce five different working memory load levels (from 0-back up to 4-back) forcing the participants to continuously update, memorize, and recall the previous ‘n’ speed sequences and adjust their speed accordingly while they drove for approximately 60 min on a highway with concurrent traffic in a virtual reality driving simulator. We measured brain activation using multichannel whole head, high density functional near-infrared spectroscopy (fNIRS) and predicted working memory load level from the fNIRS data by combining multivariate lasso regression and cross-validation. This allowed us to predict variations in working memory load in a continuous time-resolved manner with mean Pearson correlations between induced and predicted working memory load over 15 participants of 0.61 [standard error (SE) 0.04] and a maximum of 0.8. Restricting the analysis to prefrontal sensors placed over the forehead reduced the mean correlation to 0.38 (SE 0.04), indicating additional information gained through whole head coverage. Moreover, working memory load predictions derived from peripheral heart rate parameters achieved much lower correlations (mean 0.21, SE 0.1). Importantly, whole head fNIRS sampling revealed increasing brain activation in bilateral inferior frontal and bilateral temporo-occipital brain areas with increasing working memory load levels suggesting that these areas are specifically involved in workload-related processing. PMID

Assessing the Driver’s Current Level of Working Memory Load with High Density Functional Near-infrared Spectroscopy: A Realistic Driving Simulator Study

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Anirudh Unni

2017-04-01

Full Text Available Cognitive overload or underload results in a decrease in human performance which may result in fatal incidents while driving. We envision that driver assistive systems which adapt their functionality to the driver’s cognitive state could be a promising approach to reduce road accidents due to human errors. This research attempts to predict variations of cognitive working memory load levels in a natural driving scenario with multiple parallel tasks and to reveal predictive brain areas. We used a modified version of the n-back task to induce five different working memory load levels (from 0-back up to 4-back forcing the participants to continuously update, memorize, and recall the previous ‘n’ speed sequences and adjust their speed accordingly while they drove for approximately 60 min on a highway with concurrent traffic in a virtual reality driving simulator. We measured brain activation using multichannel whole head, high density functional near-infrared spectroscopy (fNIRS and predicted working memory load level from the fNIRS data by combining multivariate lasso regression and cross-validation. This allowed us to predict variations in working memory load in a continuous time-resolved manner with mean Pearson correlations between induced and predicted working memory load over 15 participants of 0.61 [standard error (SE 0.04] and a maximum of 0.8. Restricting the analysis to prefrontal sensors placed over the forehead reduced the mean correlation to 0.38 (SE 0.04, indicating additional information gained through whole head coverage. Moreover, working memory load predictions derived from peripheral heart rate parameters achieved much lower correlations (mean 0.21, SE 0.1. Importantly, whole head fNIRS sampling revealed increasing brain activation in bilateral inferior frontal and bilateral temporo-occipital brain areas with increasing working memory load levels suggesting that these areas are specifically involved in workload

Psychophysiology of prospective memory.

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Rothen, Nicolas; Meier, Beat

2014-01-01

Prospective memory involves the self-initiated retrieval of an intention upon an appropriate retrieval cue. Cue identification can be considered as an orienting reaction and may thus trigger a psychophysiological response. Here we present two experiments in which skin conductance responses (SCRs) elicited by prospective memory cues were compared to SCRs elicited by aversive stimuli to test whether a single prospective memory cue triggers a similar SCR as an aversive stimulus. In Experiment 2 we also assessed whether cue specificity had a differential influence on prospective memory performance and on SCRs. We found that detecting a single prospective memory cue is as likely to elicit a SCR as an aversive stimulus. Missed prospective memory cues also elicited SCRs. On a behavioural level, specific intentions led to better prospective memory performance. However, on a psychophysiological level specificity had no influence. More generally, the results indicate reliable SCRs for prospective memory cues and point to psychophysiological measures as valuable approach, which offers a new way to study one-off prospective memory tasks. Moreover, the findings are consistent with a theory that posits multiple prospective memory retrieval stages.

Reduced memory skills and increased hair cortisol levels in recent Ecstasy/MDMA users: significant but independent neurocognitive and neurohormonal deficits.

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Downey, Luke A; Sands, Helen; Jones, Lewis; Clow, Angela; Evans, Phil; Stalder, Tobias; Parrott, Andrew C

2015-05-01

The goals of this study were to measure the neurocognitive performance of recent users of recreational Ecstasy and investigate whether it was associated with the stress hormone cortisol. The 101 participants included 27 recent light users of Ecstasy (one to four times in the last 3 months), 23 recent heavier Ecstasy users (five or more times) and 51 non-users. Rivermead paragraph recall provided an objective measure for immediate and delayed recall. The prospective and retrospective memory questionnaire provided a subjective index of memory deficits. Cortisol levels were taken from near-scalp 3-month hair samples. Cortisol was significantly raised in recent heavy Ecstasy users compared with controls, whereas hair cortisol in light Ecstasy users was not raised. Both Ecstasy groups were significantly impaired on the Rivermead delayed word recall, and both groups reported significantly more retrospective and prospective memory problems. Stepwise regression confirmed that lifetime Ecstasy predicted the extent of these memory deficits. Recreational Ecstasy is associated with increased levels of the bio-energetic stress hormone cortisol and significant memory impairments. No significant relationship between cortisol and the cognitive deficits was observed. Ecstasy users did display evidence of a metacognitive deficit, with the strength of the correlations between objective and subjective memory performances being significantly lower in the Ecstasy users. Copyright © 2015 John Wiley & Sons, Ltd.

Exogenous galanin attenuates spatial memory impairment and decreases hippocampal β-amyloid levels in rat model of Alzheimer's disease.

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Li, Lei; Yu, Liling; Kong, Qingxia

2013-11-01

One of the major pathological characteristics of Alzheimer's disease (AD) is the presence of enhanced deposits of beta-amyloid peptide (Aβ). The neuropeptide galanin (GAL) and its receptors are overexpressed in degenerating brain regions in AD. The functional consequences of galaninergic systems plasticity in AD are unclear. The objective of the present study was to investigate whether exogenous galanin could attenuate spatial memory impairment and hippocampal Aβ aggregation in rat model of AD. The effects of Aβ, galanin, galanin receptor 1 agonist M617 and galanin receptor 2 agonist AR-M1896 on spatial memory were tested by Morris water maze. The effects of Aβ, galanin, M617 and AR-M1896 on hippocampal Aβ protein expression were evaluated by western blot assay. The expression of galanin, galanin receptors 1 and 2 in rats' hippocampus were detected by real time PCR and western blot assay. The results showed that (1) Galanin administration was effective in improving the spatial memory and decreasing hippocampal Aβ levels after intracerebroventricular injection of Aβ; (2) AR-M1896 rather than M617 could imitate these effects of galanin; (3) GAL and GALR2 mRNA and protein levels increased significantly in hippocampus after Aβ administration, while GALR1 mRNA and protein levels did not change; (4) GAL, AR-M1896 and M617 administration did not show significant effect on GAL, GalR1 and GalR2 mRNA and protein levels in hippocampus after Aβ administration. These results implied that galanin receptor 2, but not receptor 1 was involved in the protective effects against spatial memory impairment and hippocampal Aβ aggregation.

Structural basis of a novel PD-L1 nanobody for immune checkpoint blockade.

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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.

Leveling the playing field: attention mitigates the effects of intelligence on memory.

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Markant, Julie; Amso, Dima

2014-05-01

Effective attention and memory skills are fundamental to typical development and essential for achievement during the formal education years. It is critical to identify the specific mechanisms linking efficiency of attentional selection of an item and the quality of its memory retention. The present study capitalized on the spatial cueing paradigm to examine the role of selection via suppression in modulating children and adolescents' memory encoding. By varying a single parameter, the spatial cueing task can elicit either a simple orienting mechanism (i.e., facilitation) or one that involves both target selection and simultaneous suppression of competing information (i.e., IOR). We modified this paradigm to include images of common items in target locations. Participants were not instructed to learn the items and were not told they would be completing a memory test later. Following the cueing task, we imposed a 7-min delay and then asked participants to complete a recognition memory test. Results indicated that selection via suppression promoted recognition memory among 7-17year-olds. Moreover, individual differences in the extent of suppression during encoding predicted recognition memory accuracy. When basic cueing facilitated orienting to target items during encoding, IQ was the best predictor of recognition memory performance for the attended items. In contrast, engaging suppression (i.e., IOR) during encoding counteracted individual differences in intelligence, effectively improving recognition memory performance among children with lower IQs. This work demonstrates that engaging selection via suppression during learning and encoding improves memory retention and has broad implications for developing effective educational techniques. Copyright © 2014 Elsevier B.V. All rights reserved.

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.

Checkpoint Kinase Rad53 Couples Leading- and Lagging-Strand DNA Synthesis under Replication Stress.

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Gan, Haiyun; Yu, Chuanhe; Devbhandari, Sujan; Sharma, Sushma; Han, Junhong; Chabes, Andrei; Remus, Dirk; Zhang, Zhiguo

2017-10-19

The checkpoint kinase Rad53 is activated during replication stress to prevent fork collapse, an essential but poorly understood process. Here we show that Rad53 couples leading- and lagging-strand synthesis under replication stress. In rad53-1 cells stressed by dNTP depletion, the replicative DNA helicase, MCM, and the leading-strand DNA polymerase, Pol ε, move beyond the site of DNA synthesis, likely unwinding template DNA. Remarkably, DNA synthesis progresses further along the lagging strand than the leading strand, resulting in the exposure of long stretches of single-stranded leading-strand template. The asymmetric DNA synthesis in rad53-1 cells is suppressed by elevated levels of dNTPs in vivo, and the activity of Pol ε is compromised more than lagging-strand polymerase Pol δ at low dNTP concentrations in vitro. Therefore, we propose that Rad53 prevents the generation of excessive ssDNA under replication stress by coordinating DNA unwinding with synthesis of both strands. Copyright © 2017 Elsevier Inc. All rights reserved.

Individual differences in working memory, secondary memory, and fluid intelligence: evidence from the levels-of-processing span task.

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Rose, Nathan S

2013-12-01

Individual differences in working memory (WM) are related to performance on secondary memory (SM), and fluid intelligence (gF) tests. However, the source of the relation remains unclear, in part because few studies have controlled for the nature of encoding; therefore, it is unclear whether individual variation is due to encoding, maintenance, or retrieval processes. In the current study, participants performed a WM task (the levels-of-processing span task; Rose, Myerson, Roediger III, & Hale, 2010) and a SM test that tested for both targets and the distracting processing words from the initial WM task. Deeper levels of processing at encoding did not benefit WM, but did benefit subsequent SM, although the amount of benefit was smaller for those with lower WM spans. This result suggests that, despite encoding cues that facilitate retrieval from SM, low spans may have engaged in shallower, maintenance-focused processing to maintain the words in WM. Low spans also recalled fewer targets, more distractors, and more extralist intrusions than high spans, although this was partially due to low spans' poorer recall of targets, which resulted in a greater number of opportunities to commit recall errors. Delayed recall of intrusions and commission of source errors (labeling targets as processing words and vice versa) were significant negative predictors of gF. These results suggest that the ability to use source information to recall relevant information and withhold recall of irrelevant information is a critical source of both individual variation in WM and the relation between WM, SM, and gF. (PsycINFO Database Record (c) 2013 APA, all rights reserved).

Pch2 acts through Xrs2 and Tel1/ATM to modulate interhomolog bias and checkpoint function during meiosis.

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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.

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

Checkpoint blockade in combination with cancer vaccines.

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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.

Leptin Regulation of Gonadotrope Gonadotropin-Releasing Hormone Receptors As a Metabolic Checkpoint and Gateway to Reproductive Competence

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Angela K. Odle

2018-01-01

Full Text Available The adipokine leptin signals the body’s nutritional status to the brain, and particularly, the hypothalamus. However, leptin receptors (LEPRs can be found all throughout the body and brain, including the pituitary. It is known that leptin is permissive for reproduction, and mice that cannot produce leptin (Lep/Lep are infertile. Many studies have pinpointed leptin’s regulation of reproduction to the hypothalamus. However, LEPRs exist at all levels of the hypothalamic–pituitary–gonadal axis. We have previously shown that deleting the signaling portion of the LEPR specifically in gonadotropes impairs fertility in female mice. Our recent studies have targeted this regulation to the control of gonadotropin releasing hormone receptor (GnRHR expression. The hypotheses presented here are twofold: (1 cyclic regulation of pituitary GnRHR levels sets up a target metabolic checkpoint for control of the reproductive axis and (2 multiple checkpoints are required for the metabolic signaling that regulates the reproductive axis. Here, we emphasize and explore the relationship between the hypothalamus and the pituitary with regard to the regulation of GnRHR. The original data we present strengthen these hypotheses and build on our previous studies. We show that we can cause infertility in 70% of female mice by deleting all isoforms of LEPR specifically in gonadotropes. Our findings implicate activin subunit (InhBa mRNA as a potential leptin target in gonadotropes. We further show gonadotrope-specific upregulation of GnRHR protein (but not mRNA levels following leptin stimulation. In order to try and understand this post-transcriptional regulation, we tested candidate miRNAs (identified with in silico analysis that may be binding the Gnrhr mRNA. We show significant upregulation of one of these miRNAs in our gonadotrope-Lepr-null females. The evidence provided here, combined with our previous work, lay the foundation for metabolically regulated post

A Novel Antagonist of the Immune Checkpoint Protein Adenosine A2a Receptor Restores Tumor-Infiltrating Lymphocyte Activity in the Context of the Tumor Microenvironment

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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.

When Delays Improve Memory: Stabilizing Memory in Children May Require Time.

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Darby, Kevin P; Sloutsky, Vladimir M

2015-12-01

Memory is critical for learning, cognition, and cognitive development. Recent work has suggested that preschool-age children are vulnerable to catastrophic levels of memory interference, in which new learning dramatically attenuates memory for previously acquired knowledge. In the work reported here, we investigated the effects of consolidation on children's memory by introducing a 48-hr delay between learning and testing. In Experiment 1, the delay improved children's memory and eliminated interference. Results of Experiment 2 suggest that the benefit of this delay is limited to situations in which children are given enough information to form complex memory structures. These findings have important implications for understanding consolidation processes and memory development. © The Author(s) 2015.

Levels of Interference in Long and Short-Term Memory Differentially Modulate Non-REM and REM Sleep.

Science.gov (United States)

Fraize, Nicolas; Carponcy, Julien; Joseph, Mickaël Antoine; Comte, Jean-Christophe; Luppi, Pierre-Hervé; Libourel, Paul-Antoine; Salin, Paul-Antoine; Malleret, Gaël; Parmentier, Régis

2016-12-01

It is commonly accepted that sleep is beneficial to memory processes, but it is still unclear if this benefit originates from improved memory consolidation or enhanced information processing. It has thus been proposed that sleep may also promote forgetting of undesirable and non-essential memories, a process required for optimization of cognitive resources. We tested the hypothesis that non-rapid eye movement sleep (NREMS) promotes forgetting of irrelevant information, more specifically when processing information in working memory (WM), while REM sleep (REMS) facilitates the consolidation of important information. We recorded sleep patterns of rats trained in a radial maze in three different tasks engaging either the long-term or short-term storage of information, as well as a gradual level of interference. We observed a transient increase in REMS amount on the day the animal learned the rule of a long-term/reference memory task (RM), and, in contrast, a positive correlation between the performance of rats trained in a WM task involving an important processing of interference and the amount of NREMS or slow wave activity. Various oscillatory events were also differentially modulated by the type of training involved. Notably, NREMS spindles and REMS rapid theta increase with RM training, while sharp-wave ripples increase with all types of training. These results suggest that REMS, but also rapid oscillations occurring during NREMS would be specifically implicated in the long-term memory in RM, whereas NREMS and slow oscillations could be involved in the forgetting of irrelevant information required for WM. © 2016 Associated Professional Sleep Societies, LLC.

Serine/threonine-protein phosphatase 1 α levels are paralleling olfactory memory formation in the CD1 mouse.

Science.gov (United States)

Winding, Christiana; Sun, Yanwei; Höger, Harald; Bubna-Littitz, Hermann; Pollak, Arnold; Schmidt, Peter; Lubec, Gert

2011-06-01

Although olfactory discrimination has already been studied in several mouse strains, data on protein levels linked to olfactory memory are limited. Wild mouse strains Mus musculus musculus, Mus musculus domesticus and CD1 laboratory outbred mice were tested in a conditioned odor preference task and trained to discriminate between two odors, Rose and Lemon, by pairing one odor with a sugar reward. Six hours following the final test, mice were sacrificed and olfactory bulbs (OB) were taken for gel-based proteomics analyses and immunoblotting. OB proteins were extracted, separated by 2-DE and quantified using specific software (Proteomweaver). Odor-trained mice showed a preference for the previously rewarded odor suggesting that conditioned odor preference occurred. In CD1 mice levels, one out of 482 protein spots was significantly increased in odor-trained mice as compared with the control group; it was in-gel digested by trypsin and chymotrypsin and analyzed by tandem mass spectrometry (nano-ESI-LC-MS/MS). The spot was unambiguously identified as serine/threonine-protein phosphatase PP1-α catalytic subunit (PP-1A) and differential levels observed in gel-based proteomic studies were verified by immunoblotting. PP-1A is a key signalling element in synaptic plasticity and memory processes and is herein shown to be paralleling olfactory discrimination representing olfactory memory. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Effects of attention and levels of processing on explicit and implicit memory function with interesting and unteresting tasks in university students

OpenAIRE

Mahdavian, Alireza; Kormi-Nouri, Reza

2008-01-01

This study aims to investigate the effect of attention and levels of processing on memory function and recalling words in two situations when students are interested in the subject and when they are not. This is an experimental study of 160 students conducted individually using a computer software. Results reveal focused attention, interest in the subject and deep processing caused the explicit memory to be at its highest level of functionality. On the contrary, shallow processing, divided at...

Moderate variations in CDC25B protein levels modulate the response to DNA damaging agents

International Nuclear Information System (INIS)

Aressy, B.; Bugler, B.; Valette, A.; Ducommun, B.; Biard, D.

2008-01-01

CDC25B, one of the three members of the CDC25 dual-specificity phosphatase family, plays a critical role in the control of the cell cycle and in the checkpoint response to DNA damage. CDC25B is responsible for the initial dephosphorylation and activation of the cyclin-dependent kinases, thus initiating the train of events leading to entry into mitosis. The critical role played by CDC25B is illustrated by the fact that it is specifically required for checkpoint recovery and that unscheduled accumulation of CDC25B is responsible for illegitimate entry into mitosis. Here, we report that in p53 colon carcinoma cells, a moderate increase in the CDC25B level is sufficient to impair the DNA damage checkpoint, to increase spontaneous mutagenesis, and to sensitize cells to ionising radiation and genotoxic agents. Using a tumour cell spheroid assay as an alternative to animal studies, we demonstrate that the level of CDC25B expression modulates growth inhibition and apoptotic death. Since CDC25B overexpression has been observed in a significant number of human cancers, including colon carcinoma, and is often associated with high grade tumours and poor prognosis, our work suggests that the expression level of CDC25B might be a potential key parameter of the cellular response to cancer therapy. (authors)

Working memory predicts the rejection of false memories.

Science.gov (United States)

Leding, Juliana K

2012-01-01

The relationship between working memory capacity (WMC) and false memories in the memory conjunction paradigm was explored. Previous research using other paradigms has shown that individuals high in WMC are not as likely to experience false memories as low-WMC individuals, the explanation being that high-WMC individuals are better able to engage in source monitoring. In the memory conjunction paradigm participants are presented at study with parent words (e.g., eyeglasses, whiplash). At test, in addition to being presented with targets and foils, participants are presented with lures that are composed of previously studied features (e.g., eyelash). It was found that high-WMC individuals had lower levels of false recognition than low-WMC individuals. Furthermore, recall-to-reject responses were analysed (e.g., "I know I didn't see eyelash because I remember seeing eyeglasses") and it was found that high-WMC individuals were more likely to utilise this memory editing strategy, providing direct evidence that one reason that high-WMC individuals are not as prone to false memories is because they are better able to engage in source monitoring.

Longitudinal Associations of Subjective Memory with Memory Performance and Depressive Symptoms: Between-Person and Within-Person Perspectives

Science.gov (United States)

Hülür, Gizem; Hertzog, Christopher; Pearman, Ann; Ram, Nilam; Gerstorf, Denis

2015-01-01

Clinical diagnostic criteria for memory loss in adults typically assume that subjective memory ratings accurately reflect compromised memory functioning. Research has documented small positive between-person associations between subjective memory and memory performance in older adults. Less is known, however, about whether within-person fluctuations in subjective memory covary with within-person variance in memory performance and depressive symptoms. The present study applied multilevel models of change to nine waves of data from 27,395 participants of the Health and Retirement Study (HRS; mean age at baseline = 63.78; SD = 10.30; 58% women) to examine whether subjective memory is associated with both between-person differences and within-person variability in memory performance and depressive symptoms and explored the moderating role of known correlates (age, gender, education, and functional limitations). Results revealed that across persons, level of subjective memory indeed covaried with level of memory performance and depressive symptoms, with small-to-moderate between-person standardized effect sizes (0.19 for memory performance and 0.21 for depressive symptoms). Within individuals, occasions when participants scored higher than usual on a test of episodic memory or reported fewer-than-average depressive symptoms generated above-average subjective memory. At the within-person level, subjective memory ratings became more sensitive to within-person alterations in memory performance over time and those suffering from functional limitations were more sensitive to within-person alterations in memory performance and depressive symptoms. We take our results to suggest that within-person changes in subjective memory in part reflect monitoring flux in one’s own memory functioning, but are also influenced by flux in depressive symptoms. PMID:25244464

Longitudinal associations of subjective memory with memory performance and depressive symptoms: between-person and within-person perspectives.

Science.gov (United States)

Hülür, Gizem; Hertzog, Christopher; Pearman, Ann; Ram, Nilam; Gerstorf, Denis

2014-12-01

Clinical diagnostic criteria for memory loss in adults typically assume that subjective memory ratings accurately reflect compromised memory functioning. Research has documented small positive between-person associations between subjective memory and memory performance in older adults. Less is known, however, about whether within-person fluctuations in subjective memory covary with within-person variance in memory performance and depressive symptoms. The present study applied multilevel models of change to 9 waves of data from 27,395 participants of the Health and Retirement Study (HRS; mean age at baseline = 63.78; SD = 10.30; 58% women) to examine whether subjective memory is associated with both between-person differences and within-person variability in memory performance and depressive symptoms and explored the moderating role of known correlates (age, gender, education, and functional limitations). Results revealed that across persons, level of subjective memory indeed covaried with level of memory performance and depressive symptoms, with small-to-moderate between-person standardized effect sizes (0.19 for memory performance and -0.21 for depressive symptoms). Within individuals, occasions when participants scored higher than usual on a test of episodic memory or reported fewer-than-average depressive symptoms generated above-average subjective memory. At the within-person level, subjective memory ratings became more sensitive to within-person alterations in memory performance over time and those suffering from functional limitations were more sensitive to within-person alterations in memory performance and depressive symptoms. We take our results to suggest that within-person changes in subjective memory in part reflect monitoring flux in one's own memory functioning, but are also influenced by flux in depressive symptoms. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

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

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

A non-destructive crossbar architecture of multi-level memory-based resistor

Science.gov (United States)

Sahebkarkhorasani, Seyedmorteza

Nowadays, researchers are trying to shrink the memory cell in order to increase the capacity of the memory system and reduce the hardware costs. In recent years, there has been a revolution in electronics by using fundamentals of physics to build a new memory for computer application in order to increase the capacity and decrease the power consumption. Increasing the capacity of the memory causes a growth in the chip area. From 1971 to 2012 semiconductor manufacturing process improved from 6mum to 22 mum. In May 2008, S.Williams stated that "it is time to stop shrinking". In his paper, he declared that the process of shrinking memory element has recently become very slow and it is time to use another alternative in order to create memory elements [9]. In this project, we present a new design of a memory array using the new element named Memristor [3]. Memristor is a two-terminal passive electrical element that relates the charge and magnetic flux to each other. The device remained unknown since 1971 when it was discovered by Chua and introduced as the fourth fundamental passive element like capacitor, inductor and resistor [3]. Memristor has a dynamic resistance and it can retain its previous value even after disconnecting the power supply. Due to this interesting behavior of the Memristor, it can be a good replacement for all of the Non-Volatile Memories (NVMs) in the near future. Combination of this newly introduced element with the nanowire crossbar architecture would be a great structure which is called Crossbar Memristor. Some frameworks have recently been introduced in literature that utilized Memristor crossbar array, but there are many challenges to implement the Memristor crossbar array due to fabrication and device limitations. In this work, we proposed a simple design of Memristor crossbar array architecture which uses input feedback in order to preserve its data after each read operation.

Fluidity in autobiographical memories: relationship memories sampled on two occasions.

Science.gov (United States)

Drivdahl, Sarah B; Hyman, Ira E

2014-01-01

We investigated consistency of relationship memories. College undergraduates described five events (first meeting, first date, first fight, most embarrassing event, and favourite memory) from their current relationship or, if not currently dating, most recent relationship. Three months later, they were asked to describe the same events again. We scored the consistency of these narratives at three levels of analysis: event, basic information and propositions. The participants demonstrated low consistency in their descriptions, particularly at more detailed levels of analysis. Consistency depended somewhat on the events being recalled, with participants being more consistent for commonly retrieved relationship memories such as first dates. We also found that those individuals who continued in a relationship were less consistent than those describing a previous relationship. These still dating couples had increased opportunities to narrate event stories together and to update knowledge about the relationship through new episodes. In this fashion, updating of experiences may have led to more inconsistencies in recall over time. When considered with research on flashbulb memories, our findings indicate that updating and revisions may be general features of autobiographical memory.

Gender differences in episodic memory and visual working memory including the effects of age.

Science.gov (United States)

Pauls, Franz; Petermann, Franz; Lepach, Anja Christina

2013-01-01

Analysing the relationship between gender and memory, and examining the effects of age on the overall memory-related functioning, are the ongoing goals of psychological research. The present study examined gender and age group differences in episodic memory with respect to the type of task. In addition, these subgroup differences were also analysed in visual working memory. A sample of 366 women and 330 men, aged between 16 and 69 years of age, participated in the current study. Results indicate that women outperformed men on auditory memory tasks, whereas male adolescents and older male adults showed higher level performances on visual episodic and visual working memory measures. However, the size of gender-linked effects varied somewhat across age groups. Furthermore, results partly support a declining performance on episodic memory and visual working memory measures with increasing age. Although age-related losses in episodic memory could not be explained by a decreasing verbal and visuospatial ability with age, women's advantage in auditory episodic memory could be explained by their advantage in verbal ability. Men's higher level visual episodic memory performance was found to result from their advantage in visuospatial ability. Finally, possible methodological, biological, and cognitive explanations for the current findings are discussed.

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...

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.

The Use of Dual Task Paradigms in Memory Research: A Methodological Assessment and an Evaluation of Effort as a Measure of Levels of Processing.

Science.gov (United States)

1982-03-01

sustained monitoring tasks. Human Factors, 1979, 21, 647-653. Craik , F. I. M., & Lockhart , R. Levels of processing : A framework for memory research...original levels approach to human memory ( Craik & Lockhart , 1972) contended that verbal stimuli could be classified along a continuum ranging from...AND AN EVALUATION OF EFFORT AS A MEASURr OF LEVELS OF PROCESSING Arthur D. Fisk, William L. Derrick, and Walter Schneider REPORT HARL-ONR-8105 E. C

Reading Comprehension, Working Memory and Higher-Level Language Skills in Children with SLI and/or Dyslexia

Science.gov (United States)

Wong, Anita M.-Y.; Ho, Connie S.-H.; Au, Terry K.-F.; McBride, Catherine; Ng, Ashley K.-H.; Yip, Lesley P.-W.; Lam, Catherine C.-C.

2017-01-01

This study examined (1) whether working memory and higher-level languages skills--inferencing and comprehension monitoring--accounted for individual differences among Chinese children in Chinese reading comprehension, after controlling for age, Chinese word reading and oral language skills, and (2) whether children with specific language…

Electrically-controlled nonlinear switching and multi-level storage characteristics in WOx film-based memory cells

Science.gov (United States)

Duan, W. J.; Wang, J. B.; Zhong, X. L.

2018-05-01

Resistive switching random access memory (RRAM) is considered as a promising candidate for the next generation memory due to its scalability, high integration density and non-volatile storage characteristics. Here, the multiple electrical characteristics in Pt/WOx/Pt cells are investigated. Both of the nonlinear switching and multi-level storage can be achieved by setting different compliance current in the same cell. The correlations among the current, time and temperature are analyzed by using contours and 3D surfaces. The switching mechanism is explained in terms of the formation and rupture of conductive filament which is related to oxygen vacancies. The experimental results show that the non-stoichiometric WOx film-based device offers a feasible way for the applications of oxide-based RRAMs.

Habitat stability, predation risk and 'memory syndromes'.

Science.gov (United States)

Dalesman, S; Rendle, A; Dall, S R X

2015-05-27

Habitat stability and predation pressure are thought to be major drivers in the evolutionary maintenance of behavioural syndromes, with trait covariance only occurring within specific habitats. However, animals also exhibit behavioural plasticity, often through memory formation. Memory formation across traits may be linked, with covariance in memory traits (memory syndromes) selected under particular environmental conditions. This study tests whether the pond snail, Lymnaea stagnalis, demonstrates consistency among memory traits ('memory syndrome') related to threat avoidance and foraging. We used eight populations originating from three different habitat types: i) laboratory populations (stable habitat, predator-free); ii) river populations (fairly stable habitat, fish predation); and iii) ditch populations (unstable habitat, invertebrate predation). At a population level, there was a negative relationship between memories related to threat avoidance and food selectivity, but no consistency within habitat type. At an individual level, covariance between memory traits was dependent on habitat. Laboratory populations showed no covariance among memory traits, whereas river populations showed a positive correlation between food memories, and ditch populations demonstrated a negative relationship between threat memory and food memories. Therefore, selection pressures among habitats appear to act independently on memory trait covariation at an individual level and the average response within a population.

Attention, working memory, and phenomenal experience of WM content: memory levels determined by different types of top-down modulation

OpenAIRE

Jacob, Jane; Jacobs, Christianne; Silvanto, Juha

2015-01-01

What is the role of top-down attentional modulation in consciously accessing working memory (WM) content? In influential WM models, information can exist in different states, determined by allocation of attention; placing the original memory representation in the center of focused attention gives rise to conscious access. Here we discuss various lines of evidence indicating that such attentional modulation is not sufficient for memory content to be phenomenally experienced. We propose that, i...

Iconic memory requires attention.

Science.gov (United States)

Persuh, Marjan; Genzer, Boris; Melara, Robert D

2012-01-01

Two experiments investigated whether attention plays a role in iconic memory, employing either a change detection paradigm (Experiment 1) or a partial-report paradigm (Experiment 2). In each experiment, attention was taxed during initial display presentation, focusing the manipulation on consolidation of information into iconic memory, prior to transfer into working memory. Observers were able to maintain high levels of performance (accuracy of change detection or categorization) even when concurrently performing an easy visual search task (low load). However, when the concurrent search was made difficult (high load), observers' performance dropped to almost chance levels, while search accuracy held at single-task levels. The effects of attentional load remained the same across paradigms. The results suggest that, without attention, participants consolidate in iconic memory only gross representations of the visual scene, information too impoverished for successful detection of perceptual change or categorization of features.

Iconic memory requires attention

Directory of Open Access Journals (Sweden)

Marjan ePersuh

2012-05-01

Full Text Available Two experiments investigated whether attention plays a role in iconic memory, employing either a change-detection paradigm (Experiment 1 or a partial-report paradigm (Experiment 2. In each experiment, attention was taxed during initial display presentation, focusing the manipulation on consolidation of information into iconic memory, prior to transfer into working memory. Observers were able to maintain high levels of performance (accuracy of change detection or categorization even when concurrently performing an easy visual search task (low load. However, when the concurrent search was made difficult (high load, observers’ performance dropped to almost chance levels, while search accuracy held at single-task levels. The effects of attentional load remained the same across paradigms. The results suggest that, without attention, participants consolidate in iconic memory only gross representations of the visual scene, information too impoverished for successful detection of perceptual change or categorization of features.

In vivo evaluation of the hippocampal glutamate, GABA and the BDNF levels associated with spatial memory performance in a rodent model of neuropathic pain.

Science.gov (United States)

Saffarpour, S; Shaabani, M; Naghdi, N; Farahmandfar, M; Janzadeh, A; Nasirinezhad, F

2017-06-01

Patients with chronic pain usually suffer from learning and memory impairment which may significantly decrease their quality of life. Despite laboratory and clinical studies, the mechanism underlying this memory impairment remains elusive. We evaluated the effect of chronic pain on the glutamate and GABA levels and BDNF expression in the CA1 region of hippocampus as a possible explanation for memory impairment related to neuropathic pain. In this respect, 30 male rats were randomly allocated to 3 groups as control, sham and neuropathic. Neuropathic pain was induced by a chronic constriction injury of the sciatic nerve (CCI) and mechanical allodynia and the spatial memory was assessed using the Von Frey filaments and Morris water maze respectively. To determine the potential mechanisms, the in vivo extracellular levels of glutamate and γ-aminobutyric acid (GABA) were measured by microdialysis and the brain-derived neurotrophic factor (BDNF) expression was determined by using western blots technique in the hippocampus on days 14 and 21 post-CCI. We showed that CCI impaired spatial learning and memory in Morris water maze (MWM) task. BDNF expression level and glutamate concentration significantly decreased in rats with chronic constriction injury of the sciatic nerve (PGABA increased in hippocampal CA1 region (PGABA concentration and decrease in the glutamate and BDNF levels in the CA1 region of the hippocampus. Copyright © 2017 Elsevier Inc. All rights reserved.

Examining Differences in the Levels of False Memories in Children and Adults Using Child-Normed Lists

Science.gov (United States)

Anastasi, Jeffrey S.; Rhodes, Matthew G.

2008-01-01

Several previous studies have demonstrated that children, when compared with adults, exhibit both lower levels of veridical memory and fewer intrusions when given semantically associated lists. However, researchers have drawn these conclusions using semantically associated word lists that were normed with adults, which may not lead to the same…

Reviewing the Role of Cognitive Load, Expertise Level, Motivation, and Unconscious Processing in Working Memory Performance

Science.gov (United States)

Kuldas, Seffetullah; Hashim, Shahabuddin; Ismail, Hairul Nizam; Abu Bakar, Zainudin

2015-01-01

Human cognitive capacity is unavailable for conscious processing of every amount of instructional messages. Aligning an instructional design with learner expertise level would allow better use of available working memory capacity in a cognitive learning task. Motivating students to learn consciously is also an essential determinant of the capacity…

Prognostic utility of baseline neutrophil-to-lymphocyte ratio in patients receiving immune checkpoint inhibitors: a review and meta-analysis

Directory of Open Access Journals (Sweden)

Sacdalan DB

2018-02-01

Full Text Available Danielle Benedict Sacdalan,1 Josephine Anne Lucero,2 Dennis Lee Sacdalan1 1Section of Medical Oncology, Department of Medicine, University of the Philippines Manila and Philippine General Hospital, Manila, Philippines; 2Department of Medicine, University of the Philippines Manila and Philippine General Hospital, Manila, Philippines Introduction: Systemic inflammation is associated with prognosis in solid tumors. The neutrophil-to-lymphocyte ratio (NLR is a marker for the general immune response to various stress stimuli. Studies have shown correlation of NLR to outcomes in immune checkpoint blockade, peripheral neutrophil count to intratumor neutrophil population, and NLR to intratumoral levels of myeloid-derived suppressor cells. Studies have shown elevated peripheral blood regulator T cells accompanied by elevated NLR are associated with poor outcomes further highlighting the importance of inflammation in the prognosis of cancer patients.Methods: We performed a meta-analysis of published articles on the utility of baseline NLR in predicting outcomes in patients treated with immune checkpoint inhibitors (ICIs using Review Manager, version 5.3. Seven studies on the prognostic utility of NLR in ICI treatment were included in this analysis. For outcomes of interest, the hazard ratios (HRs were computed. Subgroup analyses were planned based on type of malignancy and type of immune checkpoint inhibitor.Results/discussion: A high NLR resulted in worse overall survival (OS (HR, 1.92; 95% CI, 1.29–2.87; p=0.001 and progression-free survival (PFS; HR, 1.66; 95% CI, 1.38–2.01; p<0.00001 across types of malignancies studied (melanoma, non-small-cell lung cancer, and genitourinary cancer. Subgroup analysis across different types of malignancies treated with ICI showed similar results for OS and PFS. The single study on genitourinary cancers also showed worse OS and PFS (OS: HR, 1.82; 95% CI, 1.29–2.87; p=0.001 and PFS: HR, 1.83; 95% CI, 0.97–3

The accuracy of survival time prediction for patients with glioma is improved by measuring mitotic spindle checkpoint gene expression.

Directory of Open Access Journals (Sweden)

Li Bie

Full Text Available Identification of gene expression changes that improve prediction of survival time across all glioma grades would be clinically useful. Four Affymetrix GeneChip datasets from the literature, containing data from 771 glioma samples representing all WHO grades and eight normal brain samples, were used in an ANOVA model to screen for transcript changes that correlated with grade. Observations were confirmed and extended using qPCR assays on RNA derived from 38 additional glioma samples and eight normal samples for which survival data were available. RNA levels of eight major mitotic spindle assembly checkpoint (SAC genes (BUB1, BUB1B, BUB3, CENPE, MAD1L1, MAD2L1, CDC20, TTK significantly correlated with glioma grade and six also significantly correlated with survival time. In particular, the level of BUB1B expression was highly correlated with survival time (p<0.0001, and significantly outperformed all other measured parameters, including two standards; WHO grade and MIB-1 (Ki-67 labeling index. Measurement of the expression levels of a small set of SAC genes may complement histological grade and other clinical parameters for predicting survival time.

Calreticulin reveals a critical Ca2+ checkpoint in cardiac myofibrillogenesis

Science.gov (United States)

Li, Jian; Pucéat, Michel; Perez-Terzic, Carmen; Mery, Annabelle; Nakamura, Kimitoshi; Michalak, Marek; Krause, Karl-Heinz; Jaconi, Marisa E.

2002-01-01

Calreticulin (crt) is an ubiquitously expressed and multifunctional Ca2+-binding protein that regulates diverse vital cell functions, including Ca2+ storage in the ER and protein folding. Calreticulin deficiency in mice is lethal in utero due to defects in heart development and function. Herein, we used crt − / − embryonic stem (ES) cells differentiated in vitro into cardiac cells to investigate the molecular mechanisms underlying heart failure of knockout embryos. After 8 d of differentiation, beating areas were prominent in ES-derived wild-type (wt) embryoid bodies (EBs), but not in ES-derived crt − / − EBs, despite normal expression levels of cardiac transcription factors. Crt − / − EBs exhibited a severe decrease in expression and a lack of phosphorylation of ventricular myosin light chain 2 (MLC2v), resulting in an impaired organization of myofibrils. Crt − / − phenotype could be recreated in wt cells by chelating extracellular or cytoplasmic Ca2+ with EGTA or BAPTA, or by inhibiting Ca2+/calmodulin-dependent kinases (CaMKs). An imposed ionomycin-triggered cystolic-free Ca2+ concentration ([Ca2+]c) elevation restored the expression, phosphorylation, and insertion of MLC2v into sarcomeric structures and in turn the myofibrillogenesis. The transcription factor myocyte enhancer factor C2 failed to accumulate into nuclei of crt − / − cardiac cells in the absence of ionomycin-triggered [Ca2+]c increase. We conclude that the absence of calreticulin interferes with myofibril formation. Most importantly, calreticulin deficiency revealed the importance of a Ca2+-dependent checkpoint critical for early events during cardiac myofibrillogenesis. PMID:12105184

Bilingual recognition memory: stronger performance but weaker levels-of-processing effects in the less fluent language.

Science.gov (United States)

Francis, Wendy S; Gutiérrez, Marisela

2012-04-01

The effects of bilingual proficiency on recognition memory were examined in an experiment with Spanish-English bilinguals. Participants learned lists of words in English and Spanish under shallow- and deep-encoding conditions. Overall, hit rates were higher, discrimination greater, and response times shorter in the nondominant language, consistent with effects previously observed for lower frequency words. Levels-of-processing effects in hit rates, discrimination, and response time were stronger in the dominant language. Specifically, with shallow encoding, the advantage for the nondominant language was larger than with deep encoding. The results support the idea that memory performance in the nondominant language is impacted by both the greater demand for cognitive resources and the lower familiarity of the words.

[The effect of encoding on false memory: examination on levels of processing and list presentation format].

Science.gov (United States)

Hamajima, Hideki

2004-04-01

Using the Deese/Roediger-McDermott paradigm, the effects of lists presentation format (blocked/random) and levels of processing of critical nonpresented lures were examined. A levels-of-processing effect in a blocked presentation order was not observed for lures. Rates of false recognition and remember judgments for lures in a shallow level of processing were significantly lower than those in a deep level of processing when items from various themes were inter-mixed instead of blocked. Results showed an interaction between levels of processing and list presentation format. It is thus concluded that encoding of each word and whole list should be both considered in understanding false memory.

Are memories for sexually traumatic events "special"? A within-subjects investigation of trauma and memory in a clinical sample.

Science.gov (United States)

Peace, Kristine A; Porter, Stephen; ten Brinke, Leanne

2008-01-01

According to a long-standing clinical tradition, sexually traumatic experiences are processed and recalled differently from other experiences, often leading to memory impairment. In this study, we compared the characteristics of traumatic memories for sexual violence and two other types of emotional experiences. N=44 women recruited from a local sexual trauma agency were asked to recall and describe three autobiographical events: sexual abuse/assault, a non-sexual trauma, and a positive emotional event. The characteristics of the three memory types were compared on both subjective and objective measures. Further, the potential influences of level of traumatic impact and dissociation were assessed. Results indicated that memories for sexual trauma were not impaired or fragmented relative to other memories. Instead, memories for sexual trauma were associated with a remarkably high level of vividness, detail, and sensory components. Further, high levels of traumatic impact were not associated with memory impairment. Implications for the ongoing traumatic memory debate are discussed.

Verbal short-term memory in Down syndrome: a problem of memory, audition, or speech?

Science.gov (United States)

Jarrold, Christopher; Baddeley, Alan D; Phillips, Caroline E

2002-06-01

The current study explored three possible explanations of poor verbal short-term memory performance among individuals with Down syndrome in an attempt to determine whether the condition is associated with a fundamental verbal short-term memory deficit. The short-term memory performance of a group of 19 children and young adults with Down syndrome was contrasted with that of two control groups matched for level of receptive vocabulary. The specificity of a deficit was assessed by comparing memory for verbal and visuo-spatial information. The effect of auditory problems on performance was examined by contrasting memory for auditorily presented material with that for material presented both auditorily and visually. The influence of speech-motor difficulties was investigated by employing both a traditional recall procedure and a serial recognition procedure that reduced spoken response demands. Results confirmed that individuals with Down syndrome do show impaired verbal short-term memory performance for their level of receptive vocabulary. The findings also indicated that this deficit is specific to memory for verbal information and is not primarily caused by auditory or speech-production difficulties.

[The Brumory test, an incidental long-term memory task designed for foreign, non-French-speaking people with low educational level].

Science.gov (United States)

Vanderaspoilden, V; Nury, D; Frisque, J; Peigneux, P

2015-12-01

Cognitive assessment among foreign patients is a growing need for several reasons: foreign patients have a different culture, they have an insufficient command of the language of the consulting center, and the available cognitive tools are largely unsuitable. For these reasons, we developed a non-verbal test of long-term memory called the Brumory test. This test is based on incident encoding of 48 colored images followed by retrieval by recognition. We compared the performance of indigenous participants with that of immigrant participants (mainly from Morocco). Immigrant participants did not speak French properly and had a low educational level. The results indicate no significant difference in memory performance between the two groups of participants. Moreover, the instructions were easily understood by immigrant participants, despite the fact they do not master French. We conclude that the Brumory test is an appropriate test to assess memory among foreign non-French-speaking patients people with low educational level. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Does Controlling for Temporal Parameters Change the Levels-of-Processing Effect in Working Memory?

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Loaiza, Vanessa M; Camos, Valérie

2016-01-01

The distinguishability between working memory (WM) and long-term memory has been a frequent and long-lasting source of debate in the literature. One recent method of identifying the relationship between the two systems has been to consider the influence of long-term memory effects, such as the levels-of-processing (LoP) effect, in WM. However, the few studies that have examined the LoP effect in WM have shown divergent results. This study examined the LoP effect in WM by considering a theoretically meaningful methodological aspect of the LoP span task. Specifically, we fixed the presentation duration of the processing component a priori because such fixed complex span tasks have shown differences when compared to unfixed tasks in terms of recall from WM as well as the latent structure of WM. After establishing a fixed presentation rate from a pilot study, the LoP span task presented memoranda in red or blue font that were immediately followed by two processing words that matched the memoranda in terms of font color or semantic relatedness. On presentation of the processing words, participants made deep or shallow processing decisions for each of the memoranda before a cue to recall them from WM. Participants also completed delayed recall of the memoranda. Results indicated that LoP affected delayed recall, but not immediate recall from WM. These results suggest that fixing temporal parameters of the LoP span task does not moderate the null LoP effect in WM, and further indicate that WM and long-term episodic memory are dissociable on the basis of LoP effects.

The tumor suppressor homolog in fission yeast, myh1{sup +}, displays a strong interaction with the checkpoint gene rad1{sup +}

Energy Technology Data Exchange (ETDEWEB)

Jansson, Kristina; Warringer, Jonas; Farewell, Anne [Department of Cell and Molecular Biology, Lundberg Laboratory, Goeteborg University, P.O. Box 462, Goeteborg SE-405 30 (Sweden); Park, Han-Oh [Bioneer Corporation, 49-3, Munpyeong-dong, Daedeok-gu, Daejon 306-220 (Korea, Republic of); Hoe, Kwang-Lae; Kim, Dong-Uk [Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yusong, Daejeon (Korea, Republic of); Hayles, Jacqueline [Cell Cycle Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln' s Inn Fields, London WC2A 3PX (United Kingdom); Sunnerhagen, Per [Department of Cell and Molecular Biology, Lundberg Laboratory, Goeteborg University, P.O. Box 462, Goeteborg SE-405 30 (Sweden)], E-mail: per.sunnerhagen@cmb.gu.se

2008-09-26

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{sup +}, 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.

Acetylation-mediated suppression of transcription-independent memory: bidirectional modulation of memory by acetylation.

Directory of Open Access Journals (Sweden)

Katja Merschbaecher

Full Text Available Learning induced changes in protein acetylation, mediated by histone acetyl transferases (HATs, and the antagonistic histone deacetylases (HDACs play a critical role in memory formation. The status of histone acetylation affects the interaction between the transcription-complex and DNA and thus regulates transcription-dependent processes required for long-term memory (LTM. While the majority of studies report on the role of elevated acetylation in memory facilitation, we address the impact of both, increased and decreased acetylation on formation of appetitive olfactory memory in honeybees. We show that learning-induced changes in the acetylation of histone H3 at aminoacid-positions H3K9 and H3K18 exhibit distinct and different dynamics depending on the training strength. A strong training that induces LTM leads to an immediate increase in acetylation at H3K18 that stays elevated for hours. A weak training, not sufficient to trigger LTM, causes an initial increase in acetylation at H3K18, followed by a strong reduction in acetylation at H3K18 below the control group level. Acetylation at position H3K9 is not affected by associative conditioning, indicating specific learning-induced actions on the acetylation machinery. Elevating acetylation levels by blocking HDACs after conditioning leads to an improved memory. While memory after strong training is enhanced for at least 2 days, the enhancement after weak training is restricted to 1 day. Reducing acetylation levels by blocking HAT activity after strong training leads to a suppression of transcription-dependent LTM. The memory suppression is also observed in case of weak training, which does not require transcription processes. Thus, our findings demonstrate that acetylation-mediated processes act as bidirectional regulators of memory formation that facilitate or suppress memory independent of its transcription-requirement.

Interactions of checkpoint-genes RAD9, RAD17, RAD24 and RAD53 determining radioresistance of Yeast Saccharomyces Cerevisiae

International Nuclear Information System (INIS)

Koltovaya, N.A.; Nikulushkina, Yu.V.; Roshchina, M.P.; Devin, A.B.

2007-01-01

The mechanisms of genetic control of progress through the division cell cycle (checkpoint-control) in yeast Saccharomyces cerevisiae have been studied intensively. To investigate the role of checkpoint-genes RAD9, RAD17, RAD24, RAD53 in cell radioresistance we have investigated cell sensitivity of double mutants to γ-ray. Double mutants involving various combinations with rad9Δ show epistatic interactions, i.e. the sensitivity of the double mutants to γ-ray was no greater than that of more sensitive of the two single mutants. This suggests that all these genes govern the same pathway. This group of genes was named RAD9-epistasis group. It is interesting to note that the genes RAD9 and RAD53 have positive effect but RAD17 and RAD24 have negative effect on radiosensitivity of yeast cells. Interactions between mutations may differ depending on the agent γ-ray or UV-light, for example mutations rad9Δ and rad24Δ show additive effect for γ-ray and epistatic effect for UV-light

Coherence across consciousness levels: Symmetric visual displays spare working memory resources.

Science.gov (United States)

Dumitru, Magda L

2015-12-15

Two studies demonstrate that the need for coherence could nudge individuals to use structural similarities between binary visual displays and two concurrent cognitive tasks to unduly solve the latter in similar fashion. In an overt truth-judgement task, participants decided whether symmetric colourful displays matched conjunction or disjunction descriptions (e.g., "the black and/or the orange"). In the simultaneous covert categorisation task, they decided whether a colour name (e.g., "black") described a two-colour object or half of a single-colour object. Two response patterns emerged as follows. Participants either acknowledged or rejected matches between disjunction descriptions and two visual stimuli and, similarly, either acknowledged or rejected matches between single colour names and two-colour objects or between single colour names and half of single-colour objects. These findings confirm the coherence hypothesis, highlight the role of coherence in preserving working-memory resources, and demonstrate an interaction between high-level and low-level consciousness. Copyright © 2015 Elsevier Inc. All rights reserved.

Fault isolation through no-overhead link level CRC

Science.gov (United States)

Chen, Dong; Coteus, Paul W.; Gara, Alan G.

2007-04-24

A fault isolation technique for checking the accuracy of data packets transmitted between nodes of a parallel processor. An independent crc is kept of all data sent from one processor to another, and received from one processor to another. At the end of each checkpoint, the crcs are compared. If they do not match, there was an error. The crcs may be cleared and restarted at each checkpoint. In the preferred embodiment, the basic functionality is to calculate a CRC of all packet data that has been successfully transmitted across a given link. This CRC is done on both ends of the link, thereby allowing an independent check on all data believed to have been correctly transmitted. Preferably, all links have this CRC coverage, and the CRC used in this link level check is different from that used in the packet transfer protocol. This independent check, if successfully passed, virtually eliminates the possibility that any data errors were missed during the previous transfer period.

Frontal cortex and hippocampus neurotransmitter receptor complex level parallels spatial memory performance in the radial arm maze.

Science.gov (United States)

Shanmugasundaram, Bharanidharan; Sase, Ajinkya; Miklosi, András G; Sialana, Fernando J; Subramaniyan, Saraswathi; Aher, Yogesh D; Gröger, Marion; Höger, Harald; Bennett, Keiryn L; Lubec, Gert

2015-08-01

Several neurotransmitter receptors have been proposed to be involved in memory formation. However, information on receptor complexes (RCs) in the radial arm maze (RAM) is missing. It was therefore the aim of this study to determine major neurotransmitter RCs levels that are modulated by RAM training because receptors are known to work in homo-or heteromeric assemblies. Immediate early gene Arc expression was determined by immunohistochemistry to show if prefrontal cortices (PFC) and hippocampi were activated following RAM training as these regions are known to be mainly implicated in spatial memory. Twelve rats per group, trained and untrained in the twelve arm RAM were used, frontal cortices and hippocampi were taken, RCs in membrane protein were quantified by blue-native PAGE immunoblotting. RCs components were characterised by co-immunoprecipitation followed by mass spectrometrical analysis and by the use of the proximity ligation assay. Arc expression was significantly higher in PFC of trained as compared to untrained rats whereas it was comparable in hippocampi. Frontal cortical levels of RCs containing AMPA receptors GluA1, GluA2, NMDA receptors GluN1 and GluN2A, dopamine receptor D1, acetylcholine nicotinic receptor alpha 7 (nAChR-α7) and hippocampal levels of RCs containing D1, GluN1, GluN2B and nAChR-α7 were increased in the trained group; phosphorylated dopamine transporter levels were decreased in the trained group. D1 and GluN1 receptors were shown to be in the same complex. Taken together, distinct RCs were paralleling performance in the RAM which is relevant for interpretation of previous and design of future work on RCs in memory studies. Copyright © 2015 Elsevier B.V. All rights reserved.

System level mechanisms of adaptation, learning, memory formation and evolvability: the role of chaperone and other networks.

Science.gov (United States)

Gyurko, David M; Soti, Csaba; Stetak, Attila; Csermely, Peter

2014-05-01

During the last decade, network approaches became a powerful tool to describe protein structure and dynamics. Here, we describe first the protein structure networks of molecular chaperones, then characterize chaperone containing sub-networks of interactomes called as chaperone-networks or chaperomes. We review the role of molecular chaperones in short-term adaptation of cellular networks in response to stress, and in long-term adaptation discussing their putative functions in the regulation of evolvability. We provide a general overview of possible network mechanisms of adaptation, learning and memory formation. We propose that changes of network rigidity play a key role in learning and memory formation processes. Flexible network topology provides ' learning-competent' state. Here, networks may have much less modular boundaries than locally rigid, highly modular networks, where the learnt information has already been consolidated in a memory formation process. Since modular boundaries are efficient filters of information, in the 'learning-competent' state information filtering may be much smaller, than after memory formation. This mechanism restricts high information transfer to the 'learning competent' state. After memory formation, modular boundary-induced segregation and information filtering protect the stored information. The flexible networks of young organisms are generally in a 'learning competent' state. On the contrary, locally rigid networks of old organisms have lost their 'learning competent' state, but store and protect their learnt information efficiently. We anticipate that the above mechanism may operate at the level of both protein-protein interaction and neuronal networks.

Running throughout middle-age improves memory function, hippocampal neurogenesis and BDNF levels in female C57Bl/6J mice.

NARCIS (Netherlands)

Marlatt, M.W.; Potter, M.C.; Lucassen, P.J.; van Praag, H.

2012-01-01

Age-related memory loss is considered to commence at middle-age and coincides with reduced adult hippocampal neurogenesis and neurotrophin levels. Consistent physical activity at midlife may preserve brain-derived neurotrophic factor (BDNF) levels, new cell genesis and learning. In the present

Neural Plasticity and Memory: Is Memory Encoded in Hydrogen Bonding Patterns?

Science.gov (United States)

Amtul, Zareen; Rahman, Atta-Ur

2016-02-01

Current models of memory storage recognize posttranslational modification vital for short-term and mRNA translation for long-lasting information storage. However, at the molecular level things are quite vague. A comprehensive review of the molecular basis of short and long-lasting synaptic plasticity literature leads us to propose that the hydrogen bonding pattern at the molecular level may be a permissive, vital step of memory storage. Therefore, we propose that the pattern of hydrogen bonding network of biomolecules (glycoproteins and/or DNA template, for instance) at the synapse is the critical edifying mechanism essential for short- and long-term memories. A novel aspect of this model is that nonrandom impulsive (or unplanned) synaptic activity functions as a synchronized positive-feedback rehearsal mechanism by revising the configurations of the hydrogen bonding network by tweaking the earlier tailored hydrogen bonds. This process may also maintain the elasticity of the related synapses involved in memory storage, a characteristic needed for such networks to alter intricacy and revise endlessly. The primary purpose of this review is to stimulate the efforts to elaborate the mechanism of neuronal connectivity both at molecular and chemical levels. © The Author(s) 2014.

Are Children's Memory Illusions Created Differently from Those of Adults? Evidence from Levels-of-Processing and Divided Attention Paradigms

Science.gov (United States)

Wimmer, Marina C.; Howe, Mark L.

2010-01-01

In two experiments, we investigated the robustness and automaticity of adults' and children's generation of false memories by using a levels-of-processing paradigm (Experiment 1) and a divided attention paradigm (Experiment 2). The first experiment revealed that when information was encoded at a shallow level, true recognition rates decreased for…

Immune checkpoint inhibitors for non-small-cell lung cancer: does that represent a 'new frontier'?

Science.gov (United States)

Pilotto, Sara; Kinspergher, Stefania; Peretti, Umberto; Calio, Anna; Carbognin, Luisa; Ferrara, Roberto; Brunelli, Matteo; Chilosi, Marco; Tortora, Giampaolo; Bria, Emilio

2015-01-01

Advances in the interpretation and understanding of cancer behaviour, particularly of its ability to evade the host immunosurveillance, deregulating the balance between inhibitory and stimulatory factors, led to the development of an innovative category of immunotherapeutic agents, currently under investigation. Although the disappointing data deriving from the employment of vaccines in non-small cell lung cancer (NSCLC), more promising results have been obtained in the early phase trials with immune checkpoint inhibitors, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors. This review delineates the main features of the available immunotherapeutic agents, focusing the discussion on immune checkpoint inhibitors, those that have already demonstrated a relevant clinical activity (such as Ipilimumab and Nivolumab) and those molecules still in early development phase. Moreover, we underline the possible emerging issues deriving from the progressive diffusion of Immuno-Oncology into the standard clinical practice. The careful and accurate identification and management of immune-related toxicities, the validation of more reliable immune response criteria and the increasing research of potential predictive biomarkers are key points of discussion. The perspective is that immunotherapy might represent an effective 'magic bullet', able to change the treatment paradigm of NSCLC, particularly of those subgroups featured by a heavily mutant cancer (squamous histology and smokers), where the immunologic agents contribute in cancer development and progression seems to be strong and, concurrently, the efficacy of standard therapies particularly limited.

Strategies to overcome HBV-specific T cell exhaustion: checkpoint inhibitors and metabolic re-programming.

Science.gov (United States)

Fisicaro, Paola; Boni, Carolina; Barili, Valeria; Laccabue, Diletta; Ferrari, Carlo

2018-01-29

HBV-specific T cells play a key role in antiviral protection and failure to control HBV is associated with severely dysfunctional T cell responses. Therefore, functional T cell reconstitution represents a potential way to treat chronically infected patients. The growing understanding of the dysregulated transcriptional/epigenetic and metabolic programs underlying T cell exhaustion allows to envisage functional T cell reconstitution strategies based on the combined/sequential use of compounds able to induce decline of antigen load, checkpoint modulation, metabolic and epigenetic reprogramming with possible boosting of functionally restored responses by specific vaccines. Copyright © 2018 Elsevier B.V. All rights reserved.

Level of Formal Thought and Organizational Memory Strategies.

Science.gov (United States)

Wyatt, Kathryn B.; Geis, Mary Fulcher

1978-01-01

Early and late formal-operational adolescents having similar ages and IQs were presented tasks to assess their use of organizational memory strategies: multitrial free recall of unrelated and categorized words and a sorting task followed by free recall of the sorted words. (Author/SS)

Structure of a Blinkin-BUBR1 complex reveals an interaction crucial for kinetochore-mitotic checkpoint regulation via an unanticipated binding Site

DEFF Research Database (Denmark)

Bolanos-Garcia, Victor M; Lischetti, Tiziana; Matak-Vinković, Dijana

2011-01-01

The maintenance of genomic stability relies on the spindle assembly checkpoint (SAC), which ensures accurate chromosome segregation by delaying the onset of anaphase until all chromosomes are properly bioriented and attached to the mitotic spindle. BUB1 and BUBR1 kinases are central for this proc...

DNA damage checkpoint kinase ATM regulates germination and maintains genome stability in seeds.

Science.gov (United States)

Waterworth, Wanda M; Footitt, Steven; Bray, Clifford M; Finch-Savage, William E; West, Christopher E

2016-08-23

Genome integrity is crucial for cellular survival and the faithful transmission of genetic information. The eukaryotic cellular response to DNA damage is orchestrated by the DNA damage checkpoint kinases ATAXIA TELANGIECTASIA MUTATED (ATM) and ATM AND RAD3-RELATED (ATR). Here we identify important physiological roles for these sensor kinases in control of seed germination. We demonstrate that double-strand breaks (DSBs) are rate-limiting for germination. We identify that desiccation tolerant seeds exhibit a striking transcriptional DSB damage response during germination, indicative of high levels of genotoxic stress, which is induced following maturation drying and quiescence. Mutant atr and atm seeds are highly resistant to aging, establishing ATM and ATR as determinants of seed viability. In response to aging, ATM delays germination, whereas atm mutant seeds germinate with extensive chromosomal abnormalities. This identifies ATM as a major factor that controls germination in aged seeds, integrating progression through germination with surveillance of genome integrity. Mechanistically, ATM functions through control of DNA replication in imbibing seeds. ATM signaling is mediated by transcriptional control of the cell cycle inhibitor SIAMESE-RELATED 5, an essential factor required for the aging-induced delay to germination. In the soil seed bank, seeds exhibit increased transcript levels of ATM and ATR, with changes in dormancy and germination potential modulated by environmental signals, including temperature and soil moisture. Collectively, our findings reveal physiological functions for these sensor kinases in linking genome integrity to germination, thereby influencing seed quality, crucial for plant survival in the natural environment and sustainable crop production.

Habitat stability, predation risk and ‘memory syndromes’

Science.gov (United States)

Dalesman, S.; Rendle, A.; Dall, S.R.X.

2015-01-01

Habitat stability and predation pressure are thought to be major drivers in the evolutionary maintenance of behavioural syndromes, with trait covariance only occurring within specific habitats. However, animals also exhibit behavioural plasticity, often through memory formation. Memory formation across traits may be linked, with covariance in memory traits (memory syndromes) selected under particular environmental conditions. This study tests whether the pond snail, Lymnaea stagnalis, demonstrates consistency among memory traits (‘memory syndrome’) related to threat avoidance and foraging. We used eight populations originating from three different habitat types: i) laboratory populations (stable habitat, predator-free); ii) river populations (fairly stable habitat, fish predation); and iii) ditch populations (unstable habitat, invertebrate predation). At a population level, there was a negative relationship between memories related to threat avoidance and food selectivity, but no consistency within habitat type. At an individual level, covariance between memory traits was dependent on habitat. Laboratory populations showed no covariance among memory traits, whereas river populations showed a positive correlation between food memories, and ditch populations demonstrated a negative relationship between threat memory and food memories. Therefore, selection pressures among habitats appear to act independently on memory trait covariation at an individual level and the average response within a population. PMID:26013966

Individual differences in susceptibility to false memories: The effect of memory specificity.

Science.gov (United States)

Dewhurst, Stephen A; Anderson, Rachel J; Berry, Donna M; Garner, Sarah R

2017-06-25

Previous research has highlighted the wide individual variability in susceptibility to the false memories produced by the Deese/Roediger-McDermott (DRM) procedure [Deese, J. (1959). On the prediction of occurrence of particular verbal intrusions in immediate recall. Journal of Experimental Psychology, 58, 17-22; Roediger, H. L., III, & McDermott, K. B. (1995). Creating false memories: Remembering words not presented in lists. Journal of Experimental Psychology: Learning, Memory, & Cognition, 21, 803-814]. The current study investigated whether susceptibility to false memories is influenced by individual differences in the specificity of autobiographical memory retrieval. Memory specificity was measured using the Sentence Completion for Events from the Past Test (SCEPT) [Raes, F., Hermans, D., Williams, J. M. G., & Eelen, P. (2007). A sentence completion procedure as an alternative to the Autobiographical Memory Test for assessing overgeneral memory in non-clinical populations. Memory, 15, 495-507]. Memory specificity did not correlate with correct recognition, but a specific retrieval style was positively correlated with levels of false recognition. It is proposed that the contextual details that frequently accompany false memories of nonstudied lures are more accessible in individuals with specific retrieval styles.

Potential Association of Lead Exposure During Early Development of Mice With Alteration of Hippocampus Nitric Oxide Levels and Learning Memory

Institute of Scientific and Technical Information of China (English)

LI SUN; ZHENG-YAN ZHAO; JIAN HU; XIE-LAI ZHOU

2005-01-01

Objective Chronic lead (Pb) exposure during development is known to produce learning deficits. Nitric oxide participates in the synaptic mechanisms involved in certain forms of learning and memory. This study was designed to clarify whether Pb-induced impairment in learning and memory was associated with the changes of nitric oxide levels in mice brains.Methods Sixty Balb/c mice aged 10 days were chosen. A model of lead exposure was established by drinking 0.025%, 0.05%,0.075% lead acetate, respectively for 8 weeks. The controls were orally given distilled water. The ability to learn and memorize was examined by open field test, T-water maze test. In parallel with the behavioral data, NO level of hippocampus tissue was detected by biochemical assay. Results Compared with control groups, (1) the weight of 0.075% group was significantly reduced (P＜0.05); (2) The number of times in mice attaining the required standards in T-water maze test was lower in 0.075%group (P＜0.01). No significant difference was found between experimental and control groups in open field test (P＞0.05); (3)NO level of mouse hippocampus tissue was decreased in 0.075% group (P＜0.01). Conclusions The findings suggest that decreased hippocampus NO level may contribute to the Pb-induced deficits in learning and memory processes.

A theoretical framework for understanding recovered memory experiences.

Science.gov (United States)

Brewin, Chris R

2012-01-01

If recovered memory experiences appear counter-intuitive, this is in part due to misconceptions about trauma and memory, and to a failure to adopt a comprehensive model of memory that distinguishes personal semantic memory, autobiographical event memory, and memory appraisal. Memory performance is generally superior when events, including traumas, are central to identity. Prolonged trauma in childhood, however, can produce severe identity disturbances that may interfere with the encoding and later retrieval of personal semantic and autobiographical event information. High levels of emotion either at encoding or recall can also interfere with the creation of coherent narrative memories. For example, high levels of shock and fear when memories are recovered unexpectedly may lead to the experience of vivid flashbacks. Memory appraisals may also influence the sense that an event has been forgotten for a long time. Recovered memories, although unusual, do not contradict what we know about how memory works.

Transcriptional 'memory' of a stress: transient chromatin and memory (epigenetic) marks at stress-response genes.

Science.gov (United States)

Avramova, Zoya

2015-07-01

Drought, salinity, extreme temperature variations, pathogen and herbivory attacks are recurring environmental stresses experienced by plants throughout their life. To survive repeated stresses, plants provide responses that may be different from their response during the first encounter with the stress. A different response to a similar stress represents the concept of 'stress memory'. A coordinated reaction at the organismal, cellular and gene/genome levels is thought to increase survival chances by improving the plant's tolerance/avoidance abilities. Ultimately, stress memory may provide a mechanism for acclimation and adaptation. At the molecular level, the concept of stress memory indicates that the mechanisms responsible for memory-type transcription during repeated stresses are not based on repetitive activation of the same response pathways activated by the first stress. Some recent advances in the search for transcription 'memory factors' are discussed with an emphasis on super-induced dehydration stress memory response genes in Arabidopsis. © 2015 The Author The Plant Journal © 2015 John Wiley & Sons Ltd.

Immune Checkpoint Inhibitor-Associated Type 1 Diabetes Mellitus: Case Series, Review of the Literature, and Optimal Management

OpenAIRE

Kapke, Jonathan; Shaheen, Zachary; Kilari, Deepak; Knudson, Paul; Wong, Stuart

2017-01-01

With the introduction of immune checkpoint inhibitors into clinical practice, various autoimmune toxicities have been described. Antibodies targeting the receptor:ligand pairing of programmed death receptor-1 (PD-1) and its cognate ligand programmed death-ligand 1 (PD-L1) in rare reports have been associated with autoimmune diabetes mellitus. We report 2 cases of rapid-onset, insulin-dependent, type 1 diabetes mellitus in the setting of administration of nivolumab, a fully human monoclonal an...

Adaptive false memory: Imagining future scenarios increases false memories in the DRM paradigm.

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Dewhurst, Stephen A; Anderson, Rachel J; Grace, Lydia; van Esch, Lotte

2016-10-01

Previous research has shown that rating words for their relevance to a future scenario enhances memory for those words. The current study investigated the effect of future thinking on false memory using the Deese/Roediger-McDermott (DRM) procedure. In Experiment 1, participants rated words from 6 DRM lists for relevance to a past or future event (with or without planning) or in terms of pleasantness. In a surprise recall test, levels of correct recall did not vary between the rating tasks, but the future rating conditions led to significantly higher levels of false recall than the past and pleasantness conditions did. Experiment 2 found that future rating led to higher levels of false recognition than did past and pleasantness ratings but did not affect correct recognition. The effect in false recognition was, however, eliminated when DRM items were presented in random order. Participants in Experiment 3 were presented with both DRM lists and lists of unrelated words. Future rating increased levels of false recognition for DRM lures but did not affect correct recognition for DRM or unrelated lists. The findings are discussed in terms of the view that false memories can be associated with adaptive memory functions.

Antagonism of brain insulin-like growth factor-1 receptors blocks estradiol effects on memory and levels of hippocampal synaptic proteins in ovariectomized rats

Science.gov (United States)

Nelson, Britta S.; Springer, Rachel C.; Daniel, Jill M.

2013-01-01

Rationale Treatment with estradiol, the primary estrogen produced by the ovaries, enhances hippocampus-dependent spatial memory and increases levels of hippocampal synaptic proteins in ovariectomized rats. Increasing evidence indicates that the ability of estradiol to impact the brain and behavior is dependent upon its interaction with insulin-like growth factor-1 (IGF-1). Objectives The goal of the current experiment was to test the hypothesis that the ability of estradiol to impact hippocampus-dependent memory and levels of hippocampal synaptic proteins is dependent on its interaction with IGF-1. Methods Adult rats were ovariectomized and implanted with estradiol or control capsules and trained on a radial-maze spatial memory task. After training, rats were implanted with intracerebroventricular cannulae attached to osmotic minipumps (flow rate 0.15 μl/hr). Half of each hormone treatment group received continuous delivery of JB1 (300 μg/ml), an IGF-1 receptor antagonist, and half received delivery of aCSF vehicle. Rats were tested on trials in the radial-arm maze during which delays were imposed between the 4th and 5th arm choices. Hippocampal levels of synaptic proteins were measured by western blotting. Results Estradiol treatment resulted in significantly enhanced memory. JB1 blocked that enhancement. Estradiol treatment resulted in significantly increased hippocampal levels of postsynaptic density protein 95 (PSD-95), spinophilin, and synaptophysin. JB1 blocked the estradiol-induced increase of PSD-95 and spinophilin and attenuated the increase of synaptophysin. Conclusions Results support a role for IGF-1 receptor activity in estradiol-induced enhancement of spatial memory that may be dependent on changes in synapse structure in the hippocampus brought upon by estradiol/IGF-1 interactions. PMID:24146138

Resistance to checkpoint blockade therapy through inactivation of antigen presentation.

Science.gov (United States)

Sade-Feldman, Moshe; Jiao, Yunxin J; Chen, Jonathan H; Rooney, Michael S; Barzily-Rokni, Michal; Eliane, Jean-Pierre; Bjorgaard, Stacey L; Hammond, Marc R; Vitzthum, Hans; Blackmon, Shauna M; Frederick, Dennie T; Hazar-Rethinam, Mehlika; Nadres, Brandon A; Van Seventer, Emily E; Shukla, Sachet A; Yizhak, Keren; Ray, John P; Rosebrock, Daniel; Livitz, Dimitri; Adalsteinsson, Viktor; Getz, Gad; Duncan, Lyn M; Li, Bo; Corcoran, Ryan B; Lawrence, Donald P; Stemmer-Rachamimov, Anat; Boland, Genevieve M; Landau, Dan A; Flaherty, Keith T; Sullivan, Ryan J; Hacohen, Nir

2017-10-26

Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to these agents remain incompletely characterized and have yet to be validated in large cohorts. By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin (B2M), an essential component of MHC class I antigen presentation, in 29.4% of patients with progressing disease. In two independent cohorts of melanoma patients treated with anti-CTLA4 and anti-PD1, respectively, we find that B2M LOH is enriched threefold in non-responders (~30%) compared to responders (~10%) and associated with poorer overall survival. Loss of both copies of B2M is found only in non-responders. B2M loss is likely a common mechanism of resistance to therapies targeting CTLA4 or PD1.

Mitosis-specific phosphorylation of PML at T409 regulates spindle checkpoint.

Science.gov (United States)

Jin, J; Liu, J

2016-08-31

During mitosis, Promyelocytic leukemia nuclear bodies (PML NBs) change dramatically in morphology and composition, but little is known about function of PML in mitosis. Here, we show that PML is phosphorylated at T409 (PML p409) in a mitosis-specific manner. More importantly, PML p409 contributes to maintain the duration of pro-metaphase and regulates spindle checkpoint. Deficient PML p409 caused a shortening of pro-metaphase and challenged the nocodazole-triggered mitotic arrest. T409A mutation led to a higher frequency of misaligned chromosomes on metaphase plate, and subsequently death in late mitosis. In addition, inhibition of PML p409 repressed growth of tumor cells, suggesting that PML p409 is a potential target for cancer therapy. Collectively, our study demonstrated an important phosphorylated site of PML, which contributed to explore the role of PML in mitosis.

Short-term sleep deprivation impairs spatial working memory and modulates expression levels of ionotropic glutamate receptor subunits in hippocampus.

Science.gov (United States)

Xie, Meilan; Yan, Jie; He, Chao; Yang, Li; Tan, Gang; Li, Chao; Hu, Zhian; Wang, Jiali

2015-06-01

Hippocampus-dependent learning memory is sensitive to sleep deprivation (SD). Although the ionotropic glutamate receptors play a vital role in synaptic plasticity and learning and memory, however, whether the expression of these receptor subunits is modulated by sleep loss remains unclear. In the present study, western blotting was performed by probing with specific antibodies against the ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits GluA1, GluA2, GluA3, and against the N-methyl-d-aspartate (NMDA) glutamate receptor subunits GluN1, GluN2A, GluN2B. In hippocampus, down regulation of surface GluA1 and GluN2A surface expression were observed in both SD groups. However, surface expression level of GluA2, GluA3, GluN1 and GluN2B was significantly up-regulated in 8h-SD rats when compared to the 4h-SD rats. In parallel with the complex changes in AMPA and NMDA receptor subunit expressions, we found the 8h-SD impaired rat spatial working memory in 30-s-delay T-maze task, whereas no impairment of spatial learning was observed in 4h-SD rats. These results indicate that sleep loss alters the relative expression levels of the AMPA and NMDA receptors, thus affects the synaptic strength and capacity for plasticity and partially contributes to spatial memory impairment. Copyright © 2015. Published by Elsevier B.V.

Neuroanatomical correlates of encoding in episodic memory: levels of processing effect.

Science.gov (United States)

Kapur, S; Craik, F I; Tulving, E; Wilson, A A; Houle, S; Brown, G M

1994-03-15

Cognitive studies of memory processes demonstrate that memory for stimuli is a function of how they are encoded; stimuli processed semantically are better remembered than those processed in a perceptual or shallow fashion. This study investigates the neural correlates of this cognitive phenomenon. Twelve subjects performed two different cognitive tasks on a series of visually presented nouns. In one task, subjects detected the presence or absence of the letter a; in the other, subjects categorized each noun as living or nonliving. Positron emission tomography (PET) scans using 15O-labeled water were obtained during both tasks. Subjects showed substantially better recognition memory for nouns seen in the living/nonliving task, compared to nouns seen in the a-checking task. Comparison of the PET images between the two cognitive tasks revealed a significant activation in the left inferior prefrontal cortex (Brodmann's areas 45, 46, 47, and 10) in the semantic task as compared to the perceptual task. We propose that memory processes are subserved by a wide neurocognitive network and that encoding processes involve preferential activation of the structures in the left inferior prefrontal cortex.

SUBJECTIVE MEMORY IN OLDER AFRICAN AMERICANS

OpenAIRE

Sims, Regina C.; Whitfield, Keith E.; Ayotte, Brian J.; Gamaldo, Alyssa A.; Edwards, Christopher L.; Allaire, Jason C.

2011-01-01

The current analysis examined (a) if measures of psychological well-being predict subjective memory, and (b) if subjective memory is consistent with actual memory. Five hundred seventy-nine older African Americans from the Baltimore Study of Black Aging completed measures assessing subjective memory, depressive symptomatology, perceived stress, locus of control, and verbal and working memory. Higher levels of perceived stress and greater externalized locus of control predicted poorer subjecti...

[Curcumin improves learning and memory function through decreasing hippocampal TNF-α and iNOS levels after subarachnoid hemorrhage in rats].

Science.gov (United States)

Qiu, Zhenwei; Yue, Shuangzhu

2016-03-01

To investigate the effect of curcumin on learning and memory function of rats with subarachnoid hemorrhage (SAH) and the possible mechanism. A total of 30 male Sprague-Dawley rats were randomly divided into three groups: Sham group, SAH group and curcumin (Cur) therapy group. Experimental SAH rat models were established by injecting autologous blood into the cisterna magna. Neurological deficits of rats were examined at different time points. Spatial learning and memory abilities were tested by Morris water maze test. The hippocampal tumor necrosis factor-alpha (TNF-α) and inducible nitric oxide synthase (iNOS) were detected by ELISA. RESULTS Experimental SAH rat models were established successfully. Neurological scores of the SAH rats were significantly lower than those of the sham group. Curcumin therapy obviously improved the neurological deficits of rats compared with the SAH rats. Morris water maze test showed that SAH caused significant cognitive impairment with longer escape latency compared with the sham group. After treatment with curcumin for 4 weeks, the escape latency decreased significantly. The levels of TNF-α and iNOS in the curcumin-treated group were significantly lower than those of the SAH group. SAH can cause learning and memory impairment in rats. Curcumin can recover learning and memory function through down-regulating hippocampal TNF-α and iNOS levels.

Verbal working memory deficits predict levels of auditory hallucination in first-episode psychosis.

Science.gov (United States)

Gisselgård, Jens; Anda, Liss Gøril; Brønnick, Kolbjørn; Langeveld, Johannes; Ten Velden Hegelstad, Wenche; Joa, Inge; Johannessen, Jan Olav; Larsen, Tor Ketil

2014-03-01

Auditory verbal hallucinations are a characteristic symptom in schizophrenia. Recent causal models of auditory verbal hallucinations propose that cognitive mechanisms involving verbal working memory are involved in the genesis of auditory verbal hallucinations. Thus, in the present study, we investigate the hypothesis that verbal working memory is a specific factor behind auditory verbal hallucinations. In the present study, we investigated the association between verbal working memory manipulation (Backward Digit Span and Letter-Number Sequencing) and auditory verbal hallucinations in a population study (N=52) of first episode psychosis. The degree of auditory verbal hallucination as reported in the P3-subscale of the PANSS interview was included as dependent variable using sequential multiple regression, while controlling for age, psychosis symptom severity, executive cognitive functions and simple auditory working memory span. Multiple sequential regression analyses revealed verbal working memory manipulation to be the only significant predictor of verbal hallucination severity. Consistent with cognitive data from auditory verbal hallucinations in healthy individuals, the present results suggest a specific association between auditory verbal hallucinations, and cognitive processes involving the manipulation of phonological representations during a verbal working memory task. Copyright © 2014 Elsevier B.V. All rights reserved.

How does negative emotion cause false memories?

Science.gov (United States)

Brainerd, C J; Stein, L M; Silveira, R A; Rohenkohl, G; Reyna, V F

2008-09-01

Remembering negative events can stimulate high levels of false memory, relative to remembering neutral events. In experiments in which the emotional valence of encoded materials was manipulated with their arousal levels controlled, valence produced a continuum of memory falsification. Falsification was highest for negative materials, intermediate for neutral materials, and lowest for positive materials. Conjoint-recognition analysis produced a simple process-level explanation: As one progresses from positive to neutral to negative valence, false memory increases because (a) the perceived meaning resemblance between false and true items increases and (b) subjects are less able to use verbatim memories of true items to suppress errors.

Iconic memory requires attention

OpenAIRE

Persuh, Marjan; Genzer, Boris; Melara, Robert D.

2012-01-01

Two experiments investigated whether attention plays a role in iconic memory, employing either a change detection paradigm (Experiment 1) or a partial-report paradigm (Experiment 2). In each experiment, attention was taxed during initial display presentation, focusing the manipulation on consolidation of information into iconic memory, prior to transfer into working memory. Observers were able to maintain high levels of performance (accuracy of change detection or categorization) even when co...

Modularity in Sensory Auditory Memory

OpenAIRE

Clement, Sylvain; Moroni, Christine; Samson, Séverine

2004-01-01

The goal of this paper was to review various experimental and neuropsychological studies that support the modular conception of auditory sensory memory or auditory short-term memory. Based on initial findings demonstrating that verbal sensory memory system can be dissociated from a general auditory memory store at the functional and anatomical levels. we reported a series of studies that provided evidence in favor of multiple auditory sensory stores specialized in retaining eit...

Prospective memory, level of disability, and return to work in severe mental illness.

Science.gov (United States)

Burton, Cynthia Z; Vella, Lea; Twamley, Elizabeth W

2018-02-25

Prospective memory (the ability to remember to do things) has clear implications for everyday functioning, including employment, in people with severe mental illnesses (SMI). This study aimed to evaluate prospective memory performance and its relationship to real-world functional variables in an employment-seeking sample of people with SMI (Clinical Trial registration number NCT00895258). 153 individuals with DSM-IV diagnosis of depression (n = 58), bipolar disorder (n = 37), or schizophrenia (n = 58) who were receiving outpatient psychiatric care at a university clinic enrolled in a trial of supported employment and completed a baseline assessment. Prospective memory was measured with the Memory for Intentions Test (MIST); real-world functional status included work history variables, clinical history variables, baseline functional capacity (UCSD Performance-based Skills Assessment-Brief), and work outcomes (weeks worked and wages earned during two years of supported employment). Participants with schizophrenia performed worse on the MIST than did those with affective disorders. Independent of diagnosis, education, and estimated intellectual functioning, prospective memory significantly predicted variance in measures of disability and illness burden (disability benefits, hospitalization history, current functional capacity), and work outcomes over two years of supported employment (weeks worked). Worse prospective memory appears to be associated with greater illness burden and functional disability in SMI. Mental health clinicians and employment specialists may counsel clients to use compensatory prospective memory strategies to improve work performance and decrease functional disability associated with SMI.

Optical quantum memory

Science.gov (United States)

Lvovsky, Alexander I.; Sanders, Barry C.; Tittel, Wolfgang

2009-12-01

Quantum memory is essential for the development of many devices in quantum information processing, including a synchronization tool that matches various processes within a quantum computer, an identity quantum gate that leaves any state unchanged, and a mechanism to convert heralded photons to on-demand photons. In addition to quantum computing, quantum memory will be instrumental for implementing long-distance quantum communication using quantum repeaters. The importance of this basic quantum gate is exemplified by the multitude of optical quantum memory mechanisms being studied, such as optical delay lines, cavities and electromagnetically induced transparency, as well as schemes that rely on photon echoes and the off-resonant Faraday interaction. Here, we report on state-of-the-art developments in the field of optical quantum memory, establish criteria for successful quantum memory and detail current performance levels.

Glucose and age-related changes in memory.

Science.gov (United States)

Gold, Paul E

2005-12-01

Epinephrine, released from the adrenal medulla, enhances memory in young rats and mice and apparently does so, at least in part, by increasing blood glucose levels. Like epinephrine, administration of glucose enhances cognitive functions in humans and rodents, including reversing age-related impairments in learning and memory. Epinephrine responses to training are increased in aged rats but the subsequent increase in blood glucose levels is severely blunted. The absence of increases in blood glucose levels during training might contribute to age-related deficits in learning and memory. Also, extracellular glucose levels in the hippocampus are depleted during spontaneous alternation testing to a far greater extent in aged than in young rats. Importantly, systemic injections of glucose block the depletion in the hippocampus and also enhance performance on the alternation task. Thus, the extensive depletion of extracellular glucose during training in aged rats may be associated with age-related memory impairments, an effect that might be related to - or may exacerbate - the effects on learning and memory of an absence of the increases in blood glucose levels to training as seen in young rats. Together, these findings suggest that age-related changes in both peripheral and central glucose physiology contribute to age-related impairments in memory.

Memory-cenric video processing

NARCIS (Netherlands)

Beric, A.; Meerbergen, van J.; Haan, de G.; Sethuraman, R.

2008-01-01

This work presents a domain-specific memory subsystem based on a two-level memory hierarchy. It targets the application domain of video post-processing applications including video enhancement and format conversion. These applications are based on motion compensation and/or broad class of content

Neuroanatomical correlates of encoding in episodic memory: levels of processing effect.

OpenAIRE

Kapur, S; Craik, F I; Tulving, E; Wilson, A A; Houle, S; Brown, G M

1994-01-01

Cognitive studies of memory processes demonstrate that memory for stimuli is a function of how they are encoded; stimuli processed semantically are better remembered than those processed in a perceptual or shallow fashion. This study investigates the neural correlates of this cognitive phenomenon. Twelve subjects performed two different cognitive tasks on a series of visually presented nouns. In one task, subjects detected the presence or absence of the letter a; in the other, subjects catego...

When the genome plays dice: circumvention of the spindle assembly checkpoint and near-random chromosome segregation in multipolar cancer cell mitoses.

Science.gov (United States)

Gisselsson, David; Håkanson, Ulf; Stoller, Patrick; Marti, Dominik; Jin, Yuesheng; Rosengren, Anders H; Stewénius, Ylva; Kahl, Fredrik; Panagopoulos, Ioannis

2008-04-02

Normal cell division is coordinated by a bipolar mitotic spindle, ensuring symmetrical segregation of chromosomes. Cancer cells, however, occasionally divide into three or more directions. Such multipolar mitoses have been proposed to generate genetic diversity and thereby contribute to clonal evolution. However, this notion has been little validated experimentally. Chromosome segregation and DNA content in daughter cells from multipolar mitoses were assessed by multiphoton cross sectioning and fluorescence in situ hybridization in cancer cells and non-neoplastic transformed cells. The DNA distribution resulting from multipolar cell division was found to be highly variable, with frequent nullisomies in the daughter cells. Time-lapse imaging of H2B/GFP-labelled multipolar mitoses revealed that the time from the initiation of metaphase to the beginning of anaphase was prolonged and that the metaphase plates often switched polarity several times before metaphase-anaphase transition. The multipolar metaphase-anaphase transition was accompanied by a normal reduction of cellular cyclin B levels, but typically occurred before completion of the normal separase activity cycle. Centromeric AURKB and MAD2 foci were observed frequently to remain on the centromeres of multipolar ana-telophase chromosomes, indicating that multipolar mitoses were able to circumvent the spindle assembly checkpoint with some sister chromatids remaining unseparated after anaphase. Accordingly, scoring the distribution of individual chromosomes in multipolar daughter nuclei revealed a high frequency of nondisjunction events, resulting in a near-binomial allotment of sister chromatids to the daughter cells. The capability of multipolar mitoses to circumvent the spindle assembly checkpoint system typically results in a near-random distribution of chromosomes to daughter cells. Spindle multipolarity could thus be a highly efficient generator of genetically diverse minority clones in transformed cell

When the genome plays dice: circumvention of the spindle assembly checkpoint and near-random chromosome segregation in multipolar cancer cell mitoses.

Directory of Open Access Journals (Sweden)

David Gisselsson

Full Text Available BACKGROUND: Normal cell division is coordinated by a bipolar mitotic spindle, ensuring symmetrical segregation of chromosomes. Cancer cells, however, occasionally divide into three or more directions. Such multipolar mitoses have been proposed to generate genetic diversity and thereby contribute to clonal evolution. However, this notion has been little validated experimentally. PRINCIPAL FINDINGS: Chromosome segregation and DNA content in daughter cells from multipolar mitoses were assessed by multiphoton cross sectioning and fluorescence in situ hybridization in cancer cells and non-neoplastic transformed cells. The DNA distribution resulting from multipolar cell division was found to be highly variable, with frequent nullisomies in the daughter cells. Time-lapse imaging of H2B/GFP-labelled multipolar mitoses revealed that the time from the initiation of metaphase to the beginning of anaphase was prolonged and that the metaphase plates often switched polarity several times before metaphase-anaphase transition. The multipolar metaphase-anaphase transition was accompanied by a normal reduction of cellular cyclin B levels, but typically occurred before completion of the normal separase activity cycle. Centromeric AURKB and MAD2 foci were observed frequently to remain on the centromeres of multipolar ana-telophase chromosomes, indicating that multipolar mitoses were able to circumvent the spindle assembly checkpoint with some sister chromatids remaining unseparated after anaphase. Accordingly, scoring the distribution of individual chromosomes in multipolar daughter nuclei revealed a high frequency of nondisjunction events, resulting in a near-binomial allotment of sister chromatids to the daughter cells. CONCLUSION: The capability of multipolar mitoses to circumvent the spindle assembly checkpoint system typically results in a near-random distribution of chromosomes to daughter cells. Spindle multipolarity could thus be a highly efficient

A Look at the Memory Performance of Retarded and Normal Children Utilizing the Levels of Processing Framework.

Science.gov (United States)

Lupart, Judy L.; Mulcahy, Robert F.

Memory performance differences of mental age matched (9-12 years) educable mentally retarded (EMR) (n=56) and normal (n=56) children were examined in two experiments using the F. Craik and R. Lockhart levels of processing framework. In experiment 1, Ss were randomly assigned to an incidental, intentional, or planned intentional learning condition,…

Multicenter Evaluation of the Tolerability of Combined Treatment With PD-1 and CTLA-4 Immune Checkpoint Inhibitors and Palliative Radiation Therapy

Energy Technology Data Exchange (ETDEWEB)

Bang, Andrew [Department of Radiation Oncology, Brigham and Women' s Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts (United States); Division of Radiation Oncology, University of Ottawa, Ottawa, Ontario (Canada); Wilhite, Tyler J. [Harvard Medical School, Boston, Massachusetts (United States); Pike, Luke R.G. [Harvard Radiation Oncology Program, Brigham and Women' s Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts (United States); Cagney, Daniel N.; Aizer, Ayal A.; Taylor, Allison; Spektor, Alexander; Krishnan, Monica [Department of Radiation Oncology, Brigham and Women' s Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts (United States); Ott, Patrick A. [Department of Medical Oncology and Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (United States); Balboni, Tracy A. [Department of Radiation Oncology, Brigham and Women' s Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts (United States); Hodi, F. Stephen [Department of Medical Oncology and Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (United States); Schoenfeld, Jonathan D., E-mail: jdschoenfeld@partners.org [Department of Radiation Oncology, Brigham and Women' s Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts (United States)

2017-06-01

Purpose: To analyze immune-related adverse events (ir-AEs) in patients treated with radiation and immune checkpoint blockade. Methods and Materials: We retrospectively reviewed records from patients with metastatic non-small cell lung cancer, melanoma, or renal cell cancer who received at least 1 cycle of a CTLA-4 or PD-1 inhibitor and radiation. Immune-related adverse events, defined using Common Terminology Criteria for Adverse Events version 4.0, were tabulated in relation to treatment variables, and associations with sequencing and timing were assessed. Results: We identified 133 patients, of whom 28 received a CTLA-4 inhibitor alone, 88 received a PD-1 inhibitor alone, and 17 received both classes of inhibitors either sequentially (n=13) or concurrently (n=4). Fifty-six patients received radiation within 14 days of an immune checkpoint inhibitor. Forty-six patients experienced at least 1 ir-AE (34.6%). Patients receiving both CTLA-4 and PD-1 inhibitors experienced more any-grade ir-AEs as compared with either individually (71% vs 29%, P=.0008). Any-grade ir-AEs occurred in 39% of patients in whom radiation was administered within 14 days of immunotherapy, compared with 23% of other patients (P=.06) and more often in patients who received higher equivalent dose in 2-Gy fractions (EQD2) EQD2 (P=.01). However, most toxicities were mild. There were no associations between site irradiated and specific ir-AEs. Conclusions: Our data suggest the combination of focal palliative radiation and CTLA-4 and/or PD-1 inhibitors is well tolerated, with manageable ir-AEs that did not seem to be associated with the particular site irradiated. Although conclusions are limited by the heterogeneity of patients and treatments, and future confirmatory studies are needed, this information can help guide clinical practice for patients receiving immune checkpoint therapy who require palliative radiation therapy.

NAND flash memory technologies

CERN Document Server

Aritome, Seiichi

2016-01-01

This book discusses basic and advanced NAND flash memory technologies, including the principle of NAND flash, memory cell technologies, multi-bits cell technologies, scaling challenges of memory cell, reliability, and 3-dimensional cell as the future technology. Chapter 1 describes the background and early history of NAND flash. The basic device structures and operations are described in Chapter 2. Next, the author discusses the memory cell technologies focused on scaling in Chapter 3, and introduces the advanced operations for multi-level cells in Chapter 4. The physical limitations for scaling are examined in Chapter 5, and Chapter 6 describes the reliability of NAND flash memory. Chapter 7 examines 3-dimensional (3D) NAND flash memory cells and discusses the pros and cons in structure, process, operations, scalability, and performance. In Chapter 8, challenges of 3D NAND flash memory are dis ussed. Finally, in Chapter 9, the author summarizes and describes the prospect of technologies and market for the fu...

The association of short-term memory and cognitive impairment with ghrelin, leptin, and cortisol levels in non-diabetic and diabetic elderly individuals.

Science.gov (United States)

Sang, Yu Ming; Wang, Li Jun; Mao, Hong Xian; Lou, Xue Yong; Zhu, Yi Jun

2018-06-01

This study assessed short-term memory and biochemical indicators with the levels of ghrelin, leptin, and cortisol between cognitive impairment and normal older adults with or without diabetes. We enrolled 286 older adults (aged 65-85 years) with or without diabetes from the local community. Short-term memory was assessed using pictures of common objects; cognitive functioning was assessed using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). The physiological indexes assessed were plasma levels of fasting ghrelin and leptin, ghrelin level at 2_h after breakfast, 24-h urinary cortisol value, body mass index, and plasma cortisol levels at 8:00 a.m., 4:00 p.m., and 12:00 p.m. In both non-diabetic and diabetic subjects, short-term memory was significantly lower in the impaired cognition group (5.99 ± 2.90 in non-diabetic subjects and 4.71 ± 2.14 in diabetic subjects) than in the normal cognition group (8.14 ± 2.23 in non-diabetic subjects and 7.82 ± 3.37 in diabetic subjects). Baseline ghrelin level was significantly lower in the impaired cognition group (9.07 ± 1.13 ng/mL in non-diabetic subjects and 7.76 ± 1.34 ng/mL in diabetic subjects) than in the normal cognition group (10.94 ± 1.53 ng/mL in non-diabetic subjects and 9.93 ± 1.76 ng/mL in diabetic subjects); plasma cortisol levels at 8:00 a.m., 4:00 p.m., and 12:00 p.m. were significantly higher in the impaired cognition group than in the normal cognition group, while no significant difference was observed in plasma levels of fasting leptin between different groups. Fasting plasma ghrelin and cortisol levels may be markers of cognitive decline and memory loss. It is possible that adjusting their levels may have a therapeutic effect, and this should be investigated in future studies.

Electrophysiological signals associated with fluency of different levels of processing reveal multiple contributions to recognition memory.

Science.gov (United States)

Li, Bingbing; Taylor, Jason R; Wang, Wei; Gao, Chuanji; Guo, Chunyan

2017-08-01

Processing fluency appears to influence recognition memory judgements, and the manipulation of fluency, if misattributed to an effect of prior exposure, can result in illusory memory. Although it is well established that fluency induced by masked repetition priming leads to increased familiarity, manipulations of conceptual fluency have produced conflicting results, variously affecting familiarity or recollection. Some recent studies have found that masked conceptual priming increases correct recollection (Taylor & Henson, 2012), and the magnitude of this behavioural effect correlates with analogous fMRI BOLD priming effects in brain regions associated with recollection (Taylor, Buratto, & Henson, 2013). However, the neural correlates and time-courses of masked repetition and conceptual priming were not compared directly in previous studies. The present study used event-related potentials (ERPs) to identify and compare the electrophysiological correlates of masked repetition and conceptual priming and investigate how they contribute to recognition memory. Behavioural results were consistent with previous studies: Repetition primes increased familiarity, whereas conceptual primes increased correct recollection. Masked repetition and conceptual priming also decreased the latency of late parietal component (LPC). Masked repetition priming was associated with an early P200 effect and a later parietal maximum N400 effect, whereas masked conceptual priming was only associated with a central-parietal maximum N400 effect. In addition, the topographic distributions of the N400 repetition priming and conceptual priming effects were different. These results suggest that fluency at different levels of processing is associated with different ERP components, and contributes differentially to subjective recognition memory experiences. Copyright © 2017 Elsevier Inc. All rights reserved.

Lightweight storage and overlay networks for fault tolerance.

Energy Technology Data Exchange (ETDEWEB)

Oldfield, Ron A.

2010-01-01

The next generation of capability-class, massively parallel processing (MPP) systems is expected to have hundreds of thousands to millions of processors, In such environments, it is critical to have fault-tolerance mechanisms, including checkpoint/restart, that scale with the size of applications and the percentage of the system on which the applications execute. For application-driven, periodic checkpoint operations, the state-of-the-art does not provide a scalable solution. For example, on today's massive-scale systems that execute applications which consume most of the memory of the employed compute nodes, checkpoint operations generate I/O that consumes nearly 80% of the total I/O usage. Motivated by this observation, this project aims to improve I/O performance for application-directed checkpoints through the use of lightweight storage architectures and overlay networks. Lightweight storage provide direct access to underlying storage devices. Overlay networks provide caching and processing capabilities in the compute-node fabric. The combination has potential to signifcantly reduce I/O overhead for large-scale applications. This report describes our combined efforts to model and understand overheads for application-directed checkpoints, as well as implementation and performance analysis of a checkpoint service that uses available compute nodes as a network cache for checkpoint operations.

Associations between depressive symptoms and memory deficits vary as a function of insulin-like growth factor (IGF-1) levels in healthy older adults.

Science.gov (United States)

Lin, Feng; Suhr, Julie; Diebold, Stephanie; Heffner, Kathi L

2014-04-01

Accumulating evidence suggests an adverse association between depressive symptoms and cognition, but a positive association between insulin-like growth factor (IGF)-1 and cognition. The present study examined the influence of IGF-1 in the relationship between depressive symptoms and learning and memory. A cross-sectional study of 94 healthy fit older adults. Blood was collected and plasma IGF-1 was measured. Depressive symptoms were assessed with the Geriatric Depression Scale (GDS), and learning and memory were assessed using the Rey Auditory Verbal Learning Test (AVLT). Among older adults with lower IGF-1 levels, higher depressive symptoms scores were associated with lower AVLT delayed recall and recognition. Older adults with higher IF-1 levels showed no associations between depressive symptoms and memory. The association between depressive symptoms and cognition is stronger among older adults with lower levels of circulating IGF-1. Further validation studies on groups with depression or different stages of cognitive impairment are needed. IGF-1 may be a novel intervention target for slowing cognitive decline in older adults with depressive symptoms. Copyright © 2014 Elsevier Ltd. All rights reserved.

Levels of processing in working memory: differential involvement of frontotemporal networks.

Science.gov (United States)

Rose, Nathan S; Craik, Fergus I M; Buchsbaum, Bradley R

2015-03-01

How does the brain maintain to-be-remembered information in working memory (WM), particularly when the focus of attention is drawn to processing other information? Cognitive models of WM propose that when items are displaced from focal attention recall involves retrieval from long-term memory (LTM). In this fMRI study, we tried to clarify the role of LTM in performance on a WM task and the type of representation that is used to maintain an item in WM during rehearsal-filled versus distractor-filled delays. Participants made a deep or shallow levels-of-processing (LOP) decision about a single word at encoding and tried to recall the word after a delay filled with either rehearsal of the word or a distracting math task. Recalling one word after 10 sec of distraction demonstrated behavioral and neural indices of retrieval from LTM (i.e., LOP effects and medial-temporal lobe activity). In contrast, recall after rehearsal activated cortical areas that reflected reporting the word from focal attention. In addition, areas that showed an LOP effect at encoding (e.g., left ventrolateral VLPFC and the anterior temporal lobes [ATLs]) were reactivated at recall, especially when recall followed distraction. Moreover, activity in left VLPFC during encoding, left ATL during the delay, and left hippocampus during retrieval predicted recall success after distraction. Whereas shallow LOP and rehearsal-related areas supported active maintenance of one item in focal attention, the behavioral processes and neural substrates that support LTM supported recall of one item after it was displaced from focal attention.

Direct access inter-process shared memory

Science.gov (United States)

Brightwell, Ronald B; Pedretti, Kevin; Hudson, Trammell B

2013-10-22

A technique for directly sharing physical memory between processes executing on processor cores is described. The technique includes loading a plurality of processes into the physical memory for execution on a corresponding plurality of processor cores sharing the physical memory. An address space is mapped to each of the processes by populating a first entry in a top level virtual address table for each of the processes. The address space of each of the processes is cross-mapped into each of the processes by populating one or more subsequent entries of the top level virtual address table with the first entry in the top level virtual address table from other processes.

The future of memory

Science.gov (United States)

Marinella, M.

In the not too distant future, the traditional memory and storage hierarchy of may be replaced by a single Storage Class Memory (SCM) device integrated on or near the logic processor. Traditional magnetic hard drives, NAND flash, DRAM, and higher level caches (L2 and up) will be replaced with a single high performance memory device. The Storage Class Memory paradigm will require high speed (read/write), excellent endurance (> 1012), nonvolatility (retention > 10 years), and low switching energies (memory (PCM). All of these devices show potential well beyond that of current flash technologies and research efforts are underway to improve the endurance, write speeds, and scalabilities to be on-par with DRAM. This progress has interesting implications for space electronics: each of these emerging device technologies show excellent resistance to the types of radiation typically found in space applications. Commercially developed, high density storage class memory-based systems may include a memory that is physically radiation hard, and suitable for space applications without major shielding efforts. This paper reviews the Storage Class Memory concept, emerging memory devices, and possible applicability to radiation hardened electronics for space.

Training on Movement Figure-Ground Discrimination Remediates Low-Level Visual Timing Deficits in the Dorsal Stream, Improving High-Level Cognitive Functioning, Including Attention, Reading Fluency, and Working Memory

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Teri Lawton

2017-05-01

Full Text Available The purpose of this study was to determine whether neurotraining to discriminate a moving test pattern relative to a stationary background, figure-ground discrimination, improves vision and cognitive functioning in dyslexics, as well as typically-developing normal students. We predict that improving the speed and sensitivity of figure-ground movement discrimination (PATH to Reading neurotraining acts to remediate visual timing deficits in the dorsal stream, thereby improving processing speed, reading fluency, and the executive control functions of attention and working memory in both dyslexic and normal students who had PATH neurotraining more than in those students who had no neurotraining. This prediction was evaluated by measuring whether dyslexic and normal students improved on standardized tests of cognitive skills following neurotraining exercises, more than following computer-based guided reading (Raz-Kids (RK. The neurotraining used in this study was visually-based training designed to improve magnocellular function at both low and high levels in the dorsal stream: the input to the executive control networks coding working memory and attention. This approach represents a paradigm shift from the phonologically-based treatment for dyslexia, which concentrates on high-level speech and reading areas. This randomized controlled-validation study was conducted by training the entire second and third grade classrooms (42 students for 30 min twice a week before guided reading. Standardized tests were administered at the beginning and end of 12-weeks of intervention training to evaluate improvements in academic skills. Only movement-discrimination training remediated both low-level visual timing deficits and high-level cognitive functioning, including selective and sustained attention, reading fluency and working memory for both dyslexic and normal students. Remediating visual timing deficits in the dorsal stream revealed the causal role of visual

Training on Movement Figure-Ground Discrimination Remediates Low-Level Visual Timing Deficits in the Dorsal Stream, Improving High-Level Cognitive Functioning, Including Attention, Reading Fluency, and Working Memory.

Science.gov (United States)

Lawton, Teri; Shelley-Tremblay, John

2017-01-01

The purpose of this study was to determine whether neurotraining to discriminate a moving test pattern relative to a stationary background, figure-ground discrimination, improves vision and cognitive functioning in dyslexics, as well as typically-developing normal students. We predict that improving the speed and sensitivity of figure-ground movement discrimination ( PATH to Reading neurotraining) acts to remediate visual timing deficits in the dorsal stream, thereby improving processing speed, reading fluency, and the executive control functions of attention and working memory in both dyslexic and normal students who had PATH neurotraining more than in those students who had no neurotraining. This prediction was evaluated by measuring whether dyslexic and normal students improved on standardized tests of cognitive skills following neurotraining exercises, more than following computer-based guided reading ( Raz-Kids ( RK )). The neurotraining used in this study was visually-based training designed to improve magnocellular function at both low and high levels in the dorsal stream: the input to the executive control networks coding working memory and attention. This approach represents a paradigm shift from the phonologically-based treatment for dyslexia, which concentrates on high-level speech and reading areas. This randomized controlled-validation study was conducted by training the entire second and third grade classrooms (42 students) for 30 min twice a week before guided reading. Standardized tests were administered at the beginning and end of 12-weeks of intervention training to evaluate improvements in academic skills. Only movement-discrimination training remediated both low-level visual timing deficits and high-level cognitive functioning, including selective and sustained attention, reading fluency and working memory for both dyslexic and normal students. Remediating visual timing deficits in the dorsal stream revealed the causal role of visual movement

Training on Movement Figure-Ground Discrimination Remediates Low-Level Visual Timing Deficits in the Dorsal Stream, Improving High-Level Cognitive Functioning, Including Attention, Reading Fluency, and Working Memory

Science.gov (United States)

Lawton, Teri; Shelley-Tremblay, John