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Sample records for replicational stress response

  1. A whole genome RNAi screen identifies replication stress response genes.

    Science.gov (United States)

    Kavanaugh, Gina; Ye, Fei; Mohni, Kareem N; Luzwick, Jessica W; Glick, Gloria; Cortez, David

    2015-11-01

    Proper DNA replication is critical to maintain genome stability. When the DNA replication machinery encounters obstacles to replication, replication forks stall and the replication stress response is activated. This response includes activation of cell cycle checkpoints, stabilization of the replication fork, and DNA damage repair and tolerance mechanisms. Defects in the replication stress response can result in alterations to the DNA sequence causing changes in protein function and expression, ultimately leading to disease states such as cancer. To identify additional genes that control the replication stress response, we performed a three-parameter, high content, whole genome siRNA screen measuring DNA replication before and after a challenge with replication stress as well as a marker of checkpoint kinase signalling. We identified over 200 replication stress response genes and subsequently analyzed how they influence cellular viability in response to replication stress. These data will serve as a useful resource for understanding the replication stress response.

  2. The Role of the Transcriptional Response to DNA Replication Stress.

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    Herlihy, Anna E; de Bruin, Robertus A M

    2017-03-02

    During DNA replication many factors can result in DNA replication stress. The DNA replication stress checkpoint prevents the accumulation of replication stress-induced DNA damage and the potential ensuing genome instability. A critical role for post-translational modifications, such as phosphorylation, in the replication stress checkpoint response has been well established. However, recent work has revealed an important role for transcription in the cellular response to DNA replication stress. In this review, we will provide an overview of current knowledge of the cellular response to DNA replication stress with a specific focus on the DNA replication stress checkpoint transcriptional response and its role in the prevention of replication stress-induced DNA damage.

  3. Stress responses and replication of plasmids in bacterial cells

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    Wegrzyn Alicja

    2002-05-01

    Full Text Available Abstract Plasmids, DNA (or rarely RNA molecules which replicate in cells autonomously (independently of chromosomes as non-essential genetic elements, play important roles for microbes grown under specific environmental conditions as well as in scientific laboratories and in biotechnology. For example, bacterial plasmids are excellent models in studies on regulation of DNA replication, and their derivatives are the most commonly used vectors in genetic engineering. Detailed mechanisms of replication initiation, which is the crucial process for efficient maintenance of plasmids in cells, have been elucidated for several plasmids. However, to understand plasmid biology, it is necessary to understand regulation of plasmid DNA replication in response to different environmental conditions in which host cells exist. Knowledge of such regulatory processes is also very important for those who use plasmids as expression vectors to produce large amounts of recombinant proteins. Variable conditions in large-scale fermentations must influence replication of plasmid DNA in cells, thus affecting the efficiency of recombinant gene expression significantly. Contrary to extensively investigated biochemistry of plasmid replication, molecular mechanisms of regulation of plasmid DNA replication in response to various environmental stress conditions are relatively poorly understood. There are, however, recently published studies that add significant data to our knowledge on relations between cellular stress responses and control of plasmid DNA replication. In this review we focus on plasmids derived from bacteriophage λ that are among the best investigated replicons. Nevertheless, recent results of studies on other plasmids are also discussed shortly.

  4. A Blm-Recql5 partnership in replication stress response

    Institute of Scientific and Technical Information of China (English)

    Xincheng Lu; Hua Lou; Guangbin Luo

    2011-01-01

    Deficiencies in DNA damage response and repair not only can result in genome instability and cancer predisposition, but also can render the cancer cells intrinsically more vulnerable to certain types of DNA damage insults. Particularly, replication stress is both a hallmark of human cancers and a common instigator for genome instability and cell death. Here, we review our work based on the genetic knockout studies on Blm and Recql5, two members of the mammalian RecQ helicase family. These studies have uncovered a unique partnership between these two helicases in the implementation of proper mitigation strategies under different circumstances to promote DNA replication and cell survival and suppress genome instability and cancer. In particular, current studies have revealed the presence of a novel Recql5/RECQL5-dependent mechanism for suppressing replication fork collapse in response to global replication fork stalling following exposure to camptothecin (CPT), a topoisomerase I inhibitor, and a potent inhibitor of DNA replication. The unique partnership between Blm and Recql5 in coping with the challenge imposed by replication stress is discussed. In addition, given that irinotecan and topotecan, two CPT derivatives, are currently used in clinic for treating human cancer patients with very promising results, the potential implication of the new findings from these studies in anticancer treatments is also discussed.

  5. Mcm2 phosphorylation and the response to replicative stress

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    Stead Brent E

    2012-05-01

    Full Text Available Abstract Background The replicative helicase in eukaryotic cells is comprised of minichromosome maintenance (Mcm proteins 2 through 7 (Mcm2-7 and is a key target for regulation of cell proliferation. In addition, it is regulated in response to replicative stress. One of the protein kinases that targets Mcm2-7 is the Dbf4-dependent kinase Cdc7 (DDK. In a previous study, we showed that alanine mutations of the DDK phosphorylation sites at S164 and S170 in Saccharomyces cerevisiae Mcm2 result in sensitivity to caffeine and methyl methanesulfonate (MMS leading us to suggest that DDK phosphorylation of Mcm2 is required in response to replicative stress. Results We show here that a strain with the mcm2 allele lacking DDK phosphorylation sites (mcm2AA is also sensitive to the ribonucleotide reductase inhibitor, hydroxyurea (HU and to the base analogue 5-fluorouracil (5-FU but not the radiomimetic drug, phleomycin. We screened the budding yeast non-essential deletion collection for synthetic lethal interactions with mcm2AA and isolated deletions that include genes involved in the control of genome integrity and oxidative stress. In addition, the spontaneous mutation rate, as measured by mutations in CAN1, was increased in the mcm2AA strain compared to wild type, whereas with a phosphomimetic allele (mcm2EE the mutation rate was decreased. These results led to the idea that the mcm2AA strain is unable to respond properly to DNA damage. We examined this by screening the deletion collection for suppressors of the caffeine sensitivity of mcm2AA. Deletions that decrease spontaneous DNA damage, increase homologous recombination or slow replication forks were isolated. Many of the suppressors of caffeine sensitivity suppressed other phenotypes of mcm2AA including sensitivity to genotoxic drugs, the increased frequency of cells with RPA foci and the increased mutation rate. Conclusions Together these observations point to a role for DDK-mediated phosphorylation

  6. The DNA damage checkpoint response to replication stress: A Game of Forks.

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    Rachel eJossen

    2013-03-01

    Full Text Available Conditions challenging replication fork progression, collectively referred to as replication stress, represent a major source of genomic instability and are associated to cancer onset. The replication checkpoint, a specialized branch of the DNA damage checkpoint, monitors fork problems and triggers a cellular response aimed at preserving genome integrity. Here, we review the mechanisms by which the replication checkpoint monitors and responds to replication stress, focusing on the checkpoint-mediated pathways contributing to protect replication fork integrity. We discuss how cells achieve checkpoint signaling inactivation once replication stress is overcome and how a failure to timely revert checkpoint-mediated changes in cellular physiology might impact on replication dynamics and genome integrity. We also highlight the checkpoint function as an anti-cancer barrier preventing cells malignant transformation following oncogene-induced replication stress.

  7. A Comprehensive Analysis of the Dynamic Response to Aphidicolin-Mediated Replication Stress Uncovers Targets for ATM and ATMIN.

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    Mazouzi, Abdelghani; Stukalov, Alexey; Müller, André C; Chen, Doris; Wiedner, Marc; Prochazkova, Jana; Chiang, Shih-Chieh; Schuster, Michael; Breitwieser, Florian P; Pichlmair, Andreas; El-Khamisy, Sherif F; Bock, Christoph; Kralovics, Robert; Colinge, Jacques; Bennett, Keiryn L; Loizou, Joanna I

    2016-04-14

    The cellular response to replication stress requires the DNA-damage-responsive kinase ATM and its cofactor ATMIN; however, the roles of this signaling pathway following replication stress are unclear. To identify the functions of ATM and ATMIN in response to replication stress, we utilized both transcriptomics and quantitative mass-spectrometry-based phosphoproteomics. We found that replication stress induced by aphidicolin triggered widespread changes in both gene expression and protein phosphorylation patterns. These changes gave rise to distinct early and late replication stress responses. Furthermore, our analysis revealed previously unknown targets of ATM and ATMIN downstream of replication stress. We demonstrate ATMIN-dependent phosphorylation of H2AX and of CRMP2, a protein previously implicated in Alzheimer's disease but not in the DNA damage response. Overall, our dataset provides a comprehensive resource for discovering the cellular responses to replication stress and, potentially, associated pathologies. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  8. A Comprehensive Analysis of the Dynamic Response to Aphidicolin-Mediated Replication Stress Uncovers Targets for ATM and ATMIN

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    Abdelghani Mazouzi

    2016-04-01

    Full Text Available The cellular response to replication stress requires the DNA-damage-responsive kinase ATM and its cofactor ATMIN; however, the roles of this signaling pathway following replication stress are unclear. To identify the functions of ATM and ATMIN in response to replication stress, we utilized both transcriptomics and quantitative mass-spectrometry-based phosphoproteomics. We found that replication stress induced by aphidicolin triggered widespread changes in both gene expression and protein phosphorylation patterns. These changes gave rise to distinct early and late replication stress responses. Furthermore, our analysis revealed previously unknown targets of ATM and ATMIN downstream of replication stress. We demonstrate ATMIN-dependent phosphorylation of H2AX and of CRMP2, a protein previously implicated in Alzheimer’s disease but not in the DNA damage response. Overall, our dataset provides a comprehensive resource for discovering the cellular responses to replication stress and, potentially, associated pathologies.

  9. Enhancer of Rudimentary Homolog Affects the Replication Stress Response through Regulation of RNA Processing

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    Kavanaugh, Gina; Zhao, Runxiang; Guo, Yan; Mohni, Kareem N.; Glick, Gloria; Lacy, Monica E.; Hutson, M. Shane; Ascano, Manuel

    2015-01-01

    Accurate replication of DNA is imperative for the maintenance of genomic integrity. We identified Enhancer of Rudimentary Homolog (ERH) using a whole-genome RNA interference (RNAi) screen to discover novel proteins that function in the replication stress response. Here we report that ERH is important for DNA replication and recovery from replication stress. ATR pathway activity is diminished in ERH-deficient cells. The reduction in ATR signaling corresponds to a decrease in the expression of multiple ATR pathway genes, including ATR itself. ERH interacts with multiple RNA processing complexes, including splicing regulators. Furthermore, splicing of ATR transcripts is deficient in ERH-depleted cells. Transcriptome-wide analysis indicates that ERH depletion affects the levels of ∼1,500 transcripts, with DNA replication and repair genes being highly enriched among those with reduced expression. Splicing defects were evident in ∼750 protein-coding genes, which again were enriched for DNA metabolism genes. Thus, ERH regulation of RNA processing is needed to ensure faithful DNA replication and repair. PMID:26100022

  10. Proteome-wide analysis of SUMO2 targets in response to pathological DNA replication stress in human cells

    DEFF Research Database (Denmark)

    Bursomanno, Sara; Beli, Petra; Khan, Asif M;

    2015-01-01

    SUMOylation is a form of post-translational modification involving covalent attachment of SUMO (Small Ubiquitin-like Modifier) polypeptides to specific lysine residues in the target protein. In human cells, there are four SUMO proteins, SUMO1-4, with SUMO2 and SUMO3 forming a closely related...... subfamily. SUMO2/3, in contrast to SUMO1, are predominantly involved in the cellular response to certain stresses, including heat shock. Substantial evidence from studies in yeast has shown that SUMOylation plays an important role in the regulation of DNA replication and repair. Here, we report a proteomic...... repair. We have also shown that deficiency of POLD3 leads to an increase in RPA-bound ssDNA when cells are under replication stress, suggesting that POLD3 plays a role in the cellular response to DNA replication stress. Considering that DNA replication stress is a source of genome instability...

  11. Proteome-wide analysis of SUMO2 targets in response to pathological DNA replication stress in human cells.

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    Bursomanno, Sara; Beli, Petra; Khan, Asif M; Minocherhomji, Sheroy; Wagner, Sebastian A; Bekker-Jensen, Simon; Mailand, Niels; Choudhary, Chunaram; Hickson, Ian D; Liu, Ying

    2015-01-01

    SUMOylation is a form of post-translational modification involving covalent attachment of SUMO (Small Ubiquitin-like Modifier) polypeptides to specific lysine residues in the target protein. In human cells, there are four SUMO proteins, SUMO1-4, with SUMO2 and SUMO3 forming a closely related subfamily. SUMO2/3, in contrast to SUMO1, are predominantly involved in the cellular response to certain stresses, including heat shock. Substantial evidence from studies in yeast has shown that SUMOylation plays an important role in the regulation of DNA replication and repair. Here, we report a proteomic analysis of proteins modified by SUMO2 in response to DNA replication stress in S phase in human cells. We have identified a panel of 22 SUMO2 targets with increased SUMOylation during DNA replication stress, many of which play key functions within the DNA replication machinery and/or in the cellular response to DNA damage. Interestingly, POLD3 was found modified most significantly in response to a low dose aphidicolin treatment protocol that promotes common fragile site (CFS) breakage. POLD3 is the human ortholog of POL32 in budding yeast, and has been shown to act during break-induced recombinational repair. We have also shown that deficiency of POLD3 leads to an increase in RPA-bound ssDNA when cells are under replication stress, suggesting that POLD3 plays a role in the cellular response to DNA replication stress. Considering that DNA replication stress is a source of genome instability, and that excessive replication stress is a hallmark of pre-neoplastic and tumor cells, our characterization of SUMO2 targets during a perturbed S-phase should provide a valuable resource for future functional studies in the fields of DNA metabolism and cancer biology.

  12. Exploiting replicative stress to treat cancer

    DEFF Research Database (Denmark)

    Dobbelstein, Matthias; Sørensen, Claus Storgaard

    2015-01-01

    DNA replication in cancer cells is accompanied by stalling and collapse of the replication fork and signalling in response to DNA damage and/or premature mitosis; these processes are collectively known as 'replicative stress'. Progress is being made to increase our understanding of the mechanisms...

  13. DNA replication stress: causes, resolution and disease.

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    Mazouzi, Abdelghani; Velimezi, Georgia; Loizou, Joanna I

    2014-11-15

    DNA replication is a fundamental process of the cell that ensures accurate duplication of the genetic information and subsequent transfer to daughter cells. Various pertubations, originating from endogenous or exogenous sources, can interfere with proper progression and completion of the replication process, thus threatening genome integrity. Coordinated regulation of replication and the DNA damage response is therefore fundamental to counteract these challenges and ensure accurate synthesis of the genetic material under conditions of replication stress. In this review, we summarize the main sources of replication stress and the DNA damage signaling pathways that are activated in order to preserve genome integrity during DNA replication. We also discuss the association of replication stress and DNA damage in human disease and future perspectives in the field. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  14. Analysis of replication profiles reveals key role of RFC-Ctf18 in yeast replication stress response.

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    Crabbé, Laure; Thomas, Aubin; Pantesco, Véronique; De Vos, John; Pasero, Philippe; Lengronne, Armelle

    2010-11-01

    Maintenance of genome integrity relies on surveillance mechanisms that detect and signal arrested replication forks. Although evidence from budding yeast indicates that the DNA replication checkpoint (DRC) is primarily activated by single-stranded DNA (ssDNA), studies in higher eukaryotes have implicated primer ends in this process. To identify factors that signal primed ssDNA in Saccharomyces cerevisiae, we have screened a collection of checkpoint mutants for their ability to activate the DRC, using the repression of late origins as readout for checkpoint activity. This quantitative analysis reveals that neither RFC(Rad24) and the 9-1-1 clamp nor the alternative clamp loader RFC(Elg1) is required to signal paused forks. In contrast, we found that RFC(Ctf18) is essential for the Mrc1-dependent activation of Rad53 and for the maintenance of paused forks. These data identify RFC(Ctf18) as a key DRC mediator, potentially bridging Mrc1 and primed ssDNA to signal paused forks.

  15. HERP Binds TBK1 To Activate Innate Immunity and Repress Virus Replication in Response to Endoplasmic Reticulum Stress.

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    Ge, Maolin; Luo, Zhen; Qiao, Zhi; Zhou, Yao; Cheng, Xin; Geng, Qibin; Cai, Yanyan; Wan, Pin; Xiong, Ying; Liu, Fang; Wu, Kailang; Liu, Yingle; Wu, Jianguo

    2017-09-27

    Host innate immunity is crucial for cellular responses against viral infection sensed by distinct pattern recognition receptors and endoplasmic reticulum (ER) stress. Enterovirus 71 (EV71) is a causative agent of hand, foot, and mouth disease and neurological diseases. However, the exact mechanism underlying the link between ER stress induced by EV71 infection and host innate immunity is largely unknown. In this study, we demonstrated that EV71 infection induces the homocysteine-induced ER protein (HERP), a modulator of the ER stress response which is dependent on the participation of MAVS. Virus-induced HERP subsequently stimulates host innate immunity to repress viral replication by promoting type-I IFNs (IFN-α and IFN-β) and type-III IFN (IFN-λ1) expression. Through interacting with TANK-binding kinase 1, HERP amplifies the MAVS signaling and facilitates the phosphorylation and nuclear translocation of IFN regulatory factor 3 and NF-κB to enhance the expression of IFNs, which leads to a broad inhibition of the replication of RNA viruses, including EV71, Sendai virus, influenza A virus, and vesicular stomatitis virus. Therefore, we demonstrated that HERP plays an important role in the regulation of host innate immunity in response to ER stress during the infection of RNA viruses. These findings provide new insights into the mechanism underlying the replication of RNA viruses and the production of IFNs, and also demonstrate a new role of HERP in the regulation of host innate immunity in response to viral infection. Copyright © 2017 by The American Association of Immunologists, Inc.

  16. Targeting DNA Replication Stress for Cancer Therapy

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    Zhang, Jun; Dai, Qun; Park, Dongkyoo; Deng, Xingming

    2016-01-01

    The human cellular genome is under constant stress from extrinsic and intrinsic factors, which can lead to DNA damage and defective replication. In normal cells, DNA damage response (DDR) mediated by various checkpoints will either activate the DNA repair system or induce cellular apoptosis/senescence, therefore maintaining overall genomic integrity. Cancer cells, however, due to constitutive growth signaling and defective DDR, may exhibit “replication stress” —a phenomenon unique to cancer cells that is described as the perturbation of error-free DNA replication and slow-down of DNA synthesis. Although replication stress has been proven to induce genomic instability and tumorigenesis, recent studies have counterintuitively shown that enhancing replicative stress through further loosening of the remaining checkpoints in cancer cells to induce their catastrophic failure of proliferation may provide an alternative therapeutic approach. In this review, we discuss the rationale to enhance replicative stress in cancer cells, past approaches using traditional radiation and chemotherapy, and emerging approaches targeting the signaling cascades induced by DNA damage. We also summarize current clinical trials exploring these strategies and propose future research directions including the use of combination therapies, and the identification of potential new targets and biomarkers to track and predict treatment responses to targeting DNA replication stress. PMID:27548226

  17. Targeting DNA Replication Stress for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Jun Zhang

    2016-08-01

    Full Text Available The human cellular genome is under constant stress from extrinsic and intrinsic factors, which can lead to DNA damage and defective replication. In normal cells, DNA damage response (DDR mediated by various checkpoints will either activate the DNA repair system or induce cellular apoptosis/senescence, therefore maintaining overall genomic integrity. Cancer cells, however, due to constitutive growth signaling and defective DDR, may exhibit “replication stress” —a phenomenon unique to cancer cells that is described as the perturbation of error-free DNA replication and slow-down of DNA synthesis. Although replication stress has been proven to induce genomic instability and tumorigenesis, recent studies have counterintuitively shown that enhancing replicative stress through further loosening of the remaining checkpoints in cancer cells to induce their catastrophic failure of proliferation may provide an alternative therapeutic approach. In this review, we discuss the rationale to enhance replicative stress in cancer cells, past approaches using traditional radiation and chemotherapy, and emerging approaches targeting the signaling cascades induced by DNA damage. We also summarize current clinical trials exploring these strategies and propose future research directions including the use of combination therapies, and the identification of potential new targets and biomarkers to track and predict treatment responses to targeting DNA replication stress.

  18. Excess Polθ functions in response to replicative stress in homologous recombination-proficient cancer cells

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    de Rugy, T. Goullet; Bashkurov, M.; Datti, A.; Betous, R.; Guitton-Sert, L.; Cazaux, C.; Durocher, D.

    2016-01-01

    ABSTRACT DNA polymerase theta (Polθ) is a specialized A-family DNA polymerase that functions in processes such as translesion synthesis (TLS), DNA double-strand break repair and DNA replication timing. Overexpression of POLQ, the gene encoding Polθ, is a prognostic marker for an adverse outcome in a wide range of human cancers. While increased Polθ dosage was recently suggested to promote survival of homologous recombination (HR)-deficient cancer cells, it remains unclear whether POLQ overexpression could be also beneficial to HR-proficient cancer cells. By performing a short interfering (si)RNA screen in which genes encoding druggable proteins were knocked down in Polθ-overexpressing cells as a means to uncover genetic vulnerabilities associated with POLQ overexpression, we could not identify genes that were essential for viability in Polθ-overexpressing cells in normal growth conditions. We also showed that, upon external DNA replication stress, Polθ expression promotes cell survival and limits genetic instability. Finally, we report that POLQ expression correlates with the expression of a set of HR genes in breast, lung and colorectal cancers. Collectively, our data suggest that Polθ upregulation, besides its importance for survival of HR-deficient cancer cells, may be crucial also for HR-proficient cells to better tolerate DNA replication stress, as part of a global gene deregulation response, including HR genes. PMID:27612511

  19. Excess Polθ functions in response to replicative stress in homologous recombination-proficient cancer cells

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    T. Goullet de Rugy

    2016-10-01

    Full Text Available DNA polymerase theta (Polθ is a specialized A-family DNA polymerase that functions in processes such as translesion synthesis (TLS, DNA double-strand break repair and DNA replication timing. Overexpression of POLQ, the gene encoding Polθ, is a prognostic marker for an adverse outcome in a wide range of human cancers. While increased Polθ dosage was recently suggested to promote survival of homologous recombination (HR-deficient cancer cells, it remains unclear whether POLQ overexpression could be also beneficial to HR-proficient cancer cells. By performing a short interfering (siRNA screen in which genes encoding druggable proteins were knocked down in Polθ-overexpressing cells as a means to uncover genetic vulnerabilities associated with POLQ overexpression, we could not identify genes that were essential for viability in Polθ-overexpressing cells in normal growth conditions. We also showed that, upon external DNA replication stress, Polθ expression promotes cell survival and limits genetic instability. Finally, we report that POLQ expression correlates with the expression of a set of HR genes in breast, lung and colorectal cancers. Collectively, our data suggest that Polθ upregulation, besides its importance for survival of HR-deficient cancer cells, may be crucial also for HR-proficient cells to better tolerate DNA replication stress, as part of a global gene deregulation response, including HR genes.

  20. Subversion of Host Responses to Energy Insufficiency by Us3 Supports Herpes Simplex Virus 1 Replication during Stress.

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    Vink, Elizabeth I; Smiley, James R; Mohr, Ian

    2017-07-15

    Cellular stress responses to energy insufficiency can impact virus reproduction. In particular, activation of the host AMP-activated protein kinase (AMPK) by low energy could limit protein synthesis by inhibiting mTORC1. Although many herpesviruses, including herpes simplex virus 1 (HSV-1), stimulate mTORC1, how HSV-1-infected cells respond to energy availability, a physiological indicator regulating mTORC1, has not been investigated. In addition, the impact of low-energy stress on productive HSV-1 growth and viral genetic determinants potentially enabling replication under physiological stress remains undefined. Here, we demonstrate that mTORC1 activity in HSV-1-infected cells is largely insensitive to stress induced by simulated energy insufficiency. Furthermore, resistance of mTORC1 activity to low-energy-induced stress, while not significantly influenced by the HSV-1 UL46-encoded phosphatidylinositol 3-kinase (PI3K)-Akt activator, was dependent upon the Ser/Thr kinase activity of Us3. A Us3-deficient virus was hypersensitive to low-energy-induced stress as infected cell protein synthesis and productive replication were reduced compared to levels in cells infected with a Us3-expressing virus. Although Us3 did not detectably prevent energy stress-induced AMPK activation, it enforced mTORC1 activation despite the presence of activated AMPK. In the absence of applied low-energy stress, AMPK activity in infected cells was restricted in a Us3-dependent manner. This establishes that the Us3 kinase not only activated mTORC1 but also enabled sustained mTORC1 signaling during simulated energy insufficiency that would otherwise restrict protein synthesis and virus replication. Moreover, it identifies the alphaherpesvirus-specific Us3 kinase as an mTORC1 activator that subverts the host cell energy-sensing program to support viral productive growth irrespective of physiological stress.IMPORTANCE Like all viruses, herpes simplex virus type 1 (HSV-1) reproduction relies upon

  1. PCNA-Dependent Cleavage and Degradation of SDE2 Regulates Response to Replication Stress

    OpenAIRE

    Jo, Ukhyun; Cai, Winson; Wang, Jingming; Kwon,Yoojin; D’Andrea, Alan D.; Kim, Hyungjin

    2016-01-01

    Maintaining genomic integrity during DNA replication is essential for cellular survival and for preventing tumorigenesis. Proliferating cell nuclear antigen (PCNA) functions as a processivity factor for DNA replication, and posttranslational modification of PCNA plays a key role in coordinating DNA repair against replication-blocking lesions by providing a platform to recruit factors required for DNA repair and cell cycle control. Here, we identify human SDE2 as a new genome surveillance fact...

  2. The yeast PUF protein Puf5 has Pop2-independent roles in response to DNA replication stress.

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    Ana Traven

    Full Text Available PUFs are RNA binding proteins that promote mRNA deadenylation and decay and inhibit translation. Yeast Puf5 is the prototype for studying PUF-dependent gene repression. Puf5 binds to the Pop2 subunit of the Ccr4-Pop2-NOT mRNA deadenylase, recruiting the deadenylase and associated translational repressors to mRNAs. Here we used yeast genetics to show that Puf5 has additional roles in vivo that do not require Pop2. Deletion of PUF5 caused increased sensitivity to DNA replication stress in cells lacking Pop2, as well as in cells mutated for two activities recruited to mRNAs by the Puf5-Pop2 interaction, the deadenylase Ccr4 and the translational repressor Dhh1. A functional Puf5 RNA binding domain was required, and Puf5 cytoplasmic localisation was sufficient for resistance to replication stress, indicating posttranscriptional gene expression control is involved. In contrast to DNA replication stress, in response to the cell wall integrity pathway activator caffeine, PUF5 and POP2 acted in the same genetic pathway, indicating that functions of Puf5 in the caffeine response are mediated by Pop2-dependent gene repression. Our results support a model in which Puf5 uses multiple, Pop2-dependent and Pop2-independent mechanisms to control mRNA expression. The Pop2-independent roles for Puf5 could involve spatial control of gene expression, a proposition supported by our data indicating that the active form of Puf5 is localised to cytoplasmic foci.

  3. p53 induces formation of NEAT1 lncRNA-containing paraspeckles that modulate replication stress response and chemosensitivity.

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    Adriaens, Carmen; Standaert, Laura; Barra, Jasmine; Latil, Mathilde; Verfaillie, Annelien; Kalev, Peter; Boeckx, Bram; Wijnhoven, Paul W G; Radaelli, Enrico; Vermi, William; Leucci, Eleonora; Lapouge, Gaëlle; Beck, Benjamin; van den Oord, Joost; Nakagawa, Shinichi; Hirose, Tetsuro; Sablina, Anna A; Lambrechts, Diether; Aerts, Stein; Blanpain, Cédric; Marine, Jean-Christophe

    2016-08-01

    In a search for mediators of the p53 tumor suppressor pathway, which induces pleiotropic and often antagonistic cellular responses, we identified the long noncoding RNA (lncRNA) NEAT1. NEAT1 is an essential architectural component of paraspeckle nuclear bodies, whose pathophysiological relevance remains unclear. Activation of p53, pharmacologically or by oncogene-induced replication stress, stimulated the formation of paraspeckles in mouse and human cells. Silencing Neat1 expression in mice, which prevents paraspeckle formation, sensitized preneoplastic cells to DNA-damage-induced cell death and impaired skin tumorigenesis. We provide mechanistic evidence that NEAT1 promotes ATR signaling in response to replication stress and is thereby engaged in a negative feedback loop that attenuates oncogene-dependent activation of p53. NEAT1 targeting in established human cancer cell lines induced synthetic lethality with genotoxic chemotherapeutics, including PARP inhibitors, and nongenotoxic activation of p53. This study establishes a key genetic link between NEAT1 paraspeckles, p53 biology and tumorigenesis and identifies NEAT1 as a promising target to enhance sensitivity of cancer cells to both chemotherapy and p53 reactivation therapy.

  4. The MluI cell cycle box (MCB) motifs, but not damage-responsive elements (DREs), are responsible for the transcriptional induction of the rhp51+ gene in response to DNA replication stress.

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    Sartagul, Wugangerile; Zhou, Xin; Yamada, Yuki; Ma, Ning; Tanaka, Katsunori; Furuyashiki, Tomoyuki; Ma, Yan

    2014-01-01

    DNA replication stress induces the transcriptional activation of rhp51+, a fission yeast recA homolog required for repair of DNA double strand breaks. However, the mechanism by which DNA replication stress activates rhp51+ transcription is not understood. The promoter region of rhp51+ contains two damage-responsive elements (DREs) and two MluI cell cycle box (MCB) motifs. Using luciferase reporter assays, we examined the role of these elements in rhp51+ transcription. The full-length rhp51+ promoter and a promoter fragment containing MCB motifs only, but not a fragment containing DREs, mediated transcriptional activation upon DNA replication stress. Removal of the MCB motifs from the rhp51+ promoter abolished the induction of rhp51+ transcription by DNA replication stress. Consistent with a role for MCB motifs in rhp51+ transcription activation, deletion of the MBF (MCB-binding factor) co-repressors Nrm1 and Yox1 precluded rhp51+ transcriptional induction in response to DNA replication stress. Using cells deficient in checkpoint signaling molecules, we found that the Rad3-Cds1/Chk1 pathway partially mediated rhp51+ transcription in response to DNA replication stress, suggesting the involvement of unidentified checkpoint signaling pathways. Because MBF is critical for G1/S transcription, we examined how the cell cycle affected rhp51+ transcription. The transcription of rhp51+ and cdc18+, an MBF-dependent G1/S gene, peaked simultaneously in synchronized cdc25-22 cells. Furthermore, DNA replication stress maintained transcription of rhp51+ similarly to cdc18+. Collectively, these results suggest that MBF and its regulators mediate rhp51+ transcription in response to DNA replication stress, and underlie rhp51+ transcription at the G1/S transition.

  5. CtrA response regulator binding to the Caulobacter chromosome replication origin is required during nutrient and antibiotic stress as well as during cell cycle progression.

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    Bastedo, D Patrick; Marczynski, Gregory T

    2009-04-01

    The Caulobacter crescentus chromosome replication origin (Cori) has five binding sites for CtrA, an OmpR/PhoB family 'response regulator'. CtrA is degraded in replicating 'stalked' cells but is abundant in the non-replicating 'swarmer' cells, where it was proposed to repress replication by binding to Cori. We systematically mutated all Cori CtrA binding sites, and examined their consequences in the contexts of autonomous Cori-plasmid replication and in the natural chromosome locus. Remarkably, the C. crescentus chromosome tolerates severe mutations in all five CtrA binding sites, demonstrating that CtrA is not essential for replication. Further physiological and cell cycle experiments more rigorously supported the original hypothesis that CtrA represses replication. However, our experiments argued against another hypothesis that residual and/or replenished CtrA protein in stalked cells might prevent extra or unscheduled chromosome replication before cell division. Surprisingly, we also demonstrated that Cori CtrA binding sites are very advantageous and can become essential when cells encounter nutrients and antibiotics. Therefore, the CtrA cell cycle regulator co-ordinates replication with viable cell growth in stressful and rapidly changing environments. We argue that this new role for CtrA provided the primary selective pressure for evolving control by CtrA.

  6. Replication Stress: A Lifetime of Epigenetic Change

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    Simran Khurana

    2015-09-01

    Full Text Available DNA replication is essential for cell division. Challenges to the progression of DNA polymerase can result in replication stress, promoting the stalling and ultimately collapse of replication forks. The latter involves the formation of DNA double-strand breaks (DSBs and has been linked to both genome instability and irreversible cell cycle arrest (senescence. Recent technological advances have elucidated many of the factors that contribute to the sensing and repair of stalled or broken replication forks. In addition to bona fide repair factors, these efforts highlight a range of chromatin-associated changes at and near sites of replication stress, suggesting defects in epigenome maintenance as a potential outcome of aberrant DNA replication. Here, we will summarize recent insight into replication stress-induced chromatin-reorganization and will speculate on possible adverse effects for gene expression, nuclear integrity and, ultimately, cell function.

  7. Rescue from replication stress during mitosis.

    Science.gov (United States)

    Fragkos, Michalis; Naim, Valeria

    2017-04-03

    Genomic instability is a hallmark of cancer and a common feature of human disorders, characterized by growth defects, neurodegeneration, cancer predisposition, and aging. Recent evidence has shown that DNA replication stress is a major driver of genomic instability and tumorigenesis. Cells can undergo mitosis with under-replicated DNA or unresolved DNA structures, and specific pathways are dedicated to resolving these structures during mitosis, suggesting that mitotic rescue from replication stress (MRRS) is a key process influencing genome stability and cellular homeostasis. Deregulation of MRRS following oncogene activation or loss-of-function of caretaker genes may be the cause of chromosomal aberrations that promote cancer initiation and progression. In this review, we discuss the causes and consequences of replication stress, focusing on its persistence in mitosis as well as the mechanisms and factors involved in its resolution, and the potential impact of incomplete replication or aberrant MRRS on tumorigenesis, aging and disease.

  8. More forks on the road to replication stress recovery

    Institute of Scientific and Technical Information of China (English)

    Chris Allen; Amanda K. Ashley; Robert Hromas; Jac A. Nickoloff

    2011-01-01

    High-fidelity replication of DNA, and its accurate segregation to daughter cells, is critical for maintaining genome stability and suppressing cancer. DNA replication forks are stalled by many DNA lesions, activating checkpoint proteins that stabilize stalled forks.Stalled forks may eventually collapse, producing a broken DNA end. Fork restart is typically mediated by proteins initially identified by their rotes in homologous recombination repair of DNA double-strand breaks (DSBs). In recent years, several proteins involved in DSB repair by non-homologous end joining (NHEJ) have been implicated in the replication stress response, including DNA-PKcs, Ku,DNA Ligase IV-XRCC4, Artemis, XLF and Metnase. It is currently unclear whether NHEJ proteins are involved in the replication stress response through indirect (signaling) roles, and/or direct roles involving DNA end joining. Additional complexity in the replication stress response centers around RPA, which undergoes significant post-translational modification after stress, and RAD52, a conserved HR protein whose role in DSB repair may have shifted to another protein in higher eukaryotes, such as BRCA2, but retained its rote in fork restart. Most cancer therapeutic strategies create DNA reputation stress. Thus, it is imperative to gain a better understanding of replication stress response proteins and pathways to improve cancer therapy.

  9. Analysis of spatial correlations between patterns of DNA damage response and DNA replication in nuclei of cells subjected to replication stress or oxidative damage.

    Science.gov (United States)

    Bernas, Tytus; Berniak, Krzysztof; Rybak, Paulina; Zarębski, Mirosław; Zhao, Hong; Darzynkiewicz, Zbigniew; Dobrucki, Jerzy W

    2013-10-01

    Sites of DNA replication (EdU incorporation) and DNA damage signaling (γH2AX) induced by camptothecin (Cpt) or hydrogen peroxide (H2O2) form characteristic patterns of foci in cell nuclei. The overlap between these patterns is a function of the number of DNA double strand breaks (DSBs) formed in replication sites. The goal of this study was to optimize a method of quantitative assessment of a degree of correlation between these two patterns. Such a correlation can be used to estimate a probability of inducing damage in sections of replicating DNA. The damage and replication foci are imaged in 3D with confocal microscopy and their respective positions within nuclei are determined with adaptive image segmentation. Using correlation functions spatial proximity of the resultant point patterns is quantified over the range of distances in cells in early-, mid- and late S-phase. As the numbers (and nuclear densities) of γH2AX and replication foci differ significantly in the subsequent substages of S phase, the detected association values were corrected for the expected random overlap between both classes of foci. Thus, the probability of their nonrandom association was estimated. Moreover, self association (clustering) of DNA replication sites in different stages of S-phase of the cell cycle was detected and accounted for. While the analysis revealed a strong correlation between the γH2AX foci and the sites of DNA replication in cells treated with Cpt, only a low correlation was apparent in cells exposed to H2O2. © 2013 International Society for Advancement of Cytometry.

  10. ATM Couples Replication Stress and Metabolic Reprogramming during Cellular Senescence

    Directory of Open Access Journals (Sweden)

    Katherine M. Aird

    2015-05-01

    Full Text Available Replication stress induced by nucleotide deficiency plays an important role in cancer initiation. Replication stress in primary cells typically activates the cellular senescence tumor-suppression mechanism. Senescence bypass correlates with development of cancer, a disease characterized by metabolic reprogramming. However, the role of metabolic reprogramming in the cellular response to replication stress has been little explored. Here, we report that ataxia telangiectasia mutated (ATM plays a central role in regulating the cellular response to replication stress by shifting cellular metabolism. ATM inactivation bypasses senescence induced by replication stress triggered by nucleotide deficiency. This was due to restoration of deoxyribonucleotide triphosphate (dNTP levels through both upregulation of the pentose phosphate pathway via increased glucose-6-phosphate dehydrogenase (G6PD activity and enhanced glucose and glutamine consumption. These phenotypes were mediated by a coordinated suppression of p53 and upregulation of c-MYC downstream of ATM inactivation. Our data indicate that ATM status couples replication stress and metabolic reprogramming during senescence.

  11. Are renal ciliopathies (replication) stressed out?

    NARCIS (Netherlands)

    Slaats, Gisela G; Giles, R

    2015-01-01

    Juvenile renal failure is commonly caused by the ciliopathy nephronophthisis (NPHP). Since all NPHP genes regulate cilia function, it has been assumed that NPHP onset is due to cilia loss. However, recent data suggest that DNA damage caused by replication stress, possibly concomitant with or upstrea

  12. Replication stress, a source of epigenetic aberrations in cancer?

    DEFF Research Database (Denmark)

    Jasencakova, Zusana; Groth, Anja

    2010-01-01

    . Chromatin organization is transiently disrupted during DNA replication and maintenance of epigenetic information thus relies on faithful restoration of chromatin on the new daughter strands. Acute replication stress challenges proper chromatin restoration by deregulating histone H3 lysine 9 mono......-methylation on new histones and impairing parental histone recycling. This could facilitate stochastic epigenetic silencing by laying down repressive histone marks at sites of fork stalling. Deregulation of replication in response to oncogenes and other tumor-promoting insults is recognized as a significant source...... of genome instability in cancer. We propose that replication stress not only presents a threat to genome stability, but also jeopardizes chromatin integrity and increases epigenetic plasticity during tumorigenesis....

  13. ATR-p53 restricts homologous recombination in response to replicative stress but does not limit DNA interstrand crosslink repair in lung cancer cells.

    Directory of Open Access Journals (Sweden)

    Bianca M Sirbu

    Full Text Available Homologous recombination (HR is required for the restart of collapsed DNA replication forks and error-free repair of DNA double-strand breaks (DSB. However, unscheduled or hyperactive HR may lead to genomic instability and promote cancer development. The cellular factors that restrict HR processes in mammalian cells are only beginning to be elucidated. The tumor suppressor p53 has been implicated in the suppression of HR though it has remained unclear why p53, as the guardian of the genome, would impair an error-free repair process. Here, we show for the first time that p53 downregulates foci formation of the RAD51 recombinase in response to replicative stress in H1299 lung cancer cells in a manner that is independent of its role as a transcription factor. We find that this downregulation of HR is not only completely dependent on the binding site of p53 with replication protein A but also the ATR/ATM serine 15 phosphorylation site. Genetic analysis suggests that ATR but not ATM kinase modulates p53's function in HR. The suppression of HR by p53 can be bypassed under experimental conditions that cause DSB either directly or indirectly, in line with p53's role as a guardian of the genome. As a result, transactivation-inactive p53 does not compromise the resistance of H1299 cells to the interstrand crosslinking agent mitomycin C. Altogether, our data support a model in which p53 plays an anti-recombinogenic role in the ATR-dependent mammalian replication checkpoint but does not impair a cell's ability to use HR for the removal of DSB induced by cytotoxic agents.

  14. Role and regulation of homologous recombination in response to DNA double strand breaks and replication stress in Saccharomyces cerevisiae

    OpenAIRE

    Falcettoni,

    2014-01-01

    Homologous recombination (HR) is a key pathway to maintain genomic integrity from one generation to another (meiosis) and during ontogenic development in a single organism (DNA repair). Recombination is required for the repair or tolerance of DNA damage and the recovery of stalled or broken replication forks. However, recombination is also potentially dangerous as it can lead to gross chromosomal rearrangements and potentially lethal intermediates. For this reason, recombinational events must...

  15. 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.

  16. Relationship between DNA damage response, initiated by camptothecin or oxidative stress, and DNA replication, analyzed by quantitative 3D image analysis.

    Science.gov (United States)

    Berniak, K; Rybak, P; Bernas, T; Zarębski, M; Biela, E; Zhao, H; Darzynkiewicz, Z; Dobrucki, J W

    2013-10-01

    A method of quantitative analysis of spatial (3D) relationship between discrete nuclear events detected by confocal microscopy is described and applied in analysis of a dependence between sites of DNA damage signaling (γH2AX foci) and DNA replication (EdU incorporation) in cells subjected to treatments with camptothecin (Cpt) or hydrogen peroxide (H2O2). Cpt induces γH2AX foci, likely reporting formation of DNA double-strand breaks (DSBs), almost exclusively at sites of DNA replication. This finding is consistent with the known mechanism of induction of DSBs by DNA topoisomerase I (topo1) inhibitors at the sites of collisions of the moving replication forks with topo1-DNA "cleavable complexes" stabilized by Cpt. Whereas an increased level of H2AX histone phosphorylation is seen in S-phase of cells subjected to H2O2, only a minor proportion of γH2AX foci coincide with DNA replication sites. Thus, the increased level of H2AX phosphorylation induced by H2O2 is not a direct consequence of formation of DNA lesions at the sites of moving DNA replication forks. These data suggest that oxidative stress induced by H2O2 and formation of the primary H2O2-induced lesions (8-oxo-7,8-dihydroguanosine) inhibits replication globally and triggers formation of γH2AX at various distances from replication forks. Quantitative analysis of a frequency of DNA replication sites and γH2AX foci suggests also that stalling of replicating forks by Cpt leads to activation of new DNA replication origins. © 2013 International Society for Advancement of Cytometry.

  17. Cellular Responses to Replication Problems

    NARCIS (Netherlands)

    M. Budzowska (Magdalena)

    2008-01-01

    textabstractDuring every S-phase cells need to duplicate their genomes so that both daughter cells inherit complete copies of genetic information. It is a tremendous task, given the large sizes of mammalian genomes and the required precision of DNA replication. A major threat to the accuracy and eff

  18. System-wide Analysis of SUMOylation Dynamics in Response to Replication Stress Reveals Novel Small Ubiquitin-like Modified Target Proteins and Acceptor Lysines Relevant for Genome Stability

    DEFF Research Database (Denmark)

    Xiao, Zhenyu; Chang, Jer-Gung; Hendriks, Ivo A;

    2015-01-01

    . Following statistical analysis on five biological replicates, a total of 566 SUMO-2 targets were identified. After 2 hours of Hydroxyurea treatment, 10 proteins were up-regulated for SUMOylation and 2 proteins were down-regulated for SUMOylation, whereas after 24 hours, 35 proteins were up......-regulated for SUMOylation and 13 proteins were down-regulated for SUMOylation. A site-specific approach was used to map over 1,000 SUMO-2 acceptor lysines in target proteins. The methodology is generic and is widely applicable in the ubiquitin field. A large subset of these identified proteins function in one network...... that consists of interacting replication factors, transcriptional regulators, DNA damage response factors including MDC1, ATR-interacting protein ATRIP, the Bloom syndrome protein and the BLM-binding partner RMI1, the crossover junction endonuclease EME1, BRCA1 and CHAF1A. Furthermore, centromeric proteins...

  19. RAD52 Facilitates Mitotic DNA Synthesis Following Replication Stress

    DEFF Research Database (Denmark)

    Bhowmick, Rahul; Minocherhomji, Sheroy; Hickson, Ian D

    2016-01-01

    Homologous recombination (HR) is necessary to counteract DNA replication stress. Common fragile site (CFS) loci are particularly sensitive to replication stress and undergo pathological rearrangements in tumors. At these loci, replication stress frequently activates DNA repair synthesis in mitosis....... This mitotic DNA synthesis, termed MiDAS, requires the MUS81-EME1 endonuclease and a non-catalytic subunit of the Pol-delta complex, POLD3. Here, we examine the contribution of HR factors in promoting MiDAS in human cells. We report that RAD51 and BRCA2 are dispensable for MiDAS but are required to counteract...

  20. Replication forks reverse at high frequency upon replication stress in Physarum polycephalum.

    Science.gov (United States)

    Maric, Chrystelle; Bénard, Marianne

    2014-12-01

    The addition of hydroxyurea after the onset of S phase allows replication to start and permits the successive detecting of replication-dependent joint DNA molecules and chicken foot structures in the synchronous nuclei of Physarum polycephalum. We find evidence for a very high frequency of reversed replication forks upon replication stress. The formation of these reversed forks is dependent on the presence of joint DNA molecules, the impediment of the replication fork progression by hydroxyurea, and likely on the propensity of some replication origins to reinitiate replication to counteract the action of this compound. As hydroxyurea treatment enables us to successively detect the appearance of joint DNA molecules and then of reversed replication forks, we propose that chicken foot structures are formed both from the regression of hydroxyurea-frozen joint DNA molecules and from hydroxyurea-stalled replication forks. These experiments underscore the transient nature of replication fork regression, which becomes detectable due to the hydroxyurea-induced slowing down of replication fork progression.

  1. Replication stress activates DNA repair synthesis in mitosis

    DEFF Research Database (Denmark)

    Minocherhomji, Sheroy; Ying, Songmin; Bjerregaard, Victoria A

    2015-01-01

    mitosis serves as the trigger for completion of DNA replication at CFS loci in human cells. Given that this POLD3-dependent mitotic DNA synthesis is enhanced in aneuploid cancer cells that exhibit intrinsically high levels of chromosomal instability (CIN(+)) and replicative stress, we suggest...

  2. DNA replication stress restricts ribosomal DNA copy number.

    Science.gov (United States)

    Salim, Devika; Bradford, William D; Freeland, Amy; Cady, Gillian; Wang, Jianmin; Pruitt, Steven C; Gerton, Jennifer L

    2017-09-15

    Ribosomal RNAs (rRNAs) in budding yeast are encoded by ~100-200 repeats of a 9.1kb sequence arranged in tandem on chromosome XII, the ribosomal DNA (rDNA) locus. Copy number of rDNA repeat units in eukaryotic cells is maintained far in excess of the requirement for ribosome biogenesis. Despite the importance of the repeats for both ribosomal and non-ribosomal functions, it is currently not known how "normal" copy number is determined or maintained. To identify essential genes involved in the maintenance of rDNA copy number, we developed a droplet digital PCR based assay to measure rDNA copy number in yeast and used it to screen the yeast conditional temperature-sensitive mutant collection of essential genes. Our screen revealed that low rDNA copy number is associated with compromised DNA replication. Further, subculturing yeast under two separate conditions of DNA replication stress selected for a contraction of the rDNA array independent of the replication fork blocking protein, Fob1. Interestingly, cells with a contracted array grew better than their counterparts with normal copy number under conditions of DNA replication stress. Our data indicate that DNA replication stresses select for a smaller rDNA array. We speculate that this liberates scarce replication factors for use by the rest of the genome, which in turn helps cells complete DNA replication and continue to propagate. Interestingly, tumors from mini chromosome maintenance 2 (MCM2)-deficient mice also show a loss of rDNA repeats. Our data suggest that a reduction in rDNA copy number may indicate a history of DNA replication stress, and that rDNA array size could serve as a diagnostic marker for replication stress. Taken together, these data begin to suggest the selective pressures that combine to yield a "normal" rDNA copy number.

  3. The DNA Replication Stress Hypothesis of Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Yuri B. Yurov

    2011-01-01

    Full Text Available A well-recognized theory of Alzheimer’s disease (AD pathogenesis suggests ectopic cell cycle events to mediate neurodegeneration. Vulnerable neurons of the AD brain exhibit biomarkers of cell cycle progression and DNA replication suggesting a reentry into the cell cycle. Chromosome reduplication without proper cell cycle completion and mitotic division probably causes neuronal cell dysfunction and death. However, this theory seems to require some inputs in accordance with the generally recognized amyloid cascade theory as well as to explain causes and consequences of genomic instability (aneuploidy in the AD brain. We propose that unscheduled and incomplete DNA replication (replication stress destabilizes (epigenomic landscape in the brain and leads to DNA replication “catastrophe” causing cell death during the S phase (replicative cell death. DNA replication stress can be a key element of the pathogenetic cascade explaining the interplay between ectopic cell cycle events and genetic instabilities in the AD brain. Abnormal cell cycle reentry and somatic genome variations can be used for updating the cell cycle theory introducing replication stress as a missing link between cell genetics and neurobiology of AD.

  4. Replication stress activates DNA repair synthesis in mitosis.

    Science.gov (United States)

    Minocherhomji, Sheroy; Ying, Songmin; Bjerregaard, Victoria A; Bursomanno, Sara; Aleliunaite, Aiste; Wu, Wei; Mankouri, Hocine W; Shen, Huahao; Liu, Ying; Hickson, Ian D

    2015-12-10

    Oncogene-induced DNA replication stress has been implicated as a driver of tumorigenesis. Many chromosomal rearrangements characteristic of human cancers originate from specific regions of the genome called common fragile sites (CFSs). CFSs are difficult-to-replicate loci that manifest as gaps or breaks on metaphase chromosomes (termed CFS 'expression'), particularly when cells have been exposed to replicative stress. The MUS81-EME1 structure-specific endonuclease promotes the appearance of chromosome gaps or breaks at CFSs following replicative stress. Here we show that entry of cells into mitotic prophase triggers the recruitment of MUS81 to CFSs. The nuclease activity of MUS81 then promotes POLD3-dependent DNA synthesis at CFSs, which serves to minimize chromosome mis-segregation and non-disjunction. We propose that the attempted condensation of incompletely duplicated loci in early mitosis serves as the trigger for completion of DNA replication at CFS loci in human cells. Given that this POLD3-dependent mitotic DNA synthesis is enhanced in aneuploid cancer cells that exhibit intrinsically high levels of chromosomal instability (CIN(+)) and replicative stress, we suggest that targeting this pathway could represent a new therapeutic approach.

  5. Environmental stress speeds up DNA replication in Pseudomonas putida in chemostat cultivations.

    Science.gov (United States)

    Lieder, Sarah; Jahn, Michael; Koepff, Joachim; Müller, Susann; Takors, Ralf

    2016-01-01

    Cellular response to different types of stress is the hallmark of the cell's strategy for survival. How organisms adjust their cell cycle dynamics to compensate for changes in environmental conditions is an important unanswered question in bacterial physiology. A cell using binary fission for reproduction passes through three stages during its cell cycle: a stage from cell birth to initiation of replication, a DNA replication phase and a period of cell division. We present a detailed analysis of durations of cell cycle phases, investigating their dynamics under environmental stress conditions. Applying continuous steady state cultivations (chemostats), the DNA content of a Pseudomonas putida KT2440 population was quantified with flow cytometry at distinct growth rates. Data-driven modeling revealed that under stress conditions, such as oxygen deprivation, solvent exposure and decreased iron availability, DNA replication was accelerated correlated to the severity of the imposed stress (up to 1.9-fold). Cells maintained constant growth rates by balancing the shortened replication phase with extended cell cycle phases before and after replication. Transcriptome data underpin the transcriptional upregulation of crucial genes of the replication machinery. Hence adaption of DNA replication speed appears to be an important strategy to withstand environmental stress.

  6. Managing Single-Stranded DNA during Replication Stress in Fission Yeast

    Directory of Open Access Journals (Sweden)

    Sarah A. Sabatinos

    2015-09-01

    Full Text Available Replication fork stalling generates a variety of responses, most of which cause an increase in single-stranded DNA. ssDNA is a primary signal of replication distress that activates cellular checkpoints. It is also a potential source of genome instability and a substrate for mutation and recombination. Therefore, managing ssDNA levels is crucial to chromosome integrity. Limited ssDNA accumulation occurs in wild-type cells under stress. In contrast, cells lacking the replication checkpoint cannot arrest forks properly and accumulate large amounts of ssDNA. This likely occurs when the replication fork polymerase and helicase units are uncoupled. Some cells with mutations in the replication helicase (mcm-ts mimic checkpoint-deficient cells, and accumulate extensive areas of ssDNA to trigger the G2-checkpoint. Another category of helicase mutant (mcm4-degron causes fork stalling in early S-phase due to immediate loss of helicase function. Intriguingly, cells realize that ssDNA is present, but fail to detect that they accumulate ssDNA, and continue to divide. Thus, the cellular response to replication stalling depends on checkpoint activity and the time that replication stress occurs in S-phase. In this review we describe the signs, signals, and symptoms of replication arrest from an ssDNA perspective. We explore the possible mechanisms for these effects. We also advise the need for caution when detecting and interpreting data related to the accumulation of ssDNA.

  7. Potential biomarkers of DNA replication stress in cancer

    DEFF Research Database (Denmark)

    Ren, Liqun; Chen, Long; Wu, Wei

    2017-01-01

    Oncogene activation is an established driver of tumorigenesis. An apparently inevitable consequence of oncogene activation is the generation of DNA replication stress (RS), a feature common to most cancer cells. RS, in turn, is a causal factor in the development of chromosome instability (CIN), a...

  8. Replicability and heterogeneity of awake unrestrained canine FMRI responses.

    Directory of Open Access Journals (Sweden)

    Gregory S Berns

    Full Text Available Previously, we demonstrated the possibility of fMRI in two awake and unrestrained dogs. Here, we determined the replicability and heterogeneity of these results in an additional 11 dogs for a total of 13 subjects. Based on an anatomically placed region-of-interest, we compared the caudate response to a hand signal indicating the imminent availability of a food reward to a hand signal indicating no reward. 8 of 13 dogs had a positive differential caudate response to the signal indicating reward. The mean differential caudate response was 0.09%, which was similar to a comparable human study. These results show that canine fMRI is reliable and can be done with minimal stress to the dogs.

  9. Replicability and heterogeneity of awake unrestrained canine FMRI responses.

    Science.gov (United States)

    Berns, Gregory S; Brooks, Andrew; Spivak, Mark

    2013-01-01

    Previously, we demonstrated the possibility of fMRI in two awake and unrestrained dogs. Here, we determined the replicability and heterogeneity of these results in an additional 11 dogs for a total of 13 subjects. Based on an anatomically placed region-of-interest, we compared the caudate response to a hand signal indicating the imminent availability of a food reward to a hand signal indicating no reward. 8 of 13 dogs had a positive differential caudate response to the signal indicating reward. The mean differential caudate response was 0.09%, which was similar to a comparable human study. These results show that canine fMRI is reliable and can be done with minimal stress to the dogs.

  10. BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity

    DEFF Research Database (Denmark)

    Rasmussen, Rikke D.; Gajjar, Madhavsai K.; Tuckova, Lucie;

    2016-01-01

    Oncogene-evoked replication stress (RS) fuels genomic instability in diverse cancer types. Here we report that BRCA1, traditionally regarded a tumour suppressor, plays an unexpected tumour-promoting role in glioblastoma (GBM), safeguarding a protective response to supraphysiological RS levels. Hi...

  11. BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity

    DEFF Research Database (Denmark)

    Rasmussen, Rikke D.; Gajjar, Madhavsai K.; Tuckova, Lucie

    2016-01-01

    Oncogene-evoked replication stress (RS) fuels genomic instability in diverse cancer types. Here we report that BRCA1, traditionally regarded a tumour suppressor, plays an unexpected tumour-promoting role in glioblastoma (GBM), safeguarding a protective response to supraphysiological RS levels...

  12. Bid protects the mouse hematopoietic system following hydroxyurea-induced replicative stress.

    Science.gov (United States)

    Liu, Y; Aiello, A; Zinkel, S S

    2012-10-01

    Hematopoietic stem cells (HSCs) possess long-term self-renewal capacity and multipotent differentiative capacity, to maintain the hematopoietic system. Long-term hematopoietic homeostasis requires effective control of genotoxic damage to maintain HSC function and prevent propagation of deleterious mutations. Here we investigate the role of the BH3-only Bcl-2 family member Bid in the response of murine hematopoietic cells to long-term replicative stress induced by hydroxyurea (HU). The PI3-like serine/threonine kinase, ATR, initiates the DNA damage response (DDR) to replicative stress. The pro-apoptotic Bcl-2 family member, Bid, facilitates this response to replicative stress in hematopoietic cells, but the in vivo role of this DDR function of Bid has not been defined. Surprisingly, we demonstrate that long-term HU treatment expands wild-type myeloid progenitor cells (MPCs) and HSC-enriched Lin(-)Sca1(+)Kit(+) (LSK) cells to maintain bone marrow function as measured by long-term competitive repopulating ability. Bid-/- MPCs demonstrate increased sensitivity to HU and are depleted. Bid-/- LSK cells demonstrate increased mobilization manifest by increased Bromodeoxyuridine (BrdU) incorporation. Bid-/- MPCs and LSK cells are relatively depleted, however, and bone marrow from Bid-/- mice demonstrates decreased long-term competitive repopulating ability in both primary and secondary transplants. We thus describe a survival function of Bid in hematopoiesis in the setting of chronic replicative stress.

  13. Replication stress and oxidative damage contribute to aberrant constitutive activation of DNA damage signalling in human gliomas

    DEFF Research Database (Denmark)

    Bartkova, J; Hamerlik, P; Stockhausen, Marie

    2010-01-01

    brain and grade II astrocytomas, despite the degree of DDR activation was higher in grade II tumors. Markers indicative of ongoing DNA replication stress (Chk1 activation, Rad17 phosphorylation, replication protein A foci and single-stranded DNA) were present in GBM cells under high- or low...... and indicate that replication stress, rather than oxidative stress, fuels the DNA damage signalling in early stages of astrocytoma development.......Malignant gliomas, the deadliest of brain neoplasms, show rampant genetic instability and resistance to genotoxic therapies, implicating potentially aberrant DNA damage response (DDR) in glioma pathogenesis and treatment failure. Here, we report on gross, aberrant constitutive activation of DNA...

  14. Dynamic Association of the Replication Initiator and Transcription Factor DnaA with the Bacillus subtilis Chromosome during Replication Stress

    OpenAIRE

    2008-01-01

    DnaA functions as both a transcription factor and the replication initiator in bacteria. We characterized the DNA binding dynamics of DnaA on a genomic level. Based on cross-linking and chromatin immunoprecipitation data, DnaA binds at least 17 loci, 15 of which are regulated transcriptionally in response to inhibition of replication (replication stress). Six loci, each of which has a cluster of at least nine potential DnaA binding sites, had significant increases in binding by DnaA when repl...

  15. Tomato yellow leaf curl Sardinia virus-resistant tomato plants expressing the multifunctional N-terminal domain of the replication-associated protein show transcriptional changes resembling stress-related responses.

    Science.gov (United States)

    Lucioli, Alessandra; Berardi, Alessandra; Gatti, Francesca; Tavazza, Raffaela; Pizzichini, Daniele; Tavazza, Mario

    2014-01-01

    The N-terminal domain (amino acids 1-130) of the replication-associated protein (Rep130 ) of Tomato yellow leaf curl Sardinia virus (TYLCSV) retains the ability of full-length Rep to localize to the nucleus and to down-regulate C1 transcription when ectopically expressed in plants, both functions being required to inhibit homologous viral replication. In this study, we analysed the effect of Rep130 expression on virus resistance and the plant transcriptome in the natural and agronomically important host species of TYLCSV, Solanum lycopersicum. Tomato plants accumulating high levels of Rep130 were generated and proved to be resistant to TYLCSV. Using an in vitro assay, we showed that plant-expressed Rep130 also retains the catalytic activity of Rep, thus supporting the notion that this protein domain is fully functional. Interestingly, Rep130 -expressing tomatoes were characterized by an altered transcriptional profile resembling stress-related responses. Notably, the serine-type protease inhibitor (Ser-PI) category was over-represented among the 20 up-regulated genes. The involvement of Rep130 in the alteration of host mRNA steady-state levels was confirmed using a distinct set of virus-resistant transgenic tomato plants expressing the same TYLCSV Rep130 , but from a different, synthetic, gene. Eight genes were found to be up-regulated in both types of transgenic tomato and two encoded Ser-PIs. Four of these eight genes were also up-regulated in TYLCSV-infected wild-type tomato plants. Implications with regard to the ability of this Rep domain to interfere with viral infections and to alter the host transcriptome are discussed.

  16. Identification of 30 protein species involved in replicative senescence and stress-induced premature senescence

    DEFF Research Database (Denmark)

    Dierick, Jean François; Kalume, Dário E; Wenders, Frédéric

    2002-01-01

    Exposure of human proliferative cells to subcytotoxic stress triggers stress-induced premature senescence (SIPS) which is characterized by many biomarkers of replicative senescence. Proteomic comparison of replicative senescence and stress-induced premature senescence indicates that, at the level....... These changes affect different cell functions, including energy metabolism, defense systems, maintenance of the redox potential, cell morphology and transduction pathways.......Exposure of human proliferative cells to subcytotoxic stress triggers stress-induced premature senescence (SIPS) which is characterized by many biomarkers of replicative senescence. Proteomic comparison of replicative senescence and stress-induced premature senescence indicates that, at the level...... of protein expression, stress-induced premature senescence and replicative senescence are different phenotypes sharing however similarities. In this study, we identified 30 proteins showing changes of expression level specific or common to replicative senescence and/or stress-induced premature senescence...

  17. Dormant origins licensed by excess Mcm2-7 are required for human cells to survive replicative stress.

    Science.gov (United States)

    Ge, Xin Quan; Jackson, Dean A; Blow, J Julian

    2007-12-15

    In late mitosis and early G1, Mcm2-7 complexes are loaded onto DNA to license replication origins for use in the upcoming S phase. However, the amount of Mcm2-7 loaded is in significant excess over the number of origins normally used. We show here that in human cells, excess chromatin-bound Mcm2-7 license dormant replication origins that do not fire during normal DNA replication, in part due to checkpoint activity. Dormant origins were activated within active replicon clusters if replication fork progression was inhibited, despite the activation of S-phase checkpoints. After lowering levels of chromatin-bound Mcm2-7 in human cells by RNA interference (RNAi), the use of dormant origins was suppressed in response to replicative stress. Although cells with lowered chromatin-bound Mcm2-7 replicated at normal rates, when challenged with replication inhibitors they had dramatically reduced rates of DNA synthesis and reduced viability. These results suggest that the use of dormant origins licensed by excess Mcm2-7 is a new and physiologically important mechanism that cells utilize to maintain DNA replication rates under conditions of replicative stress. We propose that checkpoint kinase activity can preferentially suppress initiation within inactive replicon clusters, thereby directing new initiation events toward active clusters that are experiencing replication problems.

  18. The Replication Stress Response in Pancreatic Cancer

    Science.gov (United States)

    2014-12-01

    plate. We completed three replicas of the primary screen using a library of 1540 siRNAs, corresponding to four unique siRNA duplexes, targeting each... Gandhi , K., Kowalski, J., Kooby, D.A., El-Rayes, B.F., Staley, C.A., Adsay, N.V., Curran, W.J., Landry, J.C., Maithel, S.K., Yu, D.S. 2013. Low CHD5...Nagaraju, G.P., Liu, E.A., Saka, B., Hall, W.A., Shelton, J.W., Gandhi , K., Pauly, R., Kowalski, J., Kooby, D.A., El-Rayes, B.F., Staley, C.A., Adsay

  19. Oncogenic Herpesvirus Utilizes Stress-Induced Cell Cycle Checkpoints for Efficient Lytic Replication.

    Directory of Open Access Journals (Sweden)

    Giuseppe Balistreri

    2016-02-01

    Full Text Available Kaposi's sarcoma herpesvirus (KSHV causes Kaposi's sarcoma and certain lymphoproliferative malignancies. Latent infection is established in the majority of tumor cells, whereas lytic replication is reactivated in a small fraction of cells, which is important for both virus spread and disease progression. A siRNA screen for novel regulators of KSHV reactivation identified the E3 ubiquitin ligase MDM2 as a negative regulator of viral reactivation. Depletion of MDM2, a repressor of p53, favored efficient activation of the viral lytic transcription program and viral reactivation. During lytic replication cells activated a p53 response, accumulated DNA damage and arrested at G2-phase. Depletion of p21, a p53 target gene, restored cell cycle progression and thereby impaired the virus reactivation cascade delaying the onset of virus replication induced cytopathic effect. Herpesviruses are known to reactivate in response to different kinds of stress, and our study now highlights the molecular events in the stressed host cell that KSHV has evolved to utilize to ensure efficient viral lytic replication.

  20. Oncogenic Herpesvirus Utilizes Stress-Induced Cell Cycle Checkpoints for Efficient Lytic Replication.

    Science.gov (United States)

    Balistreri, Giuseppe; Viiliäinen, Johanna; Turunen, Mikko; Diaz, Raquel; Lyly, Lauri; Pekkonen, Pirita; Rantala, Juha; Ojala, Krista; Sarek, Grzegorz; Teesalu, Mari; Denisova, Oxana; Peltonen, Karita; Julkunen, Ilkka; Varjosalo, Markku; Kainov, Denis; Kallioniemi, Olli; Laiho, Marikki; Taipale, Jussi; Hautaniemi, Sampsa; Ojala, Päivi M

    2016-02-01

    Kaposi's sarcoma herpesvirus (KSHV) causes Kaposi's sarcoma and certain lymphoproliferative malignancies. Latent infection is established in the majority of tumor cells, whereas lytic replication is reactivated in a small fraction of cells, which is important for both virus spread and disease progression. A siRNA screen for novel regulators of KSHV reactivation identified the E3 ubiquitin ligase MDM2 as a negative regulator of viral reactivation. Depletion of MDM2, a repressor of p53, favored efficient activation of the viral lytic transcription program and viral reactivation. During lytic replication cells activated a p53 response, accumulated DNA damage and arrested at G2-phase. Depletion of p21, a p53 target gene, restored cell cycle progression and thereby impaired the virus reactivation cascade delaying the onset of virus replication induced cytopathic effect. Herpesviruses are known to reactivate in response to different kinds of stress, and our study now highlights the molecular events in the stressed host cell that KSHV has evolved to utilize to ensure efficient viral lytic replication.

  1. Chronic DNA Replication Stress Reduces Replicative Lifespan of Cells by TRP53-Dependent, microRNA-Assisted MCM2-7 Downregulation.

    Directory of Open Access Journals (Sweden)

    Gongshi Bai

    2016-01-01

    Full Text Available Circumstances that compromise efficient DNA replication, such as disruptions to replication fork progression, cause a state known as DNA replication stress (RS. Whereas normally proliferating cells experience low levels of RS, excessive RS from intrinsic or extrinsic sources can trigger cell cycle arrest and senescence. Here, we report that a key driver of RS-induced senescence is active downregulation of the Minichromosome Maintenance 2-7 (MCM2-7 factors that are essential for replication origin licensing and which constitute the replicative helicase core. Proliferating cells produce high levels of MCM2-7 that enable formation of dormant origins that can be activated in response to acute, experimentally-induced RS. However, little is known about how physiological RS levels impact MCM2-7 regulation. We found that chronic exposure of primary mouse embryonic fibroblasts (MEFs to either genetically-encoded or environmentally-induced RS triggered gradual MCM2-7 repression, followed by inhibition of replication and senescence that could be accelerated by MCM hemizygosity. The MCM2-7 reduction in response to RS is TRP53-dependent, and involves a group of Trp53-dependent miRNAs, including the miR-34 family, that repress MCM expression in replication-stressed cells before they undergo terminal cell cycle arrest. miR-34 ablation partially rescued MCM2-7 downregulation and genomic instability in mice with endogenous RS. Together, these data demonstrate that active MCM2-7 repression is a physiologically important mechanism for RS-induced cell cycle arrest and genome maintenance on an organismal level.

  2. The transcription elongation factor Bur1-Bur2 interacts with replication protein A and maintains genome stability during replication stress

    DEFF Research Database (Denmark)

    Clausing, Emanuel; Mayer, Andreas; Chanarat, Sittinan

    2010-01-01

    foci. Interestingly, the DNA damage sensitivity of an rfa1 mutant was suppressed by bur1 mutation, further underscoring a functional link between these two protein complexes. The transcription elongation factor Bur1-Bur2 interacts with RPA and maintains genome integrity during DNA replication stress....

  3. Slow Replication Fork Velocity of Homologous Recombination-Defective Cells Results from Endogenous Oxidative Stress.

    Science.gov (United States)

    Wilhelm, Therese; Ragu, Sandrine; Magdalou, Indiana; Machon, Christelle; Dardillac, Elodie; Técher, Hervé; Guitton, Jérôme; Debatisse, Michelle; Lopez, Bernard S

    2016-05-01

    Replications forks are routinely hindered by different endogenous stresses. Because homologous recombination plays a pivotal role in the reactivation of arrested replication forks, defects in homologous recombination reveal the initial endogenous stress(es). Homologous recombination-defective cells consistently exhibit a spontaneously reduced replication speed, leading to mitotic extra centrosomes. Here, we identify oxidative stress as a major endogenous source of replication speed deceleration in homologous recombination-defective cells. The treatment of homologous recombination-defective cells with the antioxidant N-acetyl-cysteine or the maintenance of the cells at low O2 levels (3%) rescues both the replication fork speed, as monitored by single-molecule analysis (molecular combing), and the associated mitotic extra centrosome frequency. Reciprocally, the exposure of wild-type cells to H2O2 reduces the replication fork speed and generates mitotic extra centrosomes. Supplying deoxynucleotide precursors to H2O2-exposed cells rescued the replication speed. Remarkably, treatment with N-acetyl-cysteine strongly expanded the nucleotide pool, accounting for the replication speed rescue. Remarkably, homologous recombination-defective cells exhibit a high level of endogenous reactive oxygen species. Consistently, homologous recombination-defective cells accumulate spontaneous γH2AX or XRCC1 foci that are abolished by treatment with N-acetyl-cysteine or maintenance at 3% O2. Finally, oxidative stress stimulated homologous recombination, which is suppressed by supplying deoxynucleotide precursors. Therefore, the cellular redox status strongly impacts genome duplication and transmission. Oxidative stress should generate replication stress through different mechanisms, including DNA damage and nucleotide pool imbalance. These data highlight the intricacy of endogenous replication and oxidative stresses, which are both evoked during tumorigenesis and senescence initiation

  4. TRAIP is a PCNA-binding ubiquitin ligase that protects genome stability after replication stress

    DEFF Research Database (Denmark)

    Hoffmann, Saskia; Smedegaard, Stine; Nakamura, Kyosuke;

    2016-01-01

    , allowing cells to mitigate the threats to genome stability posed by replication stress. We identify the E3 ubiquitin ligase TRAIP as a new factor at active and stressed replication forks that directly interacts with PCNA via a conserved PCNA-interacting peptide (PIP) box motif. We show that TRAIP promotes......Cellular genomes are highly vulnerable to perturbations to chromosomal DNA replication. Proliferating cell nuclear antigen (PCNA), the processivity factor for DNA replication, plays a central role as a platform for recruitment of genome surveillance and DNA repair factors to replication forks...... ATR-dependent checkpoint signaling in human cells by facilitating the generation of RPA-bound single-stranded DNA regions upon replication stress in a manner that critically requires its E3 ligase activity and is potentiated by the PIP box. Consequently, loss of TRAIP function leads to enhanced...

  5. The leukemia-associated Rho guanine nucleotide exchange factor LARG is required for efficient replication stress signaling.

    Science.gov (United States)

    Beveridge, Ryan D; Staples, Christopher J; Patil, Abhijit A; Myers, Katie N; Maslen, Sarah; Skehel, J Mark; Boulton, Simon J; Collis, Spencer J

    2014-01-01

    We previously identified and characterized TELO2 as a human protein that facilitates efficient DNA damage response (DDR) signaling. A subsequent yeast 2-hybrid screen identified LARG; Leukemia-Associated Rho Guanine Nucleotide Exchange Factor (also known as Arhgef12), as a potential novel TELO2 interactor. LARG was previously shown to interact with Pericentrin (PCNT), which, like TELO2, is required for efficient replication stress signaling. Here we confirm interactions between LARG, TELO2 and PCNT and show that a sub-set of LARG co-localizes with PCNT at the centrosome. LARG-deficient cells exhibit replication stress signaling defects as evidenced by; supernumerary centrosomes, reduced replication stress-induced γH2AX and RPA nuclear foci formation, and reduced activation of the replication stress signaling effector kinase Chk1 in response to hydroxyurea. As such, LARG-deficient cells are sensitive to replication stress-inducing agents such as hydroxyurea and mitomycin C. Conversely we also show that depletion of TELO2 and the replication stress signaling kinase ATR leads to RhoA signaling defects. These data therefore reveal a level of crosstalk between the RhoA and DDR signaling pathways. Given that mutations in both ATR and PCNT can give rise to the related primordial dwarfism disorders of Seckel Syndrome and Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) respectively, which both exhibit defects in ATR-dependent checkpoint signaling, these data also raise the possibility that mutations in LARG or disruption to RhoA signaling may be contributory factors to the etiology of a sub-set of primordial dwarfism disorders.

  6. Resveratrol sequentially induces replication and oxidative stresses to drive p53-CXCR2 mediated cellular senescence in cancer cells.

    Science.gov (United States)

    Li, Boxuan; Hou, Dong; Guo, Haiyang; Zhou, Haibin; Zhang, Shouji; Xu, Xiuhua; Liu, Qiao; Zhang, Xiyu; Zou, Yongxin; Gong, Yaoqin; Shao, Changshun

    2017-03-16

    Resveratrol (RSV) acts either as an antioxidant or a pro-oxidant depending on contexts. RSV-treated cancer cells may experience replication stress that can lead to cellular senescence or apoptosis. While both oxidative and replication stresses may mediate the anti-proliferation effect of RSV, to what extent each contributes to the impaired proliferation in response to RSV remains uncharacterized. We here report the study of the roles of replication and oxidative stresses in mediating cellular senescence in cancer cells treated with RSV. RSV induced S-phase arrest and cellular senescence in a dose-dependent manner in U2OS and A549 cancer cells as well as in normal human fibroblasts. We observed that nucleosides significantly alleviated RSV-induced replication stress and DNA damage response, and consequently attenuating cellular senescence. While the elevation of reactive oxygen species (ROS) also mediated the pro-senescent effect of RSV, it occurred after S-phase arrest. However, the induction of ROS by RSV was independent of S-phase arrest and actually reinforced the latter. We also demonstrated a critical role of the p53-CXCR2 axis in mediating RSV-induced senescence. Interestingly, CXCR2 also functioned as a barrier to apoptosis. Together, our results provided more insights into the biology of RSV-induced stress and its cellular consequences.

  7. TRAIP is a PCNA-binding ubiquitin ligase that protects genome stability after replication stress

    DEFF Research Database (Denmark)

    Hoffmann, Saskia; Smedegaard, Stine; Nakamura, Kyosuke

    2016-01-01

    , allowing cells to mitigate the threats to genome stability posed by replication stress. We identify the E3 ubiquitin ligase TRAIP as a new factor at active and stressed replication forks that directly interacts with PCNA via a conserved PCNA-interacting peptide (PIP) box motif. We show that TRAIP promotes...... ATR-dependent checkpoint signaling in human cells by facilitating the generation of RPA-bound single-stranded DNA regions upon replication stress in a manner that critically requires its E3 ligase activity and is potentiated by the PIP box. Consequently, loss of TRAIP function leads to enhanced...... chromosomal instability and decreased cell survival after replication stress. These findings establish TRAIP as a PCNA-binding ubiquitin ligase with an important role in protecting genome integrity after obstacles to DNA replication....

  8. Transcription-Replication Conflict Orientation Modulates R-Loop Levels and Activates Distinct DNA Damage Responses.

    Science.gov (United States)

    Hamperl, Stephan; Bocek, Michael J; Saldivar, Joshua C; Swigut, Tomek; Cimprich, Karlene A

    2017-08-10

    Conflicts between transcription and replication are a potent source of DNA damage. Co-transcriptional R-loops could aggravate such conflicts by creating an additional barrier to replication fork progression. Here, we use a defined episomal system to investigate how conflict orientation and R-loop formation influence genome stability in human cells. R-loops, but not normal transcription complexes, induce DNA breaks and orientation-specific DNA damage responses during conflicts with replication forks. Unexpectedly, the replisome acts as an orientation-dependent regulator of R-loop levels, reducing R-loops in the co-directional (CD) orientation but promoting their formation in the head-on (HO) orientation. Replication stress and deregulated origin firing increase the number of HO collisions leading to genome-destabilizing R-loops. Our findings connect DNA replication to R-loop homeostasis and suggest a mechanistic basis for genome instability resulting from deregulated DNA replication, observed in cancer and other disease states. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. New origin firing is inhibited by APC/CCdh1 activation in S-phase after severe replication stress.

    Science.gov (United States)

    Ercilla, Amaia; Llopis, Alba; Feu, Sonia; Aranda, Sergi; Ernfors, Patrik; Freire, Raimundo; Agell, Neus

    2016-06-01

    Defects in DNA replication and repair are known to promote genomic instability, a hallmark of cancer cells. Thus, eukaryotic cells have developed complex mechanisms to ensure accurate duplication of their genomes. While DNA damage response has been extensively studied in tumour cells, the pathways implicated in the response to replication stress are less well understood especially in non-transformed cells. Here we show that in non-transformed cells, APC/C(Cdh1) is activated upon severe replication stress. Activation of APC/C(Cdh1) prevents new origin firing and induces permanent arrest in S-phase. Moreover, Rad51-mediated homologous recombination is also impaired under these conditions. APC/C(Cdh1) activation in S-phase occurs after replication forks have been processed into double strand breaks. Remarkably, this activation, which correlates with decreased Emi1 levels, is not prevented by ATR/ATM inhibition, but it is abrogated in cells depleted of p53 or p21. Importantly, we found that the lack of APC/C(Cdh1) activity correlated with an increase in genomic instability. Taken together, our results define a new APC/C(Cdh1) function that prevents cell cycle resumption after prolonged replication stress by inhibiting origin firing, which may act as an additional mechanism in safeguarding genome integrity.

  10. Replication stress and mitotic dysfunction in cells expressing simian virus 40 large T antigen.

    Science.gov (United States)

    Hu, Liang; Filippakis, Harilaos; Huang, Haomin; Yen, Timothy J; Gjoerup, Ole V

    2013-12-01

    We previously demonstrated that simian virus 40 (SV40) large T antigen (LT) binds to the Bub1 kinase, a key regulator of the spindle checkpoint and chromosome segregation. Bub1 mutations or altered expression patterns are linked to chromosome missegregation and are considered to be a driving force in some human cancers. Here we report that LT, dependent on Bub1 binding, causes micronuclei, lagging chromatin, and anaphase bridges, which are hallmarks of chromosomal instability (CIN) and Bub1 insufficiency. Using time-lapse microscopy, we demonstrate that LT imposes a Bub1 binding-dependent delay in the metaphase-to-anaphase transition. Kinetochore fibers reveal that LT, via Bub1 binding, causes aberrant kinetochore (KT)-microtubule (MT) attachments and a shortened interkinetochore distance, consistent with a lack of tension. Previously, we showed that LT also induces the DNA damage response (DDR) via Bub1 binding. Using inducible LT cell lines, we show that an activated DDR was observed before the appearance of anaphase bridges and micronuclei. Furthermore, LT induction in serum-starved cells demonstrated γ-H2AX accumulation in cells that had not yet entered mitosis. Thus, DDR activation can occur independently of chromosome segregation defects. Replication stress pathways may be responsible, because signatures of replication stress were observed, which were attenuated by exogenous supplementation with nucleosides. Our observations allow us to propose a model that explains and integrates the diverse manifestations of genomic instability induced by LT.

  11. The stress-activated protein kinases p38α/β and JNK1/2 cooperate with Chk1 to inhibit mitotic entry upon DNA replication arrest.

    Science.gov (United States)

    Llopis, Alba; Salvador, Noelia; Ercilla, Amaia; Guaita-Esteruelas, Sandra; Barrantes, Ivan del Barco; Gupta, Jalaj; Gaestel, Matthias; Davis, Roger J; Nebreda, Angel R; Agell, Neus

    2012-10-01

    Accurate DNA replication is crucial for the maintenance of genome integrity. To this aim, cells have evolved complex surveillance mechanisms to prevent mitotic entry in the presence of partially replicated DNA. ATR and Chk1 are key elements in the signal transduction pathways of DNA replication checkpoint; however, other kinases also make significant contributions. We show here that the stress kinases p38 and JNK are activated when DNA replication is blocked, and that their activity allows S/M, but not G 2/M, checkpoint maintenance when Chk1 is inhibited. Activation of both kinases by DNA replication inhibition is not mediated by the caffeine-sensitive kinases ATR or ATM. Phosphorylation of MKK3/6 and MKK4, p38 and JNK upstream kinases was also observed upon DNA replication inhibition. Using a genetic approach, we dissected the p38 pathway and showed that both p38α and p38β isoforms collaborate to inhibit mitotic entry. We further defined MKK3/6 and MK2/3 as the key upstream and downstream elements in the p38 signaling cascade after replication arrest. Accordingly, we found that the stress signaling pathways collaborate with Chk1 to keep cyclin B1/Cdk1 complexes inactive when DNA replication is inhibited, thereby preventing cell cycle progression when DNA replication is stalled. Our results show a complex response to replication stress, where multiple pathways are activated and fulfill overlapping roles to prevent mitotic entry with unreplicated DNA.

  12. XRN2 Links Transcription Termination to DNA Damage and Replication Stress.

    Directory of Open Access Journals (Sweden)

    Julio C Morales

    2016-07-01

    Full Text Available XRN2 is a 5'-3' exoribonuclease implicated in transcription termination. Here we demonstrate an unexpected role for XRN2 in the DNA damage response involving resolution of R-loop structures and prevention of DNA double-strand breaks (DSBs. We show that XRN2 undergoes DNA damage-inducible nuclear re-localization, co-localizing with 53BP1 and R loops, in a transcription and R-loop-dependent process. XRN2 loss leads to increased R loops, genomic instability, replication stress, DSBs and hypersensitivity of cells to various DNA damaging agents. We demonstrate that the DSBs that arise with XRN2 loss occur at transcriptional pause sites. XRN2-deficient cells also exhibited an R-loop- and transcription-dependent delay in DSB repair after ionizing radiation, suggesting a novel role for XRN2 in R-loop resolution, suppression of replication stress, and maintenance of genomic stability. Our study highlights the importance of regulating transcription-related activities as a critical component in maintaining genetic stability.

  13. XRN2 Links Transcription Termination to DNA Damage and Replication Stress.

    Science.gov (United States)

    Morales, Julio C; Richard, Patricia; Patidar, Praveen L; Motea, Edward A; Dang, Tuyen T; Manley, James L; Boothman, David A

    2016-07-01

    XRN2 is a 5'-3' exoribonuclease implicated in transcription termination. Here we demonstrate an unexpected role for XRN2 in the DNA damage response involving resolution of R-loop structures and prevention of DNA double-strand breaks (DSBs). We show that XRN2 undergoes DNA damage-inducible nuclear re-localization, co-localizing with 53BP1 and R loops, in a transcription and R-loop-dependent process. XRN2 loss leads to increased R loops, genomic instability, replication stress, DSBs and hypersensitivity of cells to various DNA damaging agents. We demonstrate that the DSBs that arise with XRN2 loss occur at transcriptional pause sites. XRN2-deficient cells also exhibited an R-loop- and transcription-dependent delay in DSB repair after ionizing radiation, suggesting a novel role for XRN2 in R-loop resolution, suppression of replication stress, and maintenance of genomic stability. Our study highlights the importance of regulating transcription-related activities as a critical component in maintaining genetic stability.

  14. The mammalian INO80 chromatin remodeling complex is required for replication stress recovery

    Science.gov (United States)

    Vassileva, Ivelina; Yanakieva, Iskra; Peycheva, Michaela; Gospodinov, Anastas; Anachkova, Boyka

    2014-01-01

    A number of studies have implicated the yeast INO80 chromatin remodeling complex in DNA replication, but the function of the human INO80 complex during S phase remains poorly understood. Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. In the absence of the Ino80 protein, cells became hypersensitive to hydroxyurea and displayed hyperactive ATR-Chk1 signaling. Using bulk and fiber labeling of DNA, we found that cells deficient for Ino80 and Arp8 had impaired replication restart after treatment with replication inhibitors and accumulated double-strand breaks as evidenced by the formation of γ-H2AX and Rad51 foci. These data indicate that under conditions of replication stress mammalian INO80 protects stalled forks from collapsing and allows their subsequent restart. PMID:25016522

  15. Staphylococcal response to oxidative stress

    Directory of Open Access Journals (Sweden)

    Rosmarie eGaupp

    2012-03-01

    Full Text Available Staphylococci are a versatile genus of bacteria that are capable of causing acute and chronic infections in diverse host species. The success of staphylococci as pathogens is due in part to their ability to mitigate endogenous and exogenous oxidative and nitrosative stress. Endogenous oxidative stress is a consequence of life in an aerobic environment; whereas, exogenous oxidative and nitrosative stress are often due to the bacteria’s interaction with host immune systems. To overcome the deleterious effects of oxidative and nitrosative stress, staphylococci have evolved protection, detoxification, and repair mechanisms that are controlled by a network of regulators. In this review, we summarize the cellular targets of oxidative stress, the mechanisms by which staphylococci sense oxidative stress and damage, oxidative stress protection and repair mechanisms, and regulation of the oxidative stress response. When possible, special attention is given to how the oxidative stress defense mechanisms help staphylococci control oxidative stress in the host.

  16. Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis.

    Science.gov (United States)

    Pinzaru, Alexandra M; Hom, Robert A; Beal, Angela; Phillips, Aaron F; Ni, Eric; Cardozo, Timothy; Nair, Nidhi; Choi, Jaehyuk; Wuttke, Deborah S; Sfeir, Agnel; Denchi, Eros Lazzerini

    2016-06-01

    Genome sequencing studies have revealed a number of cancer-associated mutations in the telomere-binding factor POT1. Here, we show that when combined with p53 deficiency, depletion of murine POT1a in common lymphoid progenitor cells fosters genetic instability, accelerates the onset, and increases the severity of T cell lymphomas. In parallel, we examined human and mouse cells carrying POT1 mutations found in cutaneous T cell lymphoma (CTCL) patients. Inhibition of POT1 activates ATR-dependent DNA damage signaling and induces telomere fragility, replication fork stalling, and telomere elongation. Our data suggest that these phenotypes are linked to impaired CST (CTC1-STN1-TEN1) function at telomeres. Lastly, we show that proliferation of cancer cells lacking POT1 is enabled by the attenuation of the ATR kinase pathway. These results uncover a role for defective telomere replication during tumorigenesis.

  17. Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Alexandra M. Pinzaru

    2016-06-01

    Full Text Available Genome sequencing studies have revealed a number of cancer-associated mutations in the telomere-binding factor POT1. Here, we show that when combined with p53 deficiency, depletion of murine POT1a in common lymphoid progenitor cells fosters genetic instability, accelerates the onset, and increases the severity of T cell lymphomas. In parallel, we examined human and mouse cells carrying POT1 mutations found in cutaneous T cell lymphoma (CTCL patients. Inhibition of POT1 activates ATR-dependent DNA damage signaling and induces telomere fragility, replication fork stalling, and telomere elongation. Our data suggest that these phenotypes are linked to impaired CST (CTC1-STN1-TEN1 function at telomeres. Lastly, we show that proliferation of cancer cells lacking POT1 is enabled by the attenuation of the ATR kinase pathway. These results uncover a role for defective telomere replication during tumorigenesis.

  18. Inhibitors of the interferon response enhance virus replication in vitro.

    Directory of Open Access Journals (Sweden)

    Claire E Stewart

    Full Text Available Virus replication efficiency is influenced by two conflicting factors, kinetics of the cellular interferon (IFN response and induction of an antiviral state versus speed of virus replication and virus-induced inhibition of the IFN response. Disablement of a virus's capacity to circumvent the IFN response enables both basic research and various practical applications. However, such IFN-sensitive viruses can be difficult to grow to high-titer in cells that produce and respond to IFN. The current default option for growing IFN-sensitive viruses is restricted to a limited selection of cell-lines (e.g. Vero cells that have lost their ability to produce IFN. This study demonstrates that supplementing tissue-culture medium with an IFN inhibitor provides a simple, effective and flexible approach to increase the growth of IFN-sensitive viruses in a cell-line of choice. We report that IFN inhibitors targeting components of the IFN response (TBK1, IKK2, JAK1 significantly increased virus replication. More specifically, the JAK1/2 inhibitor Ruxolitinib enhances the growth of viruses that are sensitive to IFN due to (i loss of function of the viral IFN antagonist (due to mutation or species-specific constraints or (ii mutations/host cell constraints that slow virus spread such that it can be controlled by the IFN response. This was demonstrated for a variety of viruses, including, viruses with disabled IFN antagonists that represent live-attenuated vaccine candidates (Respiratory Syncytial Virus (RSV, Influenza Virus, traditionally attenuated vaccine strains (Measles, Mumps and a slow-growing wild-type virus (RSV. In conclusion, supplementing tissue culture-medium with an IFN inhibitor to increase the growth of IFN-sensitive viruses in a cell-line of choice represents an approach, which is broadly applicable to research investigating the importance of the IFN response in controlling virus infections and has utility in a number of practical applications

  19. Jnk2 effects on tumor development, genetic instability and replicative stress in an oncogene-driven mouse mammary tumor model.

    Directory of Open Access Journals (Sweden)

    Peila Chen

    Full Text Available Oncogenes induce cell proliferation leading to replicative stress, DNA damage and genomic instability. A wide variety of cellular stresses activate c-Jun N-terminal kinase (JNK proteins, but few studies have directly addressed the roles of JNK isoforms in tumor development. Herein, we show that jnk2 knockout mice expressing the Polyoma Middle T Antigen transgene developed mammary tumors earlier and experienced higher tumor multiplicity compared to jnk2 wildtype mice. Lack of jnk2 expression was associated with higher tumor aneuploidy and reduced DNA damage response, as marked by fewer pH2AX and 53BP1 nuclear foci. Comparative genomic hybridization further confirmed increased genomic instability in PyV MT/jnk2-/- tumors. In vitro, PyV MT/jnk2-/- cells underwent replicative stress and cell death as evidenced by lower BrdU incorporation, and sustained chromatin licensing and DNA replication factor 1 (CDT1 and p21(Waf1 protein expression, and phosphorylation of Chk1 after serum stimulation, but this response was not associated with phosphorylation of p53 Ser15. Adenoviral overexpression of CDT1 led to similar differences between jnk2 wildtype and knockout cells. In normal mammary cells undergoing UV induced single stranded DNA breaks, JNK2 localized to RPA (Replication Protein A coated strands indicating that JNK2 responds early to single stranded DNA damage and is critical for subsequent recruitment of DNA repair proteins. Together, these data support that JNK2 prevents replicative stress by coordinating cell cycle progression and DNA damage repair mechanisms.

  20. An overview of HCV molecular biology, replication and immune responses

    Directory of Open Access Journals (Sweden)

    Nawaz Zafar

    2011-04-01

    Full Text Available Abstract Hepatitis C virus (HCV causes acute and chronic hepatitis which can eventually lead to permanent liver damage, hepatocellular carcinoma and death. Currently, there is no vaccine available for prevention of HCV infection due to high degree of strain variation. The current treatment of care, Pegylated interferon α in combination with ribavirin is costly, has significant side effects and fails to cure about half of all infections. In this review, we summarize molecular virology, replication and immune responses against HCV and discussed how HCV escape from adaptive and humoral immune responses. This advance knowledge will be helpful for development of vaccine against HCV and discovery of new medicines both from synthetic chemistry and natural sources.

  1. IL1- and TGFβ-Nox4 signaling, oxidative stress and DNA damage response are shared features of replicative, oncogene-induced, and drug-induced paracrine ‘Bystander senescence’

    Science.gov (United States)

    Hubackova, Sona; Krejcikova, Katerina; Bartek, Jiri; Hodny, Zdenek

    2012-01-01

    Many cancers arise at sites of infection and inflammation. Cellular senescence, a permanent state of cell cycle arrest that provides a barrier against tumorigenesis, is accompanied by elevated proinflammatory cytokines such as IL1, IL6, IL8 and TNFα. Here we demonstrate that media conditioned by cells undergoing any of the three main forms of senescence, i.e. replicative, oncogene- and drug-induced, contain high levels of IL1, IL6, and TGFb capable of inducing reactive oxygen species (ROS)-mediated DNA damage response (DDR). Persistent cytokine signaling and activated DDR evoke senescence in normal bystander cells, accompanied by activation of the JAK/STAT, TGFβ/SMAD and IL1/NFκB signaling pathways. Whereas inhibition of IL6/STAT signaling had no effect on DDR induction in bystander cells, inhibition of either TGFβ/SMAD or IL1/NFκB pathway resulted in decreased ROS production and reduced DDR in bystander cells. Simultaneous inhibition of both TGFβ/SMAD and IL1/NFκB pathways completely suppressed DDR indicating that IL1 and TGFβ cooperate to induce and/or maintain bystander senescence. Furthermore, the observed IL1- and TGFβ-induced expression of NAPDH oxidase Nox4 indicates a mechanistic link between the senescence-associated secretory phenotype (SASP) and DNA damage signaling as a feature shared by development of all major forms of paracrine bystander senescence. PMID:23385065

  2. Brucella suis Vaccine Strain 2 Induces Endoplasmic Reticulum Stress that Affects Intracellular Replication in Goat Trophoblast Cells In vitro.

    Science.gov (United States)

    Wang, Xiangguo; Lin, Pengfei; Li, Yang; Xiang, Caixia; Yin, Yanlong; Chen, Zhi; Du, Yue; Zhou, Dong; Jin, Yaping; Wang, Aihua

    2016-01-01

    Brucella has been reported to impair placental trophoblasts, a cellular target where Brucella efficiently replicates in association with the endoplasmic reticulum (ER), and ultimately trigger abortion in pregnant animals. However, the precise effects of Brucella on trophoblast cells remain unclear. Here, we describe the infection and replication of Brucella suis vaccine strain 2 (B.suis.S2) in goat trophoblast cells (GTCs) and the cellular and molecular responses induced in vitro. Our studies demonstrated that B.suis.S2 was able to infect and proliferate to high titers, hamper the proliferation of GTCs and induce apoptosis due to ER stress. Tunicamycin (Tm), a pharmacological chaperone that strongly mounts ER stress-induced apoptosis, inhibited B.suis.S2 replication in GTCs. In addition, 4 phenyl butyric acid (4-PBA), a pharmacological chaperone that alleviates ER stress-induced apoptosis, significantly enhanced B.suis.S2 replication in GTCs. The Unfolded Protein Response (UPR) chaperone molecule GRP78 also promoted B.suis.S2 proliferation in GTCs by inhibiting ER stress-induced apoptosis. We also discovered that the IRE1 pathway, but not the PERK or ATF6 pathway, was activated in the process. However, decreasing the expression of phosphoIRE1α and IRE1α proteins with Irestatin 9389 (IRE1 antagonist) in GTCs did not affect the proliferation of B.suis.S2. Although GTC implantation was not affected upon B.suis.S2 infection, progesterone secretion was suppressed, and prolactin and estrogen secretion increased; these effects were accompanied by changes in the expression of genes encoding key steroidogenic enzymes. This study systematically explored the mechanisms of abortion in Brucella infection from the viewpoint of pathogen invasion, ER stress and reproductive endocrinology. Our findings may provide new insight for understanding the mechanisms involved in goat abortions caused by Brucella infection.

  3. Brucella suis vaccine strain 2 induces endoplasmic reticulum stress that affects intracellular replication in goat trophoblast cells in vitro

    Directory of Open Access Journals (Sweden)

    Xiangguo eWang

    2016-02-01

    Full Text Available Brucella has been reported to impair placental trophoblasts, a cellular target where Brucella efficiently replicates in association with the endoplasmic reticulum (ER, and ultimately trigger abortion in pregnant animals. However, the precise effects of Brucella on trophoblast cells remain unclear. Here, we describe the infection and replication of Brucella suis vaccine strain 2 (B.suis.S2 in goat trophoblast cells (GTCs and the cellular and molecular responses induced in vitro. Our studies demonstrated that B.suis.S2 was able to infect and proliferate to high titers, hamper the proliferation of GTCs and induce apoptosis due to ER stress. Tunicamycin (Tm, a pharmacological chaperone that strongly mounts ER stress-induced apoptosis, inhibited B.suis.S2 replication in GTCs. In addition, 4 phenyl butyric acid (4-PBA, a pharmacological chaperone that alleviates ER stress-induced apoptosis, significantly enhanced B.suis.S2 replication in GTCs. The Unfolded Protein Response (UPR chaperone molecule GRP78 also promoted B.suis.S2 proliferation in GTCs by inhibiting ER stress-induced apoptosis. We also discovered that the IRE1 pathway, but not the PERK or ATF6 pathway, was activated in the process. However, decreasing the expression of phosphoIRE1α and IRE1α proteins with Irestatin 9389 (IRE1 antagonist in GTCs did not affect the proliferation of B.suis.S2. Although GTC implantation was not affected upon B.suis.S2 infection, progesterone secretion was suppressed, and prolactin and estrogen secretion increased; these effects were accompanied by changes in the expression of genes encoding key steroidogenic enzymes. This study systematically explored the mechanisms of abortion in Brucella infection from the viewpoint of pathogen invasion, ER stress and reproductive endocrinology. Our findings may provide new insight for understanding the mechanisms involved in goat abortions caused by Brucella infection.

  4. Targeting radioresistant breast cancer cells by single agent CHK1 inhibitor via enhancing replication stress

    Science.gov (United States)

    Du, Zhanwen; Gao, Jinnan; Yang, Shuming; Gorityala, Shashank; Xiong, Xiahui; Deng, Ou; Ma, Zhefu; Yan, Chunhong; Susana, Gonzalo; Xu, Yan; Zhang, Junran

    2016-01-01

    Radiotherapy (RT) remains a standard therapeutic modality for breast cancer patients. However, intrinsic or acquired resistance limits the efficacy of RT. Here, we demonstrate that CHK1 inhibitor AZD7762 alone significantly inhibited the growth of radioresistant breast cancer cells (RBCC). Given the critical role of ATR/CHK1 signaling in suppressing oncogene-induced replication stress (RS), we hypothesize that CHK1 inhibition leads to the specific killing for RBCC due to its abrogation in the suppression of RS induced by oncogenes. In agreement, the expression of oncogenes c-Myc/CDC25A/c-Src/H-ras/E2F1 and DNA damage response (DDR) proteins ATR/CHK1/BRCA1/CtIP were elevated in RBCC. AZD7762 exposure led to significantly higher levels of RS in RBCC, compared to the parental cells. The mechanisms by which CHK1 inhibition led to specific increase of RS in RBCC were related to the interruptions in the replication fork dynamics and the homologous recombination (HR). In summary, RBCC activate oncogenic pathways and thus depend upon mechanisms controlled by CHK1 signaling to maintain RS under control for survival. Our study provided the first example where upregulating RS by CHK1 inhibitor contributes to the specific killing of RBCC, and highlight the importance of the CHK1 as a potential target for treatment of radioresistant cancer cells. PMID:27167194

  5. 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...

  6. Replication stress interferes with histone recycling and predeposition marking of new histones.

    Science.gov (United States)

    Jasencakova, Zuzana; Scharf, Annette N D; Ask, Katrine; Corpet, Armelle; Imhof, Axel; Almouzni, Geneviève; Groth, Anja

    2010-03-12

    To restore chromatin on new DNA during replication, recycling of histones evicted ahead of the fork is combined with new histone deposition. The Asf1 histone chaperone, which buffers excess histones under stress, is a key player in this process. Yet how histones handled by human Asf1 are modified remains unclear. Here we identify marks on histones H3-H4 bound to Asf1 and changes induced upon replication stress. In S phase, distinct cytosolic and nuclear Asf1b complexes show ubiquitous H4K5K12diAc and heterogeneous H3 marks, including K9me1, K14ac, K18ac, and K56ac. Upon acute replication arrest, the predeposition mark H3K9me1 and modifications typical of chromatin accumulate in Asf1 complexes. In parallel, ssDNA is generated at replication sites, consistent with evicted histones being trapped with Asf1. During recovery, histones stored with Asf1 are rapidly used as replication resumes. This shows that replication stress interferes with predeposition marking and histone recycling with potential impact on epigenetic stability.

  7. Human Adipose-Derived Stem Cells Expanded Under Ambient Oxygen Concentration Accumulate Oxidative DNA Lesions and Experience Procarcinogenic DNA Replication Stress.

    Science.gov (United States)

    Bétous, Rémy; Renoud, Marie-Laure; Hoede, Claire; Gonzalez, Ignacio; Jones, Natalie; Longy, Michel; Sensebé, Luc; Cazaux, Christophe; Hoffmann, Jean-Sébastien

    2017-01-01

    Adipose-derived stem cells (ADSCs) have led to growing interest in cell-based therapy because they can be easily harvested from an abundant tissue. ADSCs must be expanded in vitro before transplantation. This essential step causes concerns about the safety of adult stem cells in terms of potential transformation. Tumorigenesis is driven in its earliest step by DNA replication stress, which is characterized by the accumulation of stalled DNA replication forks and activation of the DNA damage response. Thus, to evaluate the safety of ADSCs during ex vivo expansion, we monitored DNA replication under atmospheric (21%) or physiologic (1%) oxygen concentration. Here, by combining immunofluorescence and DNA combing, we show that ADSCs cultured under 21% oxygen accumulate endogenous oxidative DNA lesions, which interfere with DNA replication by increasing fork stalling events, thereby leading to incomplete DNA replication and fork collapse. Moreover, we found by RNA sequencing (RNA-seq) that culture of ADSCs under atmospheric oxygen concentration leads to misexpression of cell cycle and DNA replication genes, which could contribute to DNA replication stress. Finally, analysis of acquired small nucleotide polymorphism shows that expansion of ADSCs under 21% oxygen induces a mutational bias toward deleterious transversions. Overall, our results suggest that expanding ADSCs at a low oxygen concentration could reduce the risk for DNA replication stress-associated transformation, as occurs in neoplastic tissues. Stem Cells Translational Medicine 2017;6:68-76.

  8. Neuronal responses to physiological stress

    Directory of Open Access Journals (Sweden)

    Konstantinos eKagias

    2012-10-01

    Full Text Available Physiological stress can be defined as any external or internal condition that challenges the homeostasis of a cell or an organism. Physiological stress can be divided into three different aspects: environmental stress, intrinsic developmental stress and aging. Throughout life all living organisms are challenged by changes in the environment. Fluctuations in oxygen levels, temperature and redox state for example, trigger molecular events that enable an organism to adapt, survive and reproduce. In addition to external stressors, organisms experience stress associated with morphogenesis and changes in inner chemistry during normal development. For example, conditions such as intrinsic hypoxia and oxidative stress, which result from an increase in tissue mass, have to be confronted by developing embryos in order to complete their development. Finally, organisms face the challenge of stochastic accumulation of molecular damage during aging that results in decline and eventual death. Studies have shown that the nervous system plays a pivotal role in responding to stress. Neurons not only receive and process information from the environment but also actively respond to various stresses to promote survival. These responses include changes in the expression of molecules such as transcription factors and microRNAs that regulate stress resistance and adaptation. Moreover, both intrinsic and extrinsic stresses have a tremendous impact on neuronal development and maintenance with implications in many diseases. Here, we review the responses of neurons to various physiological stressors at the molecular and cellular level.

  9. Regulation of Stress Responses and Translational Control by Coronavirus

    Science.gov (United States)

    Fung, To Sing; Liao, Ying; Liu, Ding Xiang

    2016-01-01

    Similar to other viruses, coronavirus infection triggers cellular stress responses in infected host cells. The close association of coronavirus replication with the endoplasmic reticulum (ER) results in the ER stress responses, which impose a challenge to the viruses. Viruses, in turn, have come up with various mechanisms to block or subvert these responses. One of the ER stress responses is inhibition of the global protein synthesis to reduce the amount of unfolded proteins inside the ER lumen. Viruses have evolved the capacity to overcome the protein translation shutoff to ensure viral protein production. Here, we review the strategies exploited by coronavirus to modulate cellular stress response pathways. The involvement of coronavirus-induced stress responses and translational control in viral pathogenesis will also be briefly discussed. PMID:27384577

  10. Regulation of Stress Responses and Translational Control by Coronavirus

    Directory of Open Access Journals (Sweden)

    To Sing Fung

    2016-07-01

    Full Text Available Similar to other viruses, coronavirus infection triggers cellular stress responses in infected host cells. The close association of coronavirus replication with the endoplasmic reticulum (ER results in the ER stress responses, which impose a challenge to the viruses. Viruses, in turn, have come up with various mechanisms to block or subvert these responses. One of the ER stress responses is inhibition of the global protein synthesis to reduce the amount of unfolded proteins inside the ER lumen. Viruses have evolved the capacity to overcome the protein translation shutoff to ensure viral protein production. Here, we review the strategies exploited by coronavirus to modulate cellular stress response pathways. The involvement of coronavirus-induced stress responses and translational control in viral pathogenesis will also be briefly discussed.

  11. Replicative Homeostasis III: implications for antiviral therapy and mechanisms of response and non-response

    Directory of Open Access Journals (Sweden)

    Sallie Richard

    2007-03-01

    Full Text Available Abstract While improved drug regimens have greatly enhanced outcomes for patients with chronic viral infection, antiviral therapy is still not ideal due to drug toxicities, treatment costs, primary drug failure and emergent resistance. New antiviral agents, alternative treatment strategies and a better understanding of viral pathobiology, host responses and drug action are desperately needed. Interferon (IFN and ribavirin, are effective drugs used to treat hepatitis C (HCV, but the mechanism(s of their action are uncertain. Error catastrophe (EC, or precipitous loss of replicative fitness caused by genomic mutation, is postulated to mediate ribavirin action, but is a deeply flawed hypothesis lacking empirical confirmation. Paradoxically ribavirin, a proven RNA mutagen, has no impact on HCV viraemia long term, suggesting real viruses, replicating in-vitro, as opposed to mathematical models, replicating in-silico, are likely to resist EC by highly selective replication of fit (~consensus sequence genomes mediated, in part, by replicative homeostasis (RH, an epicyclic mechanism that dynamically links RNApol fidelity and processivity and other viral protein functions. Replicative homeostasis provides a rational explanation for the various responses seen during treatment of HCV, including genotype-specific and viral load-dependent differential response rates, as well as otherwise unexplained phenomena like the transient inhibition and rebound of HCV viraemia seen during ribavirin monotherapy. Replicative homeostasis also suggests a primarily non-immunological mechanism that mediates increased immune responsiveness during treatment with ribavirin (and other nucleos(tide analogues, explicating the enhanced second-phase clearance of HCV ribavirin promotes and, thus, the apparent immunomodulatory action of ribavirin. More importantly, RH suggests specific new antiviral therapeutic strategies.

  12. Archaeal Genome Guardians Give Insights into Eukaryotic DNA Replication and Damage Response Proteins

    Directory of Open Access Journals (Sweden)

    David S. Shin

    2014-01-01

    Full Text Available As the third domain of life, archaea, like the eukarya and bacteria, must have robust DNA replication and repair complexes to ensure genome fidelity. Archaea moreover display a breadth of unique habitats and characteristics, and structural biologists increasingly appreciate these features. As archaea include extremophiles that can withstand diverse environmental stresses, they provide fundamental systems for understanding enzymes and pathways critical to genome integrity and stress responses. Such archaeal extremophiles provide critical data on the periodic table for life as well as on the biochemical, geochemical, and physical limitations to adaptive strategies allowing organisms to thrive under environmental stress relevant to determining the boundaries for life as we know it. Specifically, archaeal enzyme structures have informed the architecture and mechanisms of key DNA repair proteins and complexes. With added abilities to temperature-trap flexible complexes and reveal core domains of transient and dynamic complexes, these structures provide insights into mechanisms of maintaining genome integrity despite extreme environmental stress. The DNA damage response protein structures noted in this review therefore inform the basis for genome integrity in the face of environmental stress, with implications for all domains of life as well as for biomanufacturing, astrobiology, and medicine.

  13. p38 (MAPK) stress signalling in replicative senescence in fibroblasts from progeroid and genomic instability syndromes.

    Science.gov (United States)

    Tivey, Hannah S E; Brook, Amy J C; Rokicki, Michal J; Kipling, David; Davis, Terence

    2013-02-01

    Werner Syndrome (WS) is a human segmental progeria resulting from mutations in a DNA helicase. WS fibroblasts have a shortened replicative capacity, an aged appearance, and activated p38 MAPK, features that can be modulated by inhibition of the p38 pathway. Loss of the WRNp RecQ helicase has been shown to result in replicative stress, suggesting that a link between faulty DNA repair and stress-induced premature cellular senescence may lead to premature ageing in WS. Other progeroid syndromes that share overlapping pathophysiological features with WS also show defects in DNA processing, raising the possibility that faulty DNA repair, leading to replicative stress and premature cellular senescence, might be a more widespread feature of premature ageing syndromes. We therefore analysed replicative capacity, cellular morphology and p38 activation, and the effects of p38 inhibition, in fibroblasts from a range of progeroid syndromes. In general, populations of young fibroblasts from non-WS progeroid syndromes do not have a high level of cells with an enlarged morphology and F-actin stress fibres, unlike young WS cells, although this varies between strains. p38 activation and phosphorylated HSP27 levels generally correlate well with cellular morphology, and treatment with the p38 inhibitor SB203580 effects cellular morphology only in strains with enlarged cells and phosphorylated HSP27. For some syndromes fibroblast replicative capacity was within the normal range, whereas for others it was significantly shorter (e.g. HGPS and DKC). However, although in most cases SB203580 extended replicative capacity, with the exception of WS and DKC the magnitude of the effect was not significantly different from normal dermal fibroblasts. This suggests that stress-induced premature cellular senescence via p38 activation is restricted to a small subset of progeroid syndromes.

  14. Replication stress interferes with histone recycling and predeposition marking of new histones

    DEFF Research Database (Denmark)

    Jasencakova, Zuzana; Scharf, Annette N D; Ask, Katrine

    2010-01-01

    To restore chromatin on new DNA during replication, recycling of histones evicted ahead of the fork is combined with new histone deposition. The Asf1 histone chaperone, which buffers excess histones under stress, is a key player in this process. Yet how histones handled by human Asf1 are modified...

  15. Individual heat stress response

    NARCIS (Netherlands)

    Havenith, G.

    1997-01-01

    In 5 experiments, heterogeneous subject groups (large variations in _VO2 max, regular daily activity level, mass, body surface area (AD), % body fat, and AD/mass ratio) were tested for their physiological response while exercising on a cycle ergometer at a relative (45% _VO2 max; REL) or an absolute

  16. The beta subunit sliding DNA clamp is responsible for unassisted mutagenic translesion replication by DNA polymerase III holoenzyme.

    Science.gov (United States)

    Tomer, G; Reuven, N B; Livneh, Z

    1998-11-24

    The replication of damaged nucleotides that have escaped DNA repair leads to the formation of mutations caused by misincorporation opposite the lesion. In Escherichia coli, this process is under tight regulation of the SOS stress response and is carried out by DNA polymerase III in a process that involves also the RecA, UmuD' and UmuC proteins. We have shown that DNA polymerase III holoenzyme is able to replicate, unassisted, through a synthetic abasic site in a gapped duplex plasmid. Here, we show that DNA polymerase III*, a subassembly of DNA polymerase III holoenzyme lacking the beta subunit, is blocked very effectively by the synthetic abasic site in the same DNA substrate. Addition of the beta subunit caused a dramatic increase of at least 28-fold in the ability of the polymerase to perform translesion replication, reaching 52% bypass in 5 min. When the ssDNA region in the gapped plasmid was extended from 22 nucleotides to 350 nucleotides, translesion replication still depended on the beta subunit, but it was reduced by 80%. DNA sequence analysis of translesion replication products revealed mostly -1 frameshifts. This mutation type is changed to base substitution by the addition of UmuD', UmuC, and RecA, as demonstrated in a reconstituted SOS translesion replication reaction. These results indicate that the beta subunit sliding DNA clamp is the major determinant in the ability of DNA polymerase III holoenzyme to perform unassisted translesion replication and that this unassisted bypass produces primarily frameshifts.

  17. Dengue-induced autophagy, virus replication and protection from cell death require ER stress (PERK) pathway activation.

    Science.gov (United States)

    Datan, E; Roy, S G; Germain, G; Zali, N; McLean, J E; Golshan, G; Harbajan, S; Lockshin, R A; Zakeri, Z

    2016-03-03

    A virus that reproduces in a host without killing cells can easily establish a successful infection. Previously, we showed that dengue-2, a virus that threatens 40% of the world, induces autophagy, enabling dengue to reproduce in cells without triggering cell death. Autophagy further protects the virus-laden cells from further insults. In this study, we evaluate how it does so; we show that dengue upregulates host pathways that increase autophagy, namely endoplasmic reticulum (ER) stress and ataxia telangiectasia mutated (ATM) signaling followed by production of reactive oxygen species (ROS). Inhibition of ER stress or ATM signaling abrogates the dengue-conferred protection against other cell stressors. Direct inhibition of ER stress response in infected cells decreases autophagosome turnover, reduces ROS production and limits reproduction of dengue virus. Blocking ATM activation, which is an early response to infection, decreases transcription of ER stress response proteins, but ATM has limited impact on production of ROS and virus titers. Production of ROS determines only late-onset autophagy in infected cells and is not necessary for dengue-induced protection from stressors. Collectively, these results demonstrate that among the multiple autophagy-inducing pathways during infection, ER stress signaling is more important to viral replication and protection of cells than either ATM or ROS-mediated signaling. To limit virus production and survival of dengue-infected cells, one must address the earliest phase of autophagy, induced by ER stress.

  18. DNA replication and cancer

    DEFF Research Database (Denmark)

    Boyer, Anne-Sophie; Walter, David; Sørensen, Claus Storgaard

    2016-01-01

    A dividing cell has to duplicate its DNA precisely once during the cell cycle to preserve genome integrity avoiding the accumulation of genetic aberrations that promote diseases such as cancer. A large number of endogenous impacts can challenge DNA replication and cells harbor a battery of pathways...... causing DNA replication stress and genome instability. Further, we describe cellular and systemic responses to these insults with a focus on DNA replication restart pathways. Finally, we discuss the therapeutic potential of exploiting intrinsic replicative stress in cancer cells for targeted therapy....

  19. Stress disrupts response memory retrieval.

    Science.gov (United States)

    Guenzel, Friederike M; Wolf, Oliver T; Schwabe, Lars

    2013-08-01

    Stress effects on memory are well-known. Most studies, however, focused on the impact of stress on hippocampus-dependent 'declarative' memory processes. Less is known about whether stress influences also striatum-based memory processes, such as stimulus-response (S-R) memory. First evidence from rodent experiments shows that glucocorticoid stress hormones may enhance the consolidation of S-R memories. Whether stress affects also S-R memory retrieval remains largely elusive. Therefore, we tested in the present experiment in humans the effect of stress on the retrieval of S-R memories. Healthy men and women were trained to locate three objects in an S-R version of a virtual eight-arm radial maze. One week later, participants underwent a stressor or a control condition before their memory of the S-R task was tested. Our results showed that participants (n=43) who were exposed to the stressor before retention testing made significantly more errors in this test trial, suggesting that stress impaired S-R memory retrieval. Moreover, high cortisol concentrations were associated with reduced S-R memory. These findings indicate that stress may affect memory retrieval processes in humans beyond hippocampal 'declarative' memory.

  20. Auxin response under osmotic stress.

    Science.gov (United States)

    Naser, Victoria; Shani, Eilon

    2016-08-01

    The phytohormone auxin (indole-3-acetic acid, IAA) is a small organic molecule that coordinates many of the key processes in plant development and adaptive growth. Plants regulate the auxin response pathways at multiple levels including biosynthesis, metabolism, transport and perception. One of the most striking aspects of plant plasticity is the modulation of development in response to changing growth environments. In this review, we explore recent findings correlating auxin response-dependent growth and development with osmotic stresses. Studies of water deficit, dehydration, salt, and other osmotic stresses point towards direct and indirect molecular perturbations in the auxin pathway. Osmotic stress stimuli modulate auxin responses by affecting auxin biosynthesis (YUC, TAA1), transport (PIN), perception (TIR/AFB, Aux/IAA), and inactivation/conjugation (GH3, miR167, IAR3) to coordinate growth and patterning. In turn, stress-modulated auxin gradients drive physiological and developmental mechanisms such as stomata aperture, aquaporin and lateral root positioning. We conclude by arguing that auxin-mediated growth inhibition under abiotic stress conditions is one of the developmental and physiological strategies to acclimate to the changing environment.

  1. The MMS22L-TONSL complex mediates recovery from replication stress and homologous recombination.

    Science.gov (United States)

    O'Donnell, Lara; Panier, Stephanie; Wildenhain, Jan; Tkach, Johnny M; Al-Hakim, Abdallah; Landry, Marie-Claude; Escribano-Diaz, Cristina; Szilard, Rachel K; Young, Jordan T F; Munro, Meagan; Canny, Marella D; Kolas, Nadine K; Zhang, Wei; Harding, Shane M; Ylanko, Jarkko; Mendez, Megan; Mullin, Michael; Sun, Thomas; Habermann, Bianca; Datti, Alessandro; Bristow, Robert G; Gingras, Anne-Claude; Tyers, Michael D; Brown, Grant W; Durocher, Daniel

    2010-11-24

    Genome integrity is jeopardized each time DNA replication forks stall or collapse. Here we report the identification of a complex composed of MMS22L (C6ORF167) and TONSL (NFKBIL2) that participates in the recovery from replication stress. MMS22L and TONSL are homologous to yeast Mms22 and plant Tonsoku/Brushy1, respectively. MMS22L-TONSL accumulates at regions of ssDNA associated with distressed replication forks or at processed DNA breaks, and its depletion results in high levels of endogenous DNA double-strand breaks caused by an inability to complete DNA synthesis after replication fork collapse. Moreover, cells depleted of MMS22L are highly sensitive to camptothecin, a topoisomerase I poison that impairs DNA replication progression. Finally, MMS22L and TONSL are necessary for the efficient formation of RAD51 foci after DNA damage, and their depletion impairs homologous recombination. These results indicate that MMS22L and TONSL are genome caretakers that stimulate the recombination-dependent repair of stalled or collapsed replication forks. Copyright © 2010 Elsevier Inc. All rights reserved.

  2. Human PIF1 helicase supports DNA replication and cell growth under oncogenic-stress

    OpenAIRE

    2014-01-01

    Unwinding duplex DNA is a critical processing step during replication, repair and transcription. Pif1 are highly conserved non-processive 5′->3′ DNA helicases with well-established roles in maintenance of yeast genome stability. However, the function of the sole member of Pif1 family in humans remains unclear. Human PIF1 is essential for tumour cell viability, particularly during replication stress, but is dispensable in non-cancerous cells and Pif1 deficient mice. Here we report that suppres...

  3. Stress Response and Translation Control in Rotavirus Infection

    Directory of Open Access Journals (Sweden)

    Susana López

    2016-06-01

    Full Text Available The general stress and innate immune responses are closely linked and overlap at many levels. The outcomes of these responses serve to reprogram host expression patterns to prevent viral invasions. In turn, viruses counter attack these cell responses to ensure their replication. The mechanisms by which viruses attempt to control host cell responses are as varied as the number of different virus families. One of the most recurrent strategies used by viruses to control the antiviral response of the cell is to hijack the translation machinery of the host, such that viral proteins are preferentially synthesized, while the expression of the stress and antiviral responses of the cell are blocked at the translation level. Here, we will review how rotaviruses, an important agent of acute severe gastroenteritis in children, overcome the stress responses of the cell to establish a productive infectious cycle.

  4. Stress Response and Translation Control in Rotavirus Infection

    Science.gov (United States)

    López, Susana; Oceguera, Alfonso; Sandoval-Jaime, Carlos

    2016-01-01

    The general stress and innate immune responses are closely linked and overlap at many levels. The outcomes of these responses serve to reprogram host expression patterns to prevent viral invasions. In turn, viruses counter attack these cell responses to ensure their replication. The mechanisms by which viruses attempt to control host cell responses are as varied as the number of different virus families. One of the most recurrent strategies used by viruses to control the antiviral response of the cell is to hijack the translation machinery of the host, such that viral proteins are preferentially synthesized, while the expression of the stress and antiviral responses of the cell are blocked at the translation level. Here, we will review how rotaviruses, an important agent of acute severe gastroenteritis in children, overcome the stress responses of the cell to establish a productive infectious cycle. PMID:27338442

  5. The Aurora-B-dependent NoCut checkpoint prevents damage of anaphase bridges after DNA replication stress.

    Science.gov (United States)

    Amaral, Nuno; Vendrell, Alexandre; Funaya, Charlotta; Idrissi, Fatima-Zahra; Maier, Michael; Kumar, Arun; Neurohr, Gabriel; Colomina, Neus; Torres-Rosell, Jordi; Geli, María-Isabel; Mendoza, Manuel

    2016-05-01

    Anaphase chromatin bridges can lead to chromosome breakage if not properly resolved before completion of cytokinesis. The NoCut checkpoint, which depends on Aurora B at the spindle midzone, delays abscission in response to chromosome segregation defects in yeast and animal cells. How chromatin bridges are detected, and whether abscission inhibition prevents their damage, remain key unresolved questions. We find that bridges induced by DNA replication stress and by condensation or decatenation defects, but not dicentric chromosomes, delay abscission in a NoCut-dependent manner. Decatenation and condensation defects lead to spindle stabilization during cytokinesis, allowing bridge detection by Aurora B. NoCut does not prevent DNA damage following condensin or topoisomerase II inactivation; however, it protects anaphase bridges and promotes cellular viability after replication stress. Therefore, the molecular origin of chromatin bridges is critical for activation of NoCut, which plays a key role in the maintenance of genome stability after replicative stress.

  6. Stress Responses in Staphylococcus aureus

    DEFF Research Database (Denmark)

    Frees, Dorte; Ingmer, Hanne

    2016-01-01

    Staphylococcus aures are prominent members of the normal flora of humans and animals, but are also a major cause of mild and severe infections. To persist and disseminate in the human host, and to survive in environmental settings, such as hospitals, S. aureus have developed a plethora of cellular...... of the specific and general S. aureusstress responses, with a special emphasis on how stress responses contribute to virulence and antibiotic resistance in this important human pathogen....

  7. Targeting the replisome with transduced monoclonal antibodies triggers lethal DNA replication stress in cancer cells.

    Science.gov (United States)

    Desplancq, Dominique; Freund, Guillaume; Conic, Sascha; Sibler, Annie-Paule; Didier, Pascal; Stoessel, Audrey; Oulad-Abdelghani, Mustapha; Vigneron, Marc; Wagner, Jérôme; Mély, Yves; Chatton, Bruno; Tora, Laszlo; Weiss, Etienne

    2016-03-15

    Although chemical inhibition of the DNA damage response (DDR) in cancer cells triggers cell death, it is not clear if the fork blockade achieved with inhibitors that neutralise proteins of the replisome is sufficient on its own to overcome the DDR. Monoclonal antibodies to PCNA, which block the DNA elongation process in vitro, have been developed. When these antibodies were transduced into cancer cells, they are able to inhibit the incorporation of nucleoside analogues. When co-delivered with anti-PCNA siRNA, the cells were flattened and the size of their nuclei increased by up to 3-fold, prior to cell death. Analysis of these nuclei by super-resolution microscopy revealed the presence of large numbers of phosphorylated histone H2AX foci. A senescence-like phenotype of the transduced cells was also observed upon delivery of the corresponding Fab molecules or following PCNA gene disruption or when the Fab fragment of an antibody that neutralises DNA polymerase alpha was used. Primary melanoma cells and leukaemia cells that are resistant to chemical inhibitors were similarly affected by these antibody treatments. These results demonstrate that transduced antibodies can trigger a lethal DNA replication stress, which kills cancer cells by abolishing the biological activity of several constituents of the replisome.

  8. Replication protein A subunit 3 and the iron efficiency response in soybean.

    Science.gov (United States)

    Atwood, Sarah E; O'Rourke, Jamie A; Peiffer, Gregory A; Yin, Tengfei; Majumder, Mahbubul; Zhang, Chunquan; Cianzio, Silvia R; Hill, John H; Cook, Dianne; Whitham, Steven A; Shoemaker, Randy C; Graham, Michelle A

    2014-01-01

    In soybean [Glycine max (L.) Merr.], iron deficiency results in interveinal chlorosis and decreased photosynthetic capacity, leading to stunting and yield loss. In this study, gene expression analyses investigated the role of soybean replication protein A (RPA) subunits during iron stress. Nine RPA homologs were significantly differentially expressed in response to iron stress in the near isogenic lines (NILs) Clark (iron efficient) and Isoclark (iron inefficient). RPA homologs exhibited opposing expression patterns in the two NILs, with RPA expression significantly repressed during iron deficiency in Clark but induced in Isoclark. We used virus induced gene silencing (VIGS) to repress GmRPA3 expression in the iron inefficient line Isoclark and mirror expression in Clark. GmRPA3-silenced plants had improved IDC symptoms and chlorophyll content under iron deficient conditions and also displayed stunted growth regardless of iron availability. RNA-Seq comparing gene expression between GmRPA3-silenced and empty vector plants revealed massive transcriptional reprogramming with differential expression of genes associated with defense, immunity, aging, death, protein modification, protein synthesis, photosynthesis and iron uptake and transport genes. Our findings suggest the iron efficient genotype Clark is able to induce energy controlling pathways, possibly regulated by SnRK1/TOR, to promote nutrient recycling and stress responses in iron deficient conditions.

  9. Three Different Pathways Prevent Chromosome Segregation in the Presence of DNA Damage or Replication Stress in Budding Yeast.

    Directory of Open Access Journals (Sweden)

    Gloria Palou

    2015-09-01

    Full Text Available A surveillance mechanism, the S phase checkpoint, blocks progression into mitosis in response to DNA damage and replication stress. Segregation of damaged or incompletely replicated chromosomes results in genomic instability. In humans, the S phase checkpoint has been shown to constitute an anti-cancer barrier. Inhibition of mitotic cyclin dependent kinase (M-CDK activity by Wee1 kinases is critical to block mitosis in some organisms. However, such mechanism is dispensable in the response to genotoxic stress in the model eukaryotic organism Saccharomyces cerevisiae. We show here that the Wee1 ortholog Swe1 does indeed inhibit M-CDK activity and chromosome segregation in response to genotoxic insults. Swe1 dispensability in budding yeast is the result of a redundant control of M-CDK activity by the checkpoint kinase Rad53. In addition, our results indicate that Swe1 is an effector of the checkpoint central kinase Mec1. When checkpoint control on M-CDK and on Pds1/securin stabilization are abrogated, cells undergo aberrant chromosome segregation.

  10. Plant Responses to Nanoparticle Stress

    Directory of Open Access Journals (Sweden)

    Zahed Hossain

    2015-11-01

    Full Text Available With the rapid advancement in nanotechnology, release of nanoscale materials into the environment is inevitable. Such contamination may negatively influence the functioning of the ecosystems. Many manufactured nanoparticles (NPs contain heavy metals, which can cause soil and water contamination. Proteomic techniques have contributed substantially in understanding the molecular mechanisms of plant responses against various stresses by providing a link between gene expression and cell metabolism. As the coding regions of genome are responsible for plant adaptation to adverse conditions, protein signatures provide insights into the phytotoxicity of NPs at proteome level. This review summarizes the recent contributions of plant proteomic research to elaborate the complex molecular pathways of plant response to NPs stress.

  11. DNA Lesions Induced by Replication Stress Trigger Mitotic Aberration and Tetraploidy Development

    Science.gov (United States)

    Ichijima, Yosuke; Yoshioka, Ken-ichi; Yoshioka, Yoshiko; Shinohe, Keitaro; Fujimori, Hiroaki; Unno, Junya; Takagi, Masatoshi; Goto, Hidemasa; Inagaki, Masaki; Mizutani, Shuki; Teraoka, Hirobumi

    2010-01-01

    During tumorigenesis, cells acquire immortality in association with the development of genomic instability. However, it is still elusive how genomic instability spontaneously generates during the process of tumorigenesis. Here, we show that precancerous DNA lesions induced by oncogene acceleration, which induce situations identical to the initial stages of cancer development, trigger tetraploidy/aneuploidy generation in association with mitotic aberration. Although oncogene acceleration primarily induces DNA replication stress and the resulting lesions in the S phase, these lesions are carried over into the M phase and cause cytokinesis failure and genomic instability. Unlike directly induced DNA double-strand breaks, DNA replication stress-associated lesions are cryptogenic and pass through cell-cycle checkpoints due to limited and ineffective activation of checkpoint factors. Furthermore, since damaged M-phase cells still progress in mitotic steps, these cells result in chromosomal mis-segregation, cytokinesis failure and the resulting tetraploidy generation. Thus, our results reveal a process of genomic instability generation triggered by precancerous DNA replication stress. PMID:20098673

  12. DNA lesions induced by replication stress trigger mitotic aberration and tetraploidy development.

    Directory of Open Access Journals (Sweden)

    Yosuke Ichijima

    Full Text Available During tumorigenesis, cells acquire immortality in association with the development of genomic instability. However, it is still elusive how genomic instability spontaneously generates during the process of tumorigenesis. Here, we show that precancerous DNA lesions induced by oncogene acceleration, which induce situations identical to the initial stages of cancer development, trigger tetraploidy/aneuploidy generation in association with mitotic aberration. Although oncogene acceleration primarily induces DNA replication stress and the resulting lesions in the S phase, these lesions are carried over into the M phase and cause cytokinesis failure and genomic instability. Unlike directly induced DNA double-strand breaks, DNA replication stress-associated lesions are cryptogenic and pass through cell-cycle checkpoints due to limited and ineffective activation of checkpoint factors. Furthermore, since damaged M-phase cells still progress in mitotic steps, these cells result in chromosomal mis-segregation, cytokinesis failure and the resulting tetraploidy generation. Thus, our results reveal a process of genomic instability generation triggered by precancerous DNA replication stress.

  13. Slx5/Slx8 Promotes Replication Stress Tolerance by Facilitating Mitotic Progression

    Directory of Open Access Journals (Sweden)

    Yee Mon Thu

    2016-05-01

    Full Text Available Loss of minichromosome maintenance protein 10 (Mcm10 causes replication stress. We uncovered that S. cerevisiae mcm10-1 mutants rely on the E3 SUMO ligase Mms21 and the SUMO-targeted ubiquitin ligase complex Slx5/8 for survival. Using quantitative mass spectrometry, we identified changes in the SUMO proteome of mcm10-1 mutants and revealed candidates regulated by Slx5/8. Such candidates included subunits of the chromosome passenger complex (CPC, Bir1 and Sli15, known to facilitate spindle assembly checkpoint (SAC activation. We show here that Slx5 counteracts SAC activation in mcm10-1 mutants under conditions of moderate replication stress. This coincides with the proteasomal degradation of sumoylated Bir1. Importantly, Slx5-dependent mitotic relief was triggered not only by Mcm10 deficiency but also by treatment with low doses of the alkylating drug methyl methanesulfonate. Based on these findings, we propose a model in which Slx5/8 allows for passage through mitosis when replication stress is tolerable.

  14. IL1- and TGFβ-Nox4 signaling, oxidative stress and DNA damage response are shared features of replicative, oncogene-induced, and drug-induced paracrine 'bystander senescence'

    National Research Council Canada - National Science Library

    Hubackova, Sona; Krejcikova, Katerina; Bartek, Jiri; Hodny, Zdenek

    2012-01-01

    ...)-mediated DNA damage response (DDR). Persistent cytokine signaling and activated DDR evoke senescence in normal bystander cells, accompanied by activation of the JAK/STAT, TGFβ/SMAD and IL1/NFκ...

  15. Computing a Synthetic Chronic Psychosocial Stress Measurement in Multiple Datasets and its Application in the Replication of G × E Interactions of the EBF1 Gene.

    Science.gov (United States)

    Singh, Abanish; Babyak, Michael A; Brummett, Beverly H; Jiang, Rong; Watkins, Lana L; Barefoot, John C; Kraus, William E; Shah, Svati H; Siegler, Ilene C; Hauser, Elizabeth R; Williams, Redford B

    2015-09-01

    Chronic psychosocial stress adversely affects health and is associated with the development of disease [Williams, 2008]. Systematic epidemiological and genetic studies are needed to uncover genetic variants that interact with stress to modify metabolic responses across the life cycle that are the proximal contributors to the development of cardiovascular disease and precipitation of acute clinical events. Among the central challenges in the field are to perform and replicate gene-by-environment (G × E) studies. The challenge of measurement of individual experience of psychosocial stress is magnified in this context. Although many research datasets exist that contain genotyping and disease-related data, measures of psychosocial stress are often either absent or vary substantially across studies. In this paper, we provide an algorithm to create a synthetic measure of chronic psychosocial stress across multiple datasets, applying a consistent criterion that uses proxy indicators of stress components. We validated the computed scores of chronic psychosocial stress by observing moderately strong and significant correlations with the self-rated chronic psychosocial stress in the Multi-Ethnic Study of Atherosclerosis Cohort (Rho = 0.23, P psychosocial stress variable by providing three additional replications of our previous finding of gene-by-stress interaction with central obesity traits [Singh et al., 2015].

  16. STRESS RESPONSE STUDIES USING ANIMAL MODELS

    Science.gov (United States)

    This presentation will provide the evidence that ozone exposure in animal models induce neuroendocrine stress response and this stress response modulates lung injury and inflammation through adrenergic and glucocorticoid receptors.

  17. Common Chemical Inductors of Replication Stress:  Focus on Cell‐Based Studies

    Directory of Open Access Journals (Sweden)

    Eva Vesela

    2017-02-01

    Full Text Available DNA replication is a highly demanding process regarding the energy and material supply and must be precisely regulated, involving multiple cellular feedbacks. The slowing down or stalling of DNA synthesis and/or replication forks is referred to as replication stress (RS. Owing to the complexity and requirements of replication, a plethora of factors may interfere and challenge the genome stability, cell survival or affect the whole organism. This review outlines chemical compounds that are known inducers of RS and commonly used in laboratory research. These compounds act on replication by direct interaction with DNA causing DNA crosslinks and bulky lesions (cisplatin, chemical interference with the metabolism of deoxyribonucleotide triphosphates (hydroxyurea, direct inhibition of the activity of replicative DNA polymerases (aphidicolin and interference with enzymes dealing with topological DNA stress (camptothecin, etoposide. As a variety of mechanisms can induce RS, the responses of mammalian cells also vary. Here, we review the activity and mechanism of action of these compounds based on recent knowledge, accompanied by examples of induced phenotypes, cellular readouts and commonly used doses.

  18. Attenuation of replication stress-induced premature cellular senescence to assess anti-aging modalities.

    Science.gov (United States)

    Zhao, Hong; Darzynkiewicz, Zbigniew

    2014-01-01

    Described is an in vitro model of premature senescence in pulmonary adenocarcinoma A549 cells induced by persistent DNA replication stress in response to treatment with the DNA damaging drug mitoxantrone (Mxt). The degree of cellular senescence, based on characteristic changes in cell morphology, is measured by laser scanning cytometry. Specifically, the flattening of cells grown on slides (considered the hallmark of cellular senescence) is measured as the decline in local intensity of DNA-associated DAPI fluorescence (represented by maximal pixels). This change is paralleled by an increase in nuclear area. Thus, the ratio of mean intensity of maximal pixels to nuclear area provides a very sensitive morphometric biomarker for the degree of senescence. This analysis is combined with immunocytochemical detection of senescence markers, such as overexpression of cyclin kinase inhibitors (e.g., p21(WAF1) ) and phosphorylation of ribosomal protein S6 (rpS6), a key marker associated with aging/senescence that is detected using a phospho-specific antibody. These biomarker indices are presented in quantitative terms defined as a senescence index (SI), which is the fraction of the marker in test cultures relative to the same marker in exponentially growing control cultures. This system can be used to evaluate the anti-aging potential of test agents by assessing attenuation of maximal senescence. As an example, the inclusion of berberine, a natural alkaloid with reported anti-aging properties and a long history of use in traditional Chinese medicine, is shown to markedly attenuate the Mxt-induced SI and phosphorylation of rpS6. The multivariate analysis of senescence markers by laser scanning cytometry offers a promising tool to explore the potential anti-aging properties of a variety agents.

  19. Stress Response of Granular Systems

    Science.gov (United States)

    Ramola, Kabir; Chakraborty, Bulbul

    2017-10-01

    We develop a framework for stress response in two dimensional granular media, with and without friction, that respects vector force balance at the microscopic level. We introduce local gauge degrees of freedom that determine the response of contact forces between constituent grains on a given, disordered, contact network, to external perturbations. By mapping this response to the spectral properties of the graph Laplacian corresponding to the underlying contact network, we show that this naturally leads to spatial localization of forces. We present numerical evidence for localization using exact diagonalization studies of network Laplacians of soft disk packings. Finally, we discuss the role of other constraints, such as torque balance, in determining the stability of a granular packing to external perturbations.

  20. Stress Response of Granular Systems

    Science.gov (United States)

    Ramola, Kabir; Chakraborty, Bulbul

    2017-08-01

    We develop a framework for stress response in two dimensional granular media, with and without friction, that respects vector force balance at the microscopic level. We introduce local gauge degrees of freedom that determine the response of contact forces between constituent grains on a given, disordered, contact network, to external perturbations. By mapping this response to the spectral properties of the graph Laplacian corresponding to the underlying contact network, we show that this naturally leads to spatial localization of forces. We present numerical evidence for localization using exact diagonalization studies of network Laplacians of soft disk packings. Finally, we discuss the role of other constraints, such as torque balance, in determining the stability of a granular packing to external perturbations.

  1. Alpha thalassemia/mental retardation syndrome X-linked gene product ATRX is required for proper replication restart and cellular resistance to replication stress.

    Science.gov (United States)

    Leung, Justin Wai-Chung; Ghosal, Gargi; Wang, Wenqi; Shen, Xi; Wang, Jiadong; Li, Lei; Chen, Junjie

    2013-03-01

    Alpha thalassemia/mental retardation syndrome X-linked (ATRX) is a member of the SWI/SNF protein family of DNA-dependent ATPases. It functions as a chromatin remodeler and is classified as an SNF2-like helicase. Here, we showed somatic knock-out of ATRX displayed perturbed S-phase progression as well as hypersensitivity to replication stress. ATRX is recruited to sites of DNA damage, required for efficient checkpoint activation and faithful replication restart. In addition, we identified ATRX as a binding partner of MRE11-RAD50-NBS1 (MRN) complex. Together, these results suggest a non-canonical function of ATRX in guarding genomic stability.

  2. Mouse Testicular Cell Type-Specific Antiviral Response against Mumps Virus Replication

    Science.gov (United States)

    Wu, Han; Zhao, Xiang; Wang, Fei; Jiang, Qian; Shi, Lili; Gong, Maolei; Liu, Weihua; Gao, Bo; Song, Chengyi; Li, Qihan; Chen, Yongmei; Han, Daishu

    2017-01-01

    Mumps virus (MuV) infection has high tropism to the testis and usually leads to orchitis, an etiological factor in male infertility. However, MuV replication in testicular cells and the cellular antiviral responses against MuV are not fully understood. The present study showed that MuV infected the majority of testicular cells, including Leydig cells (LC), testicular macrophages, Sertoli cells (SC), and male germ cells (GC). MuV was replicated at relatively high efficiencies in SC compared with LC and testicular macrophages. In contrast, MuV did not replicate in male GC. Notably, testicular cells exhibited different innate antiviral responses against MuV replication. We showed that interferon β (IFN-β) inhibited MuV replication in LC, macrophages, and SC, which were associated with the upregulation of major antiviral proteins. We provided primary evidence that autophagy plays a role in blocking MuV replication in male GC. Autophagy was also involved in limiting MuV replication in testicular macrophages but not in Leydig and SC. These findings indicate the involvement of the innate defense against MuV replication in testicular cells. PMID:28239382

  3. Mouse hepatitis coronavirus replication induces host translational shutoff and mRNA decay, with concomitant formation of stress granules and processing bodies.

    Science.gov (United States)

    Raaben, Matthijs; Groot Koerkamp, Marian J A; Rottier, Peter J M; de Haan, Cornelis A M

    2007-09-01

    Many viruses, including coronaviruses, induce host translational shutoff, while maintaining synthesis of their own gene products. In this study we performed genome-wide microarray analyses of the expression patterns of mouse hepatitis coronavirus (MHV)-infected cells. At the time of MHV-induced host translational shutoff, downregulation of numerous mRNAs, many of which encode protein translation-related factors, was observed. This downregulation, which is reminiscent of a cellular stress response, was dependent on viral replication and caused by mRNA decay. Concomitantly, phosphorylation of the eukaryotic translation initiation factor 2alpha was increased in MHV-infected cells. In addition, stress granules and processing bodies appeared, which are sites for mRNA stalling and degradation respectively. We propose that MHV replication induces host translational shutoff by triggering an integrated stress response. However, MHV replication per se does not appear to benefit from the inhibition of host protein synthesis, at least in vitro, since viral replication was not negatively affected but rather enhanced in cells with impaired translational shutoff.

  4. Soluble histone H2AX is induced by DNA replication stress and sensitizes cells to undergo apoptosis

    Directory of Open Access Journals (Sweden)

    Duensing Stefan

    2008-07-01

    Full Text Available Abstract Background Chromatin-associated histone H2AX is a key regulator of the cellular responses to DNA damage. However, non-nucleosomal functions of histone H2AX are poorly characterized. We have recently shown that soluble H2AX can trigger apoptosis but the mechanisms leading to non-chromatin-associated H2AX are unclear. Here, we tested whether stalling of DNA replication, a common event in cancer cells and the underlying mechanism of various chemotherapeutic agents, can trigger increased soluble H2AX. Results Transient overexpression of H2AX was found to lead to a detectable fraction of soluble H2AX and was associated with increased apoptosis. This effect was enhanced by the induction of DNA replication stress using the DNA polymerase α inhibitor aphidicolin. Cells manipulated to stably express H2AX did not contain soluble H2AX, however, short-term treatment with aphidicolin (1 h resulted in detectable amounts of H2AX in the soluble nuclear fraction and enhanced apoptosis. Similarly, soluble endogenous H2AX was detected under these conditions. We found that excessive soluble H2AX causes chromatin aggregation and inhibition of ongoing gene transcription as evidenced by the redistribution and/or loss of active RNA polymerase II as well as the transcriptional co-activators CBP and p300. Conclusion Taken together, these results show that DNA replication stress rapidly leads to increased soluble H2AX and that non-chromatin-associated H2AX can sensitize cells to undergo apoptosis. Our findings encourage further studies to explore H2AX and the cellular pathways that control its expression as anti-cancer drug targets.

  5. Acute MUS81 depletion leads to replication fork slowing and a constitutive DNA damage response

    DEFF Research Database (Denmark)

    Xing, Meichun; Wang, Xiaohui; Palmai-Pallag, Timea;

    2015-01-01

    The MUS81 protein belongs to a conserved family of DNA structure-specific nucleases that play important roles in DNA replication and repair. Inactivation of the Mus81 gene in mice has no major deleterious consequences for embryonic development, although cancer susceptibility has been reported. We...... have investigated the role of MUS81 in human cells by acutely depleting the protein using shRNAs. We found that MUS81 depletion from human fibroblasts leads to accumulation of ssDNA and a constitutive DNA damage response that ultimately activates cellular senescence. Moreover, we show that MUS81...... is required for efficient replication fork progression during an unperturbed S-phase, and for recovery of productive replication following replication stalling. These results demonstrate essential roles for the MUS81 nuclease in maintenance of replication fork integrity....

  6. Characterizing and Targeting Replication Stress Response Defects in Breast Cancer

    Science.gov (United States)

    2012-08-01

    in du ce d G F P /E G F P tr an sf ec tio n) F ol d ch an ge o f B rd U rd in co rp or at io n am ou nt A B C D Peng et al. Cancer Res; 72(11...Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med 2011;364:205–14. 52. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui

  7. Characterizing and Targeting Replication Stress Response Defects in Breast Cancer

    Science.gov (United States)

    2015-08-01

    N/A 4 INTRODUCTION In both precancerous breast lesions and breast cancer, hyperproliferative activity due to...RSR defects distinguishes premalignant lesions and breast cancer from normal tissues, which makes these defects effective targets for both breast... oral gavage. i.p., intraperitoneal injection. N = 8. ! ! 8 ! ! ! ! ! !! ! Table 1. The summary of tumorigenesis assay in MDA-MB-231 xenograft model

  8. Subjective Stress, Salivary Cortisol, and Electrophysiological Responses to Psychological Stress

    OpenAIRE

    Qi, Mingming; Gao, Heming; Guan, Lili; Liu, Guangyuan; Yang, Juan

    2016-01-01

    The present study aimed to investigate the subjective stress, salivary cortisol, and electrophysiological responses to psychological stress induced by a modified version of a mental arithmetic task. Fifteen participants were asked to estimate whether the multiplication product of two-decimal numbers was above 10 or not either with a time limit (the stress condition) or without a time limit (the control condition). The results showed that participants reported higher levels of stress, anxiety,...

  9. Mechanistic insights into aging, cell cycle progression, and stress response

    Directory of Open Access Journals (Sweden)

    Troy Anthony Alan Harkness

    2012-06-01

    Full Text Available The longevity of an organism depends on the health of its cells. Throughout life cells are exposed to numerous intrinsic and extrinsic stresses, such as free radicals, generated through mitochondrial electron transport, and ultraviolet irradiation. The cell has evolved numerous mechanisms to scavenge free radicals and repair damage induced by these insults. One mechanism employed by the yeast Saccharomyces cerevisiae to combat stress utilizes the Anaphase Promoting Complex (APC, an essential multi-subunit ubiquitin-protein ligase structurally and functionally conserved from yeast to humans that controls progression through mitosis and G1. We have observed that yeast cells expressing compromised APC subunits are sensitive to multiple stresses and have shorter replicative and chronological lifespans. In a pathway that runs parallel to that regulated by the APC, members of the Forkhead box (Fox transcription factor family also regulate stress responses. The yeast Fox orthologues Fkh1 and Fkh2 appear to drive the transcription of stress response factors and slow early G1 progression, while the APC seems to regulate chromatin structure, chromosome segregation, and resetting of the transcriptome in early G1. In contrast, under non-stress conditions, the Fkhs play a complex role in cell cycle progression, partially through activation of the APC. Direct and indirect interactions between the APC and the yeast Fkhs appear to be pivotal for lifespan determination. Here we explore the potential for these interactions to be evolutionarily conserved as a mechanism to balance cell cycle regulation with stress responses.

  10. p53-Mediated Cellular Response to DNA Damage in Cells with Replicative Hepatitis B Virus

    Science.gov (United States)

    Puisieux, Alain; Ji, Jingwei; Guillot, Celine; Legros, Yann; Soussi, Thierry; Isselbacher, Kurt; Ozturk, Mehmet

    1995-02-01

    Wild-type p53 acts as a tumor suppressor gene by protecting cells from deleterious effects of genotoxic agents through the induction of a G_1/S arrest or apoptosis as a response to DNA damage. Transforming proteins of several oncogenic DNA viruses inactivate tumor suppressor activity of p53 by blocking this cellular response. To test whether hepatitis B virus displays a similar effect, we studied the p53-mediated cellular response to DNA damage in 2215 hepatoma cells with replicative hepatitis B virus. We demonstrate that hepatitis B virus replication does not interfere with known cellular functions of p53 protein.

  11. Agreeableness, Extraversion, Stressor and Physiological Stress Response

    OpenAIRE

    Xiaoyuan Chu; Zhentao Ma; Yuan Li; Jing Han

    2015-01-01

    Based on the theoretical analysis, with first-hand data collection and using multiple regression models, this study explored the relationship between agreeableness, extraversion, stressor and stress response and figured out interactive effect of agreeableness, extraversion, and stressor on stress response. We draw on the following conclusions: (1) the interaction term of stressor (work) and agreeableness can negatively predict physiological stress response; (2) the interaction term of stresso...

  12. Molecular mechanisms in plant abiotic stress response

    Directory of Open Access Journals (Sweden)

    Poltronieri Palmiro

    2011-01-01

    Full Text Available Improved crop varieties are needed to sustain the food supply, to fight climate changes, water scarcity, temperature increase and a high variability of rainfalls. Variability of drought and increase in soil salinity have negative effects on plant growth and abiotic stresses seriously threaten sustainable agricultural production. To overcome the influence of abiotic stresses, new tolerant plant varieties and breeding techniques using assisted selection are sought. A deep understanding of the mechanisms that respond to stress and sustain stress resistance is required. Here is presented an overview of several mechanisms that interact in the stress response. Localised synthesis of plant hormones, second messengers and local effectors of abiotic stress response and survival, the signaling pathways regulated by plant hormones are today better understood. Metabolic networks in drought stress responses, long distance signaling, cross-talk between plant organs finalised to tissue-specific expression of abiotic stress relieving genes have been at the centre of most recent studies.

  13. Stress responses and pre-eclampsia.

    Science.gov (United States)

    Redman, C W G

    2013-04-01

    Biological stress may affect individual cells, tissues or whole organisms, arising from disturbed homoeostasis of any cause. Stress is rarely localised. Because biological systems are closely integrated, it spreads to involve other systems. Stress responses are highly integrated and work to restore homoeostasis. Different response pathways overlap and interlink. If the responses fail or decompensate, distress ensues, of which the end-stage is death. Pre-eclampsia results from a series of biological stresses, possibly from conception, which become established by abnormal placentation and affect the mother, her foetus and her placenta. The stresses involve dialogue between mother and placenta. Even a normal placenta imposes substantial stress on maternal systems. When placental growth and perfusion is abnormal (poor placentation) then the placenta, particularly its outer trophoblast layer, becomes stressed - loosely denoted hypoxic damage or oxidative stress. Signals from the placenta spread the stress to the mother, who develops signs of pre-eclampsia. Cellular stress sensors initiate stress responses. Different stresses may trigger similar responses in specific cell types. The first cell response is reduced protein synthesis. However some synthetic pathways are spared or activated to produce stress signals. In relation to pre-eclampsia and the placenta, an excessive release of sFlt-1 a soluble decoy receptor for vascular endothelial growth factor (VEGF) is a trophoblast related stress signal. SFlt1 perturbs the angiogenic balance in the maternal circulation and is considered to cause many of the specific features of the maternal syndrome in pre-eclampsia. Three key points will be emphasised. First, multiple stressors, not simply hypoxia, stimulate the release of sFlt-1 from trophoblast. Second, sFlt-1 is only one of the group of stress signals delivered by trophoblast to the mother. Third, sFlt-1 is not the only trophoblast derived factor to perturb the maternal

  14. Neuronal responses to physiological stress

    DEFF Research Database (Denmark)

    Kagias, Konstantinos; Nehammer, Camilla; Pocock, Roger David John

    2012-01-01

    by changes in the environment. Fluctuations in oxygen levels, temperature, and redox state for example, trigger molecular events that enable an organism to adapt, survive, and reproduce. In addition to external stressors, organisms experience stress associated with morphogenesis and changes in inner...... include changes in the expression of molecules such as transcription factors and microRNAs that regulate stress resistance and adaptation. Moreover, both intrinsic and extrinsic stresses have a tremendous impact on neuronal development and maintenance with implications in many diseases. Here, we review......Physiological stress can be defined as any external or internal condition that challenges the homeostasis of a cell or an organism. It can be divided into three different aspects: environmental stress, intrinsic developmental stress, and aging. Throughout life all living organisms are challenged...

  15. Oxidative stress response in sugarcane

    Directory of Open Access Journals (Sweden)

    Luis Eduardo Soares Netto

    2001-12-01

    Full Text Available Oxidative stress response in plants is still poorly understood in comparison with the correspondent phenomenon in bacteria, yeast and mammals. For instance, nitric oxide is assumed to play various roles in plants although no nitric oxide synthase gene has yet been isolated. This research reports the results of a search of the sugarcane expressed sequence tag (SUCEST database for homologous sequences involved in the oxidative stress response. I have not found any gene similar to nitric oxide synthase in the SUCEST database although an alternative pathway for nitric oxide synthesis was proposed. I have also found several genes involved in antioxidant defense, e.g. metal chelators, low molecular weight compounds, antioxidant enzymes and repair systems. Ascorbate (vitamin C is a key antioxidant in plants because it reaches high concentrations in cells and is a substrate for ascorbate peroxidase, an enzyme that I found in different isoforms in the SUCEST database. I also found many enzymes involved in the biosynthesis of low molecular weight antioxidants, which may be potential targets for genetic manipulation. The engineering of plants for increased vitamin C and E production may lead to improvements in the nutritional value and stress tolerance of sugarcane. The components of the antioxidant defense system interact and their synthesis is probably closely regulated. Transcription factors involved in regulation of the oxidative stress response in bacteria, yeast and mammals differ considerably among themselves and when I used them to search the SUCEST database only genes with weak similarities were found, suggesting that these transcription regulators are not very conserved. The involvement of reactive oxygen species and antioxidants in plant defense against pathogens is also discussed.A resposta ao estresse oxidativo não é bem conhecida em plantas como em bactérias, leveduras e humanos. Por exemplo, assume-se que óxido nítrico tem várias fun

  16. "Does replication groups scoring reduce false positive rate in SNP interaction discovery?: Response"

    Directory of Open Access Journals (Sweden)

    González-Pérez Antonio

    2010-06-01

    Full Text Available Abstract A response to Toplak et al: Does replication groups scoring reduce false positive rate in SNP interaction discovery? BMC Genomics 2010, 11:58. Background The genomewide evaluation of genetic epistasis is a computationally demanding task, and a current challenge in Genetics. HFCC (Hypothesis-Free Clinical Cloning is one of the methods that have been suggested for genomewide epistasis analysis. In order to perform an exhaustive search of epistasis, HFCC has implemented several tools and data filters, such as the use of multiple replication groups, and direction of effect and control filters. A recent article has claimed that the use of multiple replication groups (as implemented in HFCC does not reduce the false positive rate, and we hereby try to clarify these issues. Results/Discussion HFCC uses, as an analysis strategy, the possibility of replicating findings in multiple replication groups, in order to select a liberal subset of preliminary results that are above a statistical criterion and consistent in direction of effect. We show that the use of replication groups and the direction filter reduces the false positive rate of a study, although at the expense of lowering the overall power of the study. A post-hoc analysis of these selected signals in the combined sample could then be performed to select the most promising results. Conclusion Replication of results in independent samples is generally used in scientific studies to establish credibility in a finding. Nonetheless, the combined analysis of several datasets is known to be a preferable and more powerful strategy for the selection of top signals. HFCC is a flexible and complete analysis tool, and one of its analysis options combines these two strategies: A preliminary multiple replication group analysis to eliminate inconsistent false positive results, and a post-hoc combined-group analysis to select the top signals.

  17. "Does replication groups scoring reduce false positive rate in SNP interaction discovery?: Response"

    Science.gov (United States)

    2010-01-01

    A response to Toplak et al: Does replication groups scoring reduce false positive rate in SNP interaction discovery? BMC Genomics 2010, 11:58. Background The genomewide evaluation of genetic epistasis is a computationally demanding task, and a current challenge in Genetics. HFCC (Hypothesis-Free Clinical Cloning) is one of the methods that have been suggested for genomewide epistasis analysis. In order to perform an exhaustive search of epistasis, HFCC has implemented several tools and data filters, such as the use of multiple replication groups, and direction of effect and control filters. A recent article has claimed that the use of multiple replication groups (as implemented in HFCC) does not reduce the false positive rate, and we hereby try to clarify these issues. Results/Discussion HFCC uses, as an analysis strategy, the possibility of replicating findings in multiple replication groups, in order to select a liberal subset of preliminary results that are above a statistical criterion and consistent in direction of effect. We show that the use of replication groups and the direction filter reduces the false positive rate of a study, although at the expense of lowering the overall power of the study. A post-hoc analysis of these selected signals in the combined sample could then be performed to select the most promising results. Conclusion Replication of results in independent samples is generally used in scientific studies to establish credibility in a finding. Nonetheless, the combined analysis of several datasets is known to be a preferable and more powerful strategy for the selection of top signals. HFCC is a flexible and complete analysis tool, and one of its analysis options combines these two strategies: A preliminary multiple replication group analysis to eliminate inconsistent false positive results, and a post-hoc combined-group analysis to select the top signals. PMID:20576100

  18. Rec-8 dimorphism affects longevity, stress resistance and X-chromosome nondisjunction in C. elegans, and replicative lifespan in yeast

    Directory of Open Access Journals (Sweden)

    Srinivas eAyyadevara

    2014-08-01

    Full Text Available A quantitative trait locus (QTL in the nematode C. elegans, lsq4, was recently implicated by mapping longevity genes. QTLs for lifespan and 3 stress-resistance traits coincided within a span of <300 kbp, later narrowed to <200 kbp. A single gene in this interval is now shown to modulate all lsq4-associated traits. Full-genome analysis of transcript levels indicates that lsq4 contains a dimorphic gene governing expression of sperm-specific genes, suggesting effects on spermatogenesis. Quantitation of allele-specific transcripts encoded within the lsq4 interval revealed significant, 2- to 15-fold expression differences for 10 of 33 genes. Fourteen genes, implicated by both position and expression, were tested for RNA-interference effects on QTL-linked traits. In a strain carrying the shorter-lived allele, knockdown of rec-8 (encoding a meiotic cohesin reduced its transcripts 4-fold, to a level similar to the longer-lived strain, and extended lifespan 25–26% whether begun before fertilization or at maturity. The short-lived lsq4 allele also conferred sensitivity to oxidative and thermal stresses, and lower male frequency, traits reversed uniquely by rec-8 knockdown. A strain bearing the longer-lived lsq4 allele, differing from the short-lived strain at <0.3% of its genome, derived no lifespan or stress-survival benefit from rec-8 knockdown. We consider two possible explanations: high rec-8 expression may include increased leaky expression in mitotic cells, leading to deleterious destabilization of somatic genomes; or REC-8 may act entirely in germ-line meiotic cells to reduce aberrations such as nondisjunction, thereby blunting a stress-resistance response mediated by innate immunity. Replicative lifespan was extended 20% in haploid S. cerevisiae (BY4741 by deletion of REC8, orthologous to nematode rec-8, implying that REC8 disruption of mitotic-cell survival is widespread, reflecting antagonistic pleiotropy and/or balancing selection.

  19. Amplified and Persistent Immune Responses Generated by Single-Cycle Replicating Adenovirus Vaccines

    Science.gov (United States)

    Crosby, Catherine M.; Nehete, Pramod; Sastry, K. Jagannadha

    2014-01-01

    ABSTRACT Replication-competent adenoviral (RC-Ad) vectors generate exceptionally strong gene-based vaccine responses by amplifying the antigen transgenes they carry. While they are potent, they also risk causing adenovirus infections. More common replication-defective Ad (RD-Ad) vectors with deletions of E1 avoid this risk but do not replicate their transgene and generate markedly weaker vaccine responses. To amplify vaccine transgenes while avoiding production of infectious progeny viruses, we engineered “single-cycle” adenovirus (SC-Ad) vectors by deleting the gene for IIIa capsid cement protein of lower-seroprevalence adenovirus serotype 6. In mouse, human, hamster, and macaque cells, SC-Ad6 still replicated its genome but prevented genome packaging and virion maturation. When used for mucosal intranasal immunization of Syrian hamsters, both SC-Ad and RC-Ad expressed transgenes at levels hundreds of times higher than that of RD-Ad. Surprisingly, SC-Ad, but not RC-Ad, generated higher levels of transgene-specific antibody than RD-Ad, which notably climbed in serum and vaginal wash samples over 12 weeks after single mucosal immunization. When RD-Ad and SC-Ad were tested by single sublingual immunization in rhesus macaques, SC-Ad generated higher gamma interferon (IFN-γ) responses and higher transgene-specific serum antibody levels. These data suggest that SC-Ad vectors may have utility as mucosal vaccines. IMPORTANCE This work illustrates the utility of our recently developed single-cycle adenovirus (SC-Ad6) vector as a new vaccine platform. Replication-defective (RD-Ad6) vectors produce low levels of transgene protein, which leads to minimal antibody responses in vivo. This study shows that replicating SC-Ad6 produces higher levels of luciferase and induces higher levels of green fluorescent protein (GFP)-specific antibodies than RD in a permissive Syrian hamster model. Surprisingly, although a replication-competent (RC-Ad6) vector produces more luciferase

  20. General Stress Responses in the Honey Bee

    Science.gov (United States)

    Even, Naïla; Devaud, Jean-Marc; Barron, Andrew B.

    2012-01-01

    The biological concept of stress originated in mammals, where a “General Adaptation Syndrome” describes a set of common integrated physiological responses to diverse noxious agents. Physiological mechanisms of stress in mammals have been extensively investigated through diverse behavioral and physiological studies. One of the main elements of the stress response pathway is the endocrine hypothalamo-pituitary-adrenal (HPA) axis, which underlies the “fight-or-flight” response via a hormonal cascade of catecholamines and corticoid hormones. Physiological responses to stress have been studied more recently in insects: they involve biogenic amines (octopamine, dopamine), neuropeptides (allatostatin, corazonin) and metabolic hormones (adipokinetic hormone, diuretic hormone). Here, we review elements of the physiological stress response that are or may be specific to honey bees, given the economical and ecological impact of this species. This review proposes a hypothetical integrated honey bee stress pathway somewhat analogous to the mammalian HPA, involving the brain and, particularly, the neurohemal organ corpora cardiaca and peripheral targets, including energy storage organs (fat body and crop). We discuss how this system can organize rapid coordinated changes in metabolic activity and arousal, in response to adverse environmental stimuli. We highlight physiological elements of the general stress responses that are specific to honey bees, and the areas in which we lack information to stimulate more research into how this fascinating and vital insect responds to stress. PMID:26466739

  1. Longevity and the stress response in Drosophila

    DEFF Research Database (Denmark)

    Vermeulen, Corneel J.; Loeschcke, Volker

    2007-01-01

    to affect lifespan. The progress in modern genetic techniques has allowed researchers to test this idea. The general stress response involves the expression of stress proteins, such as chaperones and antioxidative proteins, downregulation of genes involved in energy metabolism and the release of protective......The concept that lifespan is a function of the capacity to withstand extrinsic stress is very old. In concordance with this, long-lived individuals often have increased resistance against a variety of stresses throughout life. Genes underlying the stress response may therefore have the ability...... briefly review the state of the art of research on ageing and longevity in the model organism Drosophila, with focus on the role of the general stress response. We will conclude by contemplating some of the implications of the findings in this research and will suggest several directions for future...

  2. RPA mediates recombination repair during replication stress and is displaced from DNA by checkpoint signalling in human cells

    DEFF Research Database (Denmark)

    Sleeth, Kate M; Sørensen, Claus Storgaard; Issaeva, Natalia

    2007-01-01

    The replication protein A (RPA) is involved in most, if not all, nuclear metabolism involving single-stranded DNA. Here, we show that RPA is involved in genome maintenance at stalled replication forks by the homologous recombination repair system in humans. Depletion of the RPA protein inhibited...... the formation of RAD51 nuclear foci after hydroxyurea-induced replication stalling leading to persistent unrepaired DNA double-strand breaks (DSBs). We demonstrate a direct role of RPA in homology directed recombination repair. We find that RPA is dispensable for checkpoint kinase 1 (Chk1) activation...... and that RPA directly binds RAD52 upon replication stress, suggesting a direct role in recombination repair. In addition we show that inhibition of Chk1 with UCN-01 decreases dissociation of RPA from the chromatin and inhibits association of RAD51 and RAD52 with DNA. Altogether, our data suggest a direct role...

  3. Abiotic stressors and stress responses

    DEFF Research Database (Denmark)

    Sulmon, Cecile; Van Baaren, Joan; Cabello-Hurtado, Francisco

    2015-01-01

    Abstract Organisms are regularly subjected to abiotic stressors related to increasing anthropogenic activities, including chemicals and climatic changes that induce major stresses. Based on various key taxa involved in ecosystem functioning (photosynthetic microorganisms, plants, invertebrates), ...

  4. Human Immunodeficiency Virus Type 1 Vpr Induces DNA Replication Stress In Vitro and In Vivo▿

    Science.gov (United States)

    Zimmerman, Erik S.; Sherman, Michael P.; Blackett, Jana L.; Neidleman, Jason A.; Kreis, Christophe; Mundt, Pamela; Williams, Samuel A.; Warmerdam, Maria; Kahn, James; Hecht, Frederick M.; Grant, Robert M.; de Noronha, Carlos M. C.; Weyrich, Andrew S.; Greene, Warner C.; Planelles, Vicente

    2006-01-01

    The human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) causes cell cycle arrest in G2. Vpr-expressing cells display the hallmarks of certain forms of DNA damage, specifically activation of the ataxia telangiectasia mutated and Rad3-related kinase, ATR. However, evidence that Vpr function is relevant in vivo or in the context of viral infection is still lacking. In the present study, we demonstrate that HIV-1 infection of primary, human CD4+ lymphocytes causes G2 arrest in a Vpr-dependent manner and that this response requires ATR, as shown by RNA interference. The event leading to ATR activation in CD4+ lymphocytes is the accumulation of replication protein A in nuclear foci, an indication that Vpr likely induces stalling of replication forks. Primary macrophages are refractory to ATR activation by Vpr, a finding that is consistent with the lack of detectable ATR, Rad17, and Chk1 protein expression in these nondividing cells. These observations begin to explain the remarkable resilience of macrophages to HIV-1-induced cytopathicity. To study the in vivo consequences of Vpr function, we isolated CD4+ lymphocytes from HIV-1-infected individuals and interrogated the cell cycle status of anti-p24Gag-immunoreactive cells. We report that infected cells in vivo display an aberrant cell cycle profile whereby a majority of cells have a 4N DNA content, consistent with the onset of G2 arrest. PMID:16956949

  5. Asthma and influenza virus infection:focusing on cell death and stress pathways in influenza virus replication.

    Science.gov (United States)

    Yeganeh, Behzad; Rezaei Moghadam, Adel; Tran, Ahn Thuy; Rahim, Mohammad Niaz; Ande, Sudu R; Hashemi, Mohammad; Coombs, Kevin M; Ghavami, Saeid

    2013-03-01

    Asthma is one of the fastest growing syndromes in many countries and is adding a huge cost to the health care system. Increasing reports have linked airway infectious diseases to asthma. Influenza is one of the most serious airway infectious diseases and in recent years there have been some serious influenza virus pandemics which caused increased fatality in numerous different populations. Diverse host response pathways during virus infection have been identified, including different cell death and survival pathways. These pathways include 1) programmed cell death I (apoptosis), 2) programmed cell death II (autophagy), and 3) endoplasmic reticulum stress with subsequent unfolded protein response (UPR). There has been extensive research on the regulatory roles of these pathways during the influenza virus life cycle. These studies address the benefits of enhancing or inhibiting these pathways on viral replication. Here we review the most recent and significant knowledge in this area for possible benefits to clinicians and basic scientist researchers in different areas of the respiratory and virology sciences.

  6. Asthma and influenza virus infection:focusing on cell death and stress pathways in influenza virus replication.

    Directory of Open Access Journals (Sweden)

    Behzad Yeganeh

    2013-03-01

    Full Text Available Asthma is one of the fastest growing syndromes in many countries and is adding a huge cost to the health care system. Increasing reports have linked airway infectious diseases to asthma. Influenza is one of the most serious airway infectious diseases and in recent years there have been some serious influenza virus pandemics which caused increased fatality in numerous different populations. Diverse host response pathways during virus infection have been identified, including different cell death and survival pathways. These pathways include1 programmed cell death I (apoptosis, 2 programmed cell death II (autophagy, and 3 endoplasmic reticulum stress with subsequent unfolded protein response (UPR. There has been extensive research on the regulatory roles of these pathways during the influenza virus life cycle. These studies address the benefits of enhancing or inhibiting these pathways on viral replication. Here we review the most recent and significant knowledge in this area for possible  benefits  to  clinicians and  basic  scientist researchers  in  different  areas  of  the respiratory and virology sciences.

  7. Process Control Minitoring by Stress Response

    Energy Technology Data Exchange (ETDEWEB)

    Hazen, Terry C.; Stahl, David A.

    2006-04-17

    Environmental contamination with a variety of pollutants hasprompted the development of effective bioremediation strategies. But howcan these processes be best monitored and controlled? One avenue underinvestigation is the development of stress response systems as tools foreffective and general process control. Although the microbial stressresponse has been the subject of intensive laboratory investigation, theenvironmental reflection of the laboratory response to specific stresseshas been little explored. However, it is only within an environmentalcontext, in which microorganisms are constantly exposed to multiplechanging environmental stresses, that there will be full understanding ofmicrobial adaptive resiliency. Knowledge of the stress response in theenvironment will facilitate the control of bioremediation and otherprocesses mediated by complex microbial communities.

  8. Regulation of SUMO2 Target Proteins by the Proteasome in Human Cells Exposed to Replication Stress

    DEFF Research Database (Denmark)

    Bursomanno, Sara; McGouran, Joanna F; Kessler, Benedikt M

    2015-01-01

    In human cells, SUMO2 is predominantly conjugated to target proteins in response to cellular stress. Previous studies suggested that proteins conjugated to SUMO2, but not to SUMO1, could be regulated by the ubiquitin-mediated proteasome system. Hence, we set out to understand the role of the prot......In human cells, SUMO2 is predominantly conjugated to target proteins in response to cellular stress. Previous studies suggested that proteins conjugated to SUMO2, but not to SUMO1, could be regulated by the ubiquitin-mediated proteasome system. Hence, we set out to understand the role...... of genome instability, which is suggested to drive tumorigenesis and possibly aging, our data will facilitate future functional studies in the fields of DNA metabolism and cancer biology....

  9. The profile of lysosomal exoglycosidases in replicative and stress-induced senescence in early passage human fibroblasts

    Directory of Open Access Journals (Sweden)

    Małgorzata Knaś

    2012-07-01

    Full Text Available The aim of the present study was to assess the profiles of the exoglycosidases: N-acetyl-β-hexosoaminidase, β glucuronidase and β galactosidase, α mannosidase and α fucosidase in fibroblast culture undergoing replicative and stress-induced senescence. Half of the cell culture was grown in normal conditions, without the stressor, and the other half of the cell was treated with 0.15 mM tert-butylhydroperoxide. The activities of total N-acetyl-β-hexosoaminidase as well as β glucuronidase in the cell lysate were determined in duplicates using the method of Marciniak et al. The activities of β galactosidase, α mannosidase and α fucosidase in the cell lysate were determined in duplicates using the method of Chatteriee et al. with the modification by Zwierz et al. The activities of the exoglycosidases examined, with the exception of β glucuronidase, showed a significant increase between individual days of the experiment in both non-stressed and stressed fibroblast cell culture. On each day of the experiment, in the cell lysate of stressed fibroblasts, the activities of exoglycosidases were significantly higher compared to the non-stressed cells. There were very strong correlations between SA-β-GAL staining and b galactosidase activity on individual days of the experiment in both non-stressed and stressed fibroblast cell culture. Replicative and stress-induced senescence results in significant changes to the level of lysosomal exoglycosidases, and results in enhanced lysosomal degradative capacity.

  10. Myc and Ras oncogenes engage different energy metabolism programs and evoke distinct patterns of oxidative and DNA replication stress.

    Science.gov (United States)

    Maya-Mendoza, Apolinar; Ostrakova, Jitka; Kosar, Martin; Hall, Arnaldur; Duskova, Pavlina; Mistrik, Martin; Merchut-Maya, Joanna Maria; Hodny, Zdenek; Bartkova, Jirina; Christensen, Claus; Bartek, Jiri

    2015-03-01

    Both Myc and Ras oncogenes impact cellular metabolism, deregulate redox homeostasis and trigger DNA replication stress (RS) that compromises genomic integrity. However, how are such oncogene-induced effects evoked and temporally related, to what extent are these kinetic parameters shared by Myc and Ras, and how are these cellular changes linked with oncogene-induced cellular senescence in different cell context(s) remain poorly understood. Here, we addressed the above-mentioned open questions by multifaceted comparative analyses of human cellular models with inducible expression of c-Myc and H-RasV12 (Ras), two commonly deregulated oncoproteins operating in a functionally connected signaling network. Our study of DNA replication parameters using the DNA fiber approach and time-course assessment of perturbations in glycolytic flux, oxygen consumption and production of reactive oxygen species (ROS) revealed the following results. First, overabundance of nuclear Myc triggered RS promptly, already after one day of Myc induction, causing slow replication fork progression and fork asymmetry, even before any metabolic changes occurred. In contrast, Ras overexpression initially induced a burst of cell proliferation and increased the speed of replication fork progression. However, after several days of induction Ras caused bioenergetic metabolic changes that correlated with slower DNA replication fork progression and the ensuing cell cycle arrest, gradually leading to senescence. Second, the observed oncogene-induced RS and metabolic alterations were cell-type/context dependent, as shown by comparative analyses of normal human BJ fibroblasts versus U2-OS sarcoma cells. Third, the energy metabolic reprogramming triggered by Ras was more robust compared to impact of Myc. Fourth, the detected oncogene-induced oxidative stress was due to ROS (superoxide) of non-mitochondrial origin and mitochondrial OXPHOS was reduced (Crabtree effect). Overall, our study provides novel

  11. Stress, stress-induced cortisol responses, and eyewitness identification performance.

    Science.gov (United States)

    Sauerland, Melanie; Raymaekers, Linsey H C; Otgaar, Henry; Memon, Amina; Waltjen, Thijs T; Nivo, Maud; Slegers, Chiel; Broers, Nick J; Smeets, Tom

    2016-07-01

    In the eyewitness identification literature, stress and arousal at the time of encoding are considered to adversely influence identification performance. This assumption is in contrast with findings from the neurobiology field of learning and memory, showing that stress and stress hormones are critically involved in forming enduring memories. This discrepancy may be related to methodological differences between the two fields of research, such as the tendency for immediate testing or the use of very short (1-2 hours) retention intervals in eyewitness research, while neurobiology studies insert at least 24 hours. Other differences refer to the extent to which stress-responsive systems (i.e., the hypothalamic-pituitary-adrenal axis) are stimulated effectively under laboratory conditions. The aim of the current study was to conduct an experiment that accounts for the contemporary state of knowledge in both fields. In all, 123 participants witnessed a live staged theft while being exposed to a laboratory stressor that reliably elicits autonomic and glucocorticoid stress responses or while performing a control task. Salivary cortisol levels were measured to control for the effectiveness of the stress induction. One week later, participants attempted to identify the thief from target-present and target-absent line-ups. According to regression and receiver operating characteristic analyses, stress did not have robust detrimental effects on identification performance. Copyright © 2016 John Wiley & Sons, Ltd. © 2016 The Authors Behavioral Sciences & the Law Published by John Wiley & Sons Ltd.

  12. Histone H3 lysine 56 acetylation and the response to DNA replication fork damage

    DEFF Research Database (Denmark)

    Wurtele, Hugo; Kaiser, Gitte Schalck; Bacal, Julien;

    2012-01-01

    but are only mildly affected by hydroxyurea. We demonstrate that, after exposure to MMS, H3K56ac-deficient cells cannot complete DNA replication and eventually segregate chromosomes with intranuclear foci containing the recombination protein Rad52. In addition, we provide evidence that these phenotypes......In Saccharomyces cerevisiae, histone H3 lysine 56 acetylation (H3K56ac) occurs in newly synthesized histones that are deposited throughout the genome during DNA replication. Defects in H3K56ac sensitize cells to genotoxic agents, suggesting that this modification plays an important role in the DNA...... damage response. However, the links between histone acetylation, the nascent chromatin structure, and the DNA damage response are poorly understood. Here we report that cells devoid of H3K56ac are sensitive to DNA damage sustained during transient exposure to methyl methanesulfonate (MMS) or camptothecin...

  13. TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism.

    Science.gov (United States)

    Harley, Margaret E; Murina, Olga; Leitch, Andrea; Higgs, Martin R; Bicknell, Louise S; Yigit, Gökhan; Blackford, Andrew N; Zlatanou, Anastasia; Mackenzie, Karen J; Reddy, Kaalak; Halachev, Mihail; McGlasson, Sarah; Reijns, Martin A M; Fluteau, Adeline; Martin, Carol-Anne; Sabbioneda, Simone; Elcioglu, Nursel H; Altmüller, Janine; Thiele, Holger; Greenhalgh, Lynn; Chessa, Luciana; Maghnie, Mohamad; Salim, Mahmoud; Bober, Michael B; Nürnberg, Peter; Jackson, Stephen P; Hurles, Matthew E; Wollnik, Bernd; Stewart, Grant S; Jackson, Andrew P

    2016-01-01

    DNA lesions encountered by replicative polymerases threaten genome stability and cell cycle progression. Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitin ligase, in patients with microcephalic primordial dwarfism. We establish that TRAIP relocalizes to sites of DNA damage, where it is required for optimal phosphorylation of H2AX and RPA2 during S-phase in response to ultraviolet (UV) irradiation, as well as fork progression through UV-induced DNA lesions. TRAIP is necessary for efficient cell cycle progression and mutations in TRAIP therefore limit cellular proliferation, providing a potential mechanism for microcephaly and dwarfism phenotypes. Human genetics thus identifies TRAIP as a component of the DNA damage response to replication-blocking DNA lesions.

  14. "Does replication groups scoring reduce false positive rate in SNP interaction discovery?: Response"

    OpenAIRE

    González-Pérez Antonio; Gayán Javier; Ruiz Agustín

    2010-01-01

    Abstract A response to Toplak et al: Does replication groups scoring reduce false positive rate in SNP interaction discovery? BMC Genomics 2010, 11:58. Background The genomewide evaluation of genetic epistasis is a computationally demanding task, and a current challenge in Genetics. HFCC (Hypothesis-Free Clinical Cloning) is one of the methods that have been suggested for genomewide epistasis analysis. In order to perform an exhaustive search of epistasis, HFCC has implemented several tools ...

  15. Telomerase is essential to alleviate pif1-induced replication stress at telomeres

    NARCIS (Netherlands)

    Chang, Michael; Luke, Brian; Kraft, Claudine; Li, Zhijian; Peter, Matthias; Lingner, Joachim; Rothstein, Rodney

    2009-01-01

    Pif1, an evolutionarily conserved helicase, negatively regulates telomere length by removing telomerase from chromosome ends. Pif1 has also been implicated in DNA replication processes such as Okazaki fragment maturation and replication fork pausing. We find that overexpression of Saccharomyces cerv

  16. Response of Desulfovibrio vulgaris to Alkaline Stress

    Energy Technology Data Exchange (ETDEWEB)

    Stolyar, S.; He, Q.; He, Z.; Yang, Z.; Borglin, S.E.; Joyner, D.; Huang, K.; Alm, E.; Hazen, T.C.; Zhou, J.; Wall, J.D.; Arkin, A.P.; Stahl, D.A.

    2007-11-30

    The response of exponentially growing Desulfovibrio vulgarisHildenborough to pH 10 stress was studied using oligonucleotidemicroarrays and a study set of mutants with genes suggested by microarraydata to be involved in the alkaline stress response deleted. The datashowed that the response of D. vulgaris to increased pH is generallysimilar to that of Escherichia coli but is apparently controlled byunique regulatory circuits since the alternative sigma factors (sigma Sand sigma E) contributing to this stress response in E. coli appear to beabsent in D. vulgaris. Genes previously reported to be up-regulated in E.coli were up-regulated in D. vulgaris; these genes included three ATPasegenes and a tryptophan synthase gene. Transcription of chaperone andprotease genes (encoding ATP-dependent Clp and La proteases and DnaK) wasalso elevated in D. vulgaris. As in E. coli, genes involved in flagellumsynthesis were down-regulated. The transcriptional data also identifiedregulators, distinct from sigma S and sigma E, that are likely part of aD. vulgaris Hildenborough-specific stress response system.Characterization of a study set of mutants with genes implicated inalkaline stress response deleted confirmed that there was protectiveinvolvement of the sodium/proton antiporter NhaC-2, tryptophanase A, andtwo putative regulators/histidine kinases (DVU0331 andDVU2580).

  17. Impaired antiviral response of adenovirus-transformed cell lines supports virus replication.

    Science.gov (United States)

    Bachmann, Mandy; Breitwieser, Theresa; Lipps, Christoph; Wirth, Dagmar; Jordan, Ingo; Reichl, Udo; Frensing, Timo

    2016-02-01

    Activation of the innate immune response represents one of the most important cellular mechanisms to limit virus replication and spread in cell culture. Here, we examined the effect of adenoviral gene expression on the antiviral response in adenovirus-transformed cell lines; HEK293, HEK293SF and AGE1.HN. We demonstrate that the expression of the early region protein 1A in these cell lines impairs their ability to activate antiviral genes by the IFN pathway. This property may help in the isolation of newly emerging viruses and the propagation of interferon-sensitive virus strains.

  18. Influenza Virus Induces Inflammatory Response in Mouse Primary Cortical Neurons with Limited Viral Replication

    Directory of Open Access Journals (Sweden)

    Gefei Wang

    2016-01-01

    Full Text Available Unlike stereotypical neurotropic viruses, influenza A viruses have been detected in the brain tissues of human and animal models. To investigate the interaction between neurons and influenza A viruses, mouse cortical neurons were isolated, infected with human H1N1 influenza virus, and then examined for the production of various inflammatory molecules involved in immune response. We found that replication of the influenza virus in neurons was limited, although early viral transcription was not affected. Virus-induced neuron viability decreased at 6 h postinfection (p.i. but increased at 24 h p.i. depending upon the viral strain. Virus-induced apoptosis and cytopathy in primary cortical neurons were not apparent at 24 h p.i. The mRNA levels of inflammatory cytokines, chemokines, and type I interferons were upregulated at 6 h and 24 h p.i. These results indicate that the influenza virus induces inflammatory response in mouse primary cortical neurons with limited viral replication. The cytokines released in viral infection-induced neuroinflammation might play critical roles in influenza encephalopathy, rather than in viral replication-induced cytopathy.

  19. Apoptosis, autophagy and unfolded protein response pathways in Arbovirus replication and pathogenesis.

    Science.gov (United States)

    Iranpour, Mahmoud; Moghadam, Adel Rezaei; Yazdi, Mina; Ande, Sudharsana R; Alizadeh, Javad; Wiechec, Emilia; Lindsay, Robbin; Drebot, Michael; Coombs, Kevin M; Ghavami, Saeid

    2016-01-19

    Arboviruses are pathogens that widely affect the health of people in different communities around the world. Recently, a few successful approaches toward production of effective vaccines against some of these pathogens have been developed, but treatment and prevention of the resulting diseases remain a major health and research concern. The arbovirus infection and replication processes are complex, and many factors are involved in their regulation. Apoptosis, autophagy and the unfolded protein response (UPR) are three mechanisms that are involved in pathogenesis of many viruses. In this review, we focus on the importance of these pathways in the arbovirus replication and infection processes. We provide a brief introduction on how apoptosis, autophagy and the UPR are initiated and regulated, and then discuss the involvement of these pathways in regulation of arbovirus pathogenesis.

  20. Fractional Response Models - A Replication Exercise of Papke and Wooldridge (1996

    Directory of Open Access Journals (Sweden)

    Harald Oberhofer

    2012-09-01

    Full Text Available This paper replicates the estimates of a fractional response model for share data reported in the seminal paper of Leslie E. Papke and Jeffrey M. Wooldridge published in the Journal of Applied Econometrics 11(6, 1996, pp.619-632. We have been able to replicate all of the reported estimation results concerning the determinants of employee participation rates in 401(k pension plans using the standard routines provided in Stata. As an alternative, we estimate a two-part model that is capable of coping with the excessive number of boundary values equalling one in the data. The estimated marginal effects are similar to those derived in the paper. A small-scale Monte Carlo simulation exercise suggests that the RESET tests proposed by Papke and Wooldridge in their robust form are useful for detecting neglected non-linearities in small samples.

  1. Identification of Proteins at Active, Stalled, and Collapsed Replication Forks Using Isolation of Proteins on Nascent DNA (iPOND) Coupled with Mass Spectrometry*

    Science.gov (United States)

    Sirbu, Bianca M.; McDonald, W. Hayes; Dungrawala, Huzefa; Badu-Nkansah, Akosua; Kavanaugh, Gina M.; Chen, Yaoyi; Tabb, David L.; Cortez, David

    2013-01-01

    Both DNA and chromatin need to be duplicated during each cell division cycle. Replication happens in the context of defects in the DNA template and other forms of replication stress that present challenges to both genetic and epigenetic inheritance. The replication machinery is highly regulated by replication stress responses to accomplish this goal. To identify important replication and stress response proteins, we combined isolation of proteins on nascent DNA (iPOND) with quantitative mass spectrometry. We identified 290 proteins enriched on newly replicated DNA at active, stalled, and collapsed replication forks. Approximately 16% of these proteins are known replication or DNA damage response proteins. Genetic analysis indicates that several of the newly identified proteins are needed to facilitate DNA replication, especially under stressed conditions. Our data provide a useful resource for investigators studying DNA replication and the replication stress response and validate the use of iPOND combined with mass spectrometry as a discovery tool. PMID:24047897

  2. Recruitment of DNA replication and damage response proteins to viral replication centers during infection with NS2 mutants of Minute Virus of Mice (MVM).

    Science.gov (United States)

    Ruiz, Zandra; Mihaylov, Ivailo S; Cotmore, Susan F; Tattersall, Peter

    2011-02-20

    MVM NS2 is essential for viral DNA amplification, but its mechanism of action is unknown. A classification scheme for autonomous parvovirus-associated replication (APAR) center development, based on NS1 distribution, was used to characterize abnormal APAR body maturation in NS2null mutant infections, and their organization examined for defects in host protein recruitment. Since acquisition of known replication factors appeared normal, we looked for differences in invoked DNA damage responses. We observed widespread association of H2AX/MDC1 damage response foci with viral replication centers, and sequestration and complex hyperphosphorylation of RPA(32), which occurred in wildtype and mutant infections. Quantifying these responses by western transfer indicated that both wildtype and NS2 mutant MVM elicited ATM activation, while phosphorylation of ATR, already basally activated in asynchronous A9 cells, was downregulated. We conclude that MVM infection invokes multiple damage responses that influence the APAR environment, but that NS2 does not modify the recruitment of cellular proteins.

  3. Rec-8 dimorphism affects longevity, stress resistance and X-chromosome nondisjunction in C. elegans, and replicative lifespan in S. cerevisiae.

    Science.gov (United States)

    Ayyadevara, Srinivas; Tazearslan, Cagdas; Alla, Ramani; Jiang, James C; Jazwinski, S Michal; Shmookler Reis, Robert J

    2014-01-01

    A quantitative trait locus (QTL) in the nematode C. elegans, "lsq4," was recently implicated by mapping longevity genes. QTLs for lifespan and three stress-resistance traits coincided within a span of thermal stresses, and lower male frequency (reflecting X-chromosome non-disjunction), traits reversed uniquely by rec-8 knockdown. A strain bearing the longer-lived lsq4 allele, differing from the short-lived strain at resistance response mediated by innate immunity. Replicative lifespan was extended 20% in haploid S. cerevisiae (BY4741) by deletion of REC8, orthologous to nematode rec-8, implying that REC8 disruption of mitotic-cell survival is widespread, exemplifying antagonistic pleiotropy (opposing effects on lifespan vs. reproduction), and/or balancing selection wherein genomic disruption increases genetic variation under harsh conditions.

  4. Endocannabinoids and the cardiovascular response to stress.

    Science.gov (United States)

    O'Sullivan, Saoirse E; Kendall, Patrick J; Kendall, David A

    2012-01-01

    Stress activates the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS), resulting in cardiovascular responses. The endocannabinoid system (ECS), a ubiquitously expressed lipid signalling system, modulates both HPA and SNS activity. The purpose of this review is to explore the possible involvement/role of the ECS in the cardiovascular response to stress. The ECS has numerous cardiovascular effects including modulation of blood pressure, heart rate, the baroreflex, and direct vascular actions. It is also involved in a protective manner in response to stressors in cardiac preconditioning, and various stressors (for example, pain, orthostasis and social stress) increase plasma levels of endocannabinoids. Given the multitude of vascular effects of endocannabinoids, this is bound to have consequences. Beneficial effects of ECS upregulation could include cardioprotection, vasodilatation, CB(2)-mediated anti-inflammatory effects and activation of peroxisome proliferator-activated receptors. Negative effects of endocannabinoids could include mediation of the effects of glucocorticoids, CB(1)-mediated metabolic changes, and metabolism to vasoconstrictor products. It is also likely that there is a central role for the ECS in modulating cardiovascular activity via the HPA and SNS. However, much more work is required to fully integrate the role of the ECS in mediating many of the physiological responses to stress, including cardiovascular responses.

  5. Replicative Stress and the FHIT Gene: Roles in Tumor Suppression, Genome Stability and Prevention of Carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Karras, Jenna R.; Paisie, Carolyn A.; Huebner, Kay, E-mail: kay.huebner@osumc.edu [Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Wexner Medical Center, Columbus, OH 43210 (United States)

    2014-06-04

    The fragile FHIT gene, encompassing the chromosomal fragile site FRA3B, is an early target of DNA damage in precancerous cells. While vulnerable to DNA damage itself, FHIT protein expression is essential to protect from DNA damage-induced cancer initiation and progression by modulating genome stability, oxidative stress and levels of accumulating DNA damage. Thus, FHIT, whose expression is lost or reduced in many human cancers, is a tumor suppressor and genome caretaker whose loss initiates genome instability in preneoplastic lesions. Ongoing studies are seeking more detailed understanding of the role of FHIT in the cellular response to oxidative damage. This review discusses the relationship between FHIT, reactive oxygen species production, and DNA damage in the context of cancer initiation and progression.

  6. Dynamics of active cellular response under stress

    Science.gov (United States)

    de, Rumi; Zemel, Assaf; Safran, Samuel

    2008-03-01

    Forces exerted by and on adherent cells are important for many physiological processes such as wound healing and tissue formation. In addition, recent experiments have shown that stem cell differentiation is controlled, at least in part, by the elasticity of the surrounding matrix. Using a simple theoretical model that includes the forces due to both the mechanosensitive nature of cells and the elastic response of the matrix, we predict the dynamics of orientation of cells. The model predicts many features observed in measurements of cellular forces and orientation including the increase with time of the forces generated by cells in the absence of applied stress and the consequent decrease of the force in the presence of quasi-static stresses. We also explain the puzzling observation of parallel alignment of cells for static and quasi-static stresses and of nearly perpendicular alignment for dynamically varying stresses. In addition, we predict the response of the cellular orientation to a sinusoidally varying applied stress as a function of frequency. The dependence of the cell orientation angle on the Poisson ratio of the surrounding material can be used to distinguish systems in which cell activity is controlled by stress from those where cell activity is controlled by strain. Reference: Nature Physics, vol. 3, pp 655 (2007).

  7. An antiviral role for antimicrobial peptides during the arthropod response to alphavirus replication.

    Science.gov (United States)

    Huang, Zhijing; Kingsolver, Megan B; Avadhanula, Vasanthi; Hardy, Richard W

    2013-04-01

    Alphaviruses establish a persistent infection in arthropod vectors which is essential for the effective transmission of the virus to vertebrate hosts. The development of persistence in insects is not well understood, although it is thought to involve the innate immune response. Using a transgenic fly system expressing a self-replicating viral RNA genome analog, we have previously demonstrated antiviral roles of the Drosophila Imd (immune deficiency) and Jak-STAT innate immunity pathways in response to alphavirus replication. In the present study, comparative microarray analysis of flies harboring an alphavirus replicon and control green fluorescent protein flies identified 95 SINrep-sensitive genes. Furthermore, a subset of these genes is regulated by Rel or STAT transcription factors of the Imd and Jak-STAT pathways, respectively. We identified two antimicrobial peptide genes, attC and dptB, which are SINrep sensitive and regulated by STAT and Rel, respectively. SINrep flies heterozygous for attC had an increased viral RNA level, while knocking down dptB in SINrep flies resulted in impaired development. When injected with whole virus, the double-stranded RNA knockdowns of either attC or dptB showed a significant increase in virus titers. Our data demonstrate an antiviral response involving the Imd and Jak-STAT mediated expression of dptB and attC.

  8. A replicated climate change field experiment reveals rapid evolutionary response in an ecologically important soil invertebrate

    DEFF Research Database (Denmark)

    Bataillon, Thomas; Galtier, Nicolas; Bernard, Aurelien

    2016-01-01

    Whether species can respond evolutionarily to current climate change is crucial for the persistence of many species. Yet, very few studies have examined genetic responses to climate change in manipulated experiments carried out innatural field conditions. We examined the evolutionary response...... to climate change in a common annelid worm using a controlled replicated experiment where climatic conditions were manipulated in a natural setting. Analyzing the transcribed genome of 15 local populations, we found that about 12% of the genetic polymorphisms exhibit differences in allele frequencies...... associated to changes in soil temperature and soil moisture. This shows an evolutionaryresponse to realistic climate change happening over short-time scale, and calls for incorporating evolution into modelspredicting future response of species to climate change. It also shows that designed climate change...

  9. Tocotrienol-Rich Fraction Ameliorates Antioxidant Defense Mechanisms and Improves Replicative Senescence-Associated Oxidative Stress in Human Myoblasts

    Directory of Open Access Journals (Sweden)

    Shy Cian Khor

    2017-01-01

    Full Text Available During aging, oxidative stress affects the normal function of satellite cells, with consequent regeneration defects that lead to sarcopenia. This study aimed to evaluate tocotrienol-rich fraction (TRF modulation in reestablishing the oxidative status of myoblasts during replicative senescence and to compare the effects of TRF with other antioxidants (α-tocopherol (ATF and N-acetyl-cysteine (NAC. Primary human myoblasts were cultured to young, presenescent, and senescent phases. The cells were treated with antioxidants for 24 h, followed by the assessment of free radical generation, lipid peroxidation, antioxidant enzyme mRNA expression and activities, and the ratio of reduced to oxidized glutathione. Our data showed that replicative senescence increased reactive oxygen species (ROS generation and lipid peroxidation in myoblasts. Treatment with TRF significantly diminished ROS production and decreased lipid peroxidation in senescent myoblasts. Moreover, the gene expression of superoxide dismutase (SOD2, catalase (CAT, and glutathione peroxidase (GPX1 was modulated by TRF treatment, with increased activity of superoxide dismutase and catalase and reduced glutathione peroxidase in senescent myoblasts. In comparison to ATF and NAC, TRF was more efficient in heightening the antioxidant capacity and reducing free radical insults. These results suggested that TRF is able to ameliorate antioxidant defense mechanisms and improves replicative senescence-associated oxidative stress in myoblasts.

  10. Replication stress and oxidative damage contribute to aberrant constitutive activation of DNA damage signalling in human gliomas

    DEFF Research Database (Denmark)

    Bartkova, J; Hamerlik, P; Stockhausen, Marie;

    2010-01-01

    damage signalling in low- and high-grade human gliomas, and analyze the sources of such endogenous genotoxic stress. Based on analyses of human glioblastoma multiforme (GBM) cell lines, normal astrocytes and clinical specimens from grade II astrocytomas (n=41) and grade IV GBM (n=60), we conclude......, initially limiting cell proliferation (low Ki-67 index) and selecting for mutations of p53 and likely other genes that allow escape (higher Ki-67 index) from the checkpoint and facilitate tumor progression. Overall, these results support the potential role of the DDR machinery as a barrier to gliomagenesis...... and indicate that replication stress, rather than oxidative stress, fuels the DNA damage signalling in early stages of astrocytoma development....

  11. Porcine sapovirus replication is restricted by the type I interferon response in cell culture.

    Science.gov (United States)

    Hosmillo, Myra; Sorgeloos, Frédéric; Hiraide, Rintaro; Lu, Jia; Goodfellow, Ian; Cho, Kyoung-Oh

    2015-01-01

    Porcine sapovirus (PSaV) of the family Caliciviridae, is the only member of the genus Sapovirus with cell culture and reverse genetics systems. When combined with the piglet model, these approaches provide a system to understand the molecular basis of sapovirus pathogenesis. The replication of PSaV in cell culture is, however, restricted, displaying an absolute requirement for bile acids and producing lower levels of infectious virus than other caliciviruses. The effect of bile acids has previously been linked to a reduction in the signal transducer and activator of transcription (STAT1)-mediated signalling pathway. In the current study, we observed that even in the presence of bile acids, PSaV replication in cell culture was restricted by soluble factors produced from infected cells. This effect was at least partially due to secreted IFN because treatment of cells with recombinant porcine IFN-β resulted in significantly reduced viral replication. Moreover, IFN-mediated signalling pathways (IFN, STAT1 and the 2',5'-oligoadenylate synthetase) were activated during PSaV infection. Characterization of PSaV growth in cell lines deficient in their ability to induce or respond to IFN showed a 100-150-fold increase in infectious virus production, indicating that the primary role of bile acids was not the inactivation of the innate immune response. Furthermore, the use of IFN-deficient cell lines enabled more efficient recovery of PSaV from cDNA constructs. Overall, the highly efficient cell culture and reverse genetics system established here for PSaV highlighted the key role of the innate immune response in the restriction of PSaV infection and should greatly facilitate further molecular studies on sapovirus host-cell interactions. © 2015 The Authors.

  12. Replication stress caused by low MCM expression limits fetal erythropoiesis and hematopoietic stem cell functionality

    DEFF Research Database (Denmark)

    Alvarez, Silvia; Díaz, Marcos; Flach, Johanna

    2015-01-01

    -chromosome maintenance (MCM)3 that limiting origin licensing in vivo affects the functionality of hematopoietic stem cells and the differentiation of rapidly-dividing erythrocyte precursors. Mcm3-deficient erythroblasts display aberrant DNA replication patterns and fail to complete maturation, causing lethal anemia. Our......' origins provide a backup in the presence of stalled forks and may confer flexibility to the replication program in specific cell types during differentiation, a role that has remained unexplored. Here we show, using a mouse strain with hypomorphic expression of the origin licensing factor mini...

  13. Stress responses in flavivirus-infected cells: activation of unfolded protein response and autophagy

    Directory of Open Access Journals (Sweden)

    Ana-Belén eBlázquez

    2014-06-01

    Full Text Available The Flavivirus is a genus of RNA viruses that includes multiple long known human, animal and zoonotic pathogens such as Dengue virus, yellow fever virus, West Nile virus or Japanese encephalitis virus, as well as other less known viruses that represent potential threats for human and animal health such as Usutu or Zika viruses. Flavivirus replication is based on endoplasmic reticulum-derived structures. Membrane remodeling and accumulation of viral factors induce endoplasmic reticulum stress that results in activation of a cellular signaling response termed unfolded protein response (UPR, which can be modulated by the viruses for their own benefit. Concomitant with the activation of the UPR, an upregulation of the autophagic pathway in cells infected with different flaviviruses has also been described. This review addresses the current knowledge of the relationship between endoplasmic reticulum stress, UPR and autophagy in flavivirus-infected cells and the growing evidences for an involvement of these cellular pathways in the replication and pathogenesis of these viruses.

  14. Effects of Cigarette Smoke Condensate on Oxidative Stress, Apoptotic Cell Death, and HIV Replication in Human Monocytic Cells.

    Directory of Open Access Journals (Sweden)

    Pss Rao

    Full Text Available While cigarette smoking is prevalent amongst HIV-infected patients, the effects of cigarette smoke constituents in cells of myeloid lineage are poorly known. Recently, we have shown that nicotine induces oxidative stress through cytochrome P450 (CYP 2A6-mediated pathway in U937 monocytic cells. The present study was designed to examine the effect of cigarette smoke condensate (CSC, which contains majority of tobacco constituents, on oxidative stress, cytotoxicity, expression of CYP1A1, and/or HIV-1 replication in HIV-infected (U1 and uninfected U937 cells. The effects of CSC on induction of CYP1 enzymes in HIV-infected primary macrophages were also analyzed. The results showed that the CSC-mediated increase in production of reactive oxygen species (ROS in U937 cells is dose- and time-dependent. Moreover, CSC treatment was found to induce cytotoxicity in U937 cells through the apoptotic pathway via activation of caspase-3. Importantly, pretreatment with vitamin C blocked the CSC-mediated production of ROS and induction of caspase-3 activity. In U1 cells, acute treatment of CSC increased ROS production at 6H (>2-fold and both ROS (>2 fold and HIV-1 replication (>3-fold after chronic treatment. The CSC mediated effects were associated with robust induction in the expression of CYP1A1 mRNA upon acute CSC treatment of U937 and U1 cells (>20-fold, and upon chronic CSC treatment to U1 cells (>30-fold. In addition, the CYP1A1 induction in U937 cells was mediated through the aromatic hydrocarbon receptor pathway. Lastly, CSC, which is known to increase viral replication in primary macrophages, was also found to induce CYP1 enzymes in HIV-infected primary macrophages. While mRNA levels of both CYP1A1 and CYP1B1 were elevated following CSC treatment, only CYP1B1 protein levels were increased in HIV-infected primary macrophages. In conclusion, these results suggest a possible association between oxidative stress, CYP1 expression, and viral replication in

  15. Endoplasmic Reticulum Stress Induced Synthesis of a Novel Viral Factor Mediates Efficient Replication of Genotype-1 Hepatitis E Virus.

    Directory of Open Access Journals (Sweden)

    Vidya P Nair

    2016-04-01

    Full Text Available Hepatitis E virus (HEV causes acute hepatitis in many parts of the world including Asia, Africa and Latin America. Though self-limiting in normal individuals, it results in ~30% mortality in infected pregnant women. It has also been reported to cause acute and chronic hepatitis in organ transplant patients. Of the seven viral genotypes, genotype-1 virus infects humans and is a major public health concern in South Asian countries. Sporadic cases of genotype-3 and 4 infection in human and animals such as pigs, deer, mongeese have been reported primarily from industrialized countries. Genotype-5, 6 and 7 viruses are known to infect animals such as wild boar and camel, respectively. Genotype-3 and 4 viruses have been successfully propagated in the laboratory in mammalian cell culture. However, genotype-1 virus replicates poorly in mammalian cell culture and no other efficient model exists to study its life cycle. Here, we report that endoplasmic reticulum (ER stress promotes genotype-1 HEV replication by inducing cap-independent, internal initiation mediated translation of a novel viral protein (named ORF4. Importantly, ORF4 expression and stimulatory effect of ER stress inducers on viral replication is specific to genotype-1. ORF4 protein sequence is mostly conserved among genotype-1 HEV isolates and ORF4 specific antibodies were detected in genotype-1 HEV patient serum. ORF4 interacted with multiple viral and host proteins and assembled a protein complex consisting of viral helicase, RNA dependent RNA polymerase (RdRp, X, host eEF1α1 (eukaryotic elongation factor 1 isoform-1 and tubulinβ. In association with eEF1α1, ORF4 stimulated viral RdRp activity. Furthermore, human hepatoma cells that stably express ORF4 or engineered proteasome resistant ORF4 mutant genome permitted enhanced viral replication. These findings reveal a positive role of ER stress in promoting genotype-1 HEV replication and pave the way towards development of an efficient

  16. Effect of transport stress on physiological responses of male bovines.

    Science.gov (United States)

    Chacon, G; Garcia-Belenguer, S; Villarroel, M; Maria, G A

    2005-12-01

    Forty-eight slaughter bulls were transported by road in groups of eight for approximately 30 min, 3 h and 6 h in two replicates. Animal welfare during the transport process was assessed. Loadings and unloadings were evaluated with a scoring method. Heart rates were monitored at the farm before loading and during all stages of transport. Blood samples were taken from all animals a week before transport and at sticking and analysed in terms of haematological values: hematocrit, haemoglobin, red and white blood cells (RBC and WBC), differential WBC counts and neutrophil:lymphocyte ratio. Glucose, creatine kinase, lactate and cortisol were also determined. To evaluate differences in meat quality, pH and water-holding capacity (WHC) were measured 24 h after slaughter. The loading and unloading scores were very low (low stress) but were associated with changes in heart rate, especially loading. Animals recovered their resting heart rate during the journey in medium and long transports. On the other hand, animals transported around 30 min maintained an elevated heart rate during the whole journey. All animals showed a stress response with significantly higher (p Animals transported for 3 and 6 hours had significantly (Pmeat quality. Under good conditions, the transport had a slight effect on welfare, meat quality or physiological parameters related with stress.

  17. Chicken hepatic response to chronic heat stress using integrated transcriptome and metabolome analysis.

    Science.gov (United States)

    Jastrebski, Sara F; Lamont, Susan J; Schmidt, Carl J

    2017-01-01

    The liver plays a central role in metabolism and is important in maintaining homeostasis throughout the body. This study integrated transcriptomic and metabolomic data to understand how the liver responds under chronic heat stress. Chickens from a rapidly growing broiler line were heat stressed for 8 hours per day for one week and liver samples were collected at 28 days post hatch. Transcriptome analysis reveals changes in genes responsible for cell cycle regulation, DNA replication, and DNA repair along with immune function. Integrating the metabolome and transcriptome data highlighted multiple pathways affected by heat stress including glucose, amino acid, and lipid metabolism along with glutathione production and beta-oxidation.

  18. Oxidative stress response in Paracoccidioides brasiliensis.

    Science.gov (United States)

    Campos, Elida G; Jesuino, Rosália Santos Amorim; Dantas, Alessandra da Silva; Brígido, Marcelo de Macedo; Felipe, Maria Sueli S

    2005-06-30

    Survival of pathogenic fungi inside human hosts depends on evasion from the host immune system and adaptation to the host environment. Among different insults that Paracoccidioides brasiliensis has to handle are reactive oxygen and nitrogen species produced by the human host cells, and by its own metabolism. Knowing how the parasite deals with reactive species is important to understand how it establishes infection and survives within humans. The initiative to describe the P. brasiliensis transcriptome fostered new approaches to study oxidative stress response in this organism. By examining genes related to oxidative stress response, one can evaluate the parasite's ability to face this condition and infer about possible ways to overcome this ability. We report the results of a search of the P. brasiliensis assembled expressed sequence tag database for homologous sequences involved in oxidative stress response. We described several genes coding proteins involved in antioxidant defense, for example, catalase and superoxide dismutase isoenzymes, peroxiredoxin, cytochrome c peroxidase, glutathione synthesis enzymes, thioredoxin, and the transcription factors Yap1 and Skn7. The transcriptome analysis of P. brasiliensis reveals a pathogen that has many resources to combat reactive species. Besides characterizing the antioxidant defense system in P. brasiliensis, we also compared the ways in which different fungi respond to oxidative damage, and we identified the basic features of this response.

  19. Over-representation of repeats in stress response genes: a strategy to increase versatility under stressful conditions?

    Science.gov (United States)

    Rocha, Eduardo P C; Matic, Ivan; Taddei, François

    2002-05-01

    The survival of individual organisms facing stress is enhanced by the induction of a set of changes. As the intensity, duration and nature of stress is highly variable, the optimal response to stress may be unpredictable. To face such an uncertain future, it may be advantageous for a clonal population to increase its phenotypic heterogeneity (bet-hedging), ensuring that at least a subset of cells would survive the current stress. With current techniques, assessing the extent of this variability experimentally remains a challenge. Here, we use a bioinformatic approach to compare stress response genes with the rest of the genome for the presence of various kinds of repeated sequences, elements known to increase variability during the transfer of genetic information (i.e. during replication, but also during gene expression). We investigated the potential for illegitimate and homologous recombination of 296 Escherichia coli genes related to repair, recombination and physiological adaptations to different stresses. Although long repeats capable of engaging in homologous recombination are almost absent in stress response genes, we observed a significant high number of short close repeats capable of inducing phenotypic variability by slipped-mispair during DNA, RNA or protein synthesis.

  20. Transcriptome response to heat stress in a chicken hepatocellular carcinoma cell line.

    Science.gov (United States)

    Sun, Liang; Lamont, Susan J; Cooksey, Amanda M; McCarthy, Fiona; Tudor, Catalina O; Vijay-Shanker, K; DeRita, Rachael M; Rothschild, Max; Ashwell, Chris; Persia, Michael E; Schmidt, Carl J

    2015-11-01

    Heat stress triggers an evolutionarily conserved set of responses in cells. The transcriptome responds to hyperthermia by altering expression of genes to adapt the cell or organism to survive the heat challenge. RNA-seq technology allows rapid identification of environmentally responsive genes on a large scale. In this study, we have used RNA-seq to identify heat stress responsive genes in the chicken male white leghorn hepatocellular (LMH) cell line. The transcripts of 812 genes were responsive to heat stress (p heat stress. Among the upregulated were genes whose products function as chaperones, along with genes affecting collagen synthesis and deposition, transcription factors, chromatin remodelers, and genes modulating the WNT and TGF-beta pathways. Predominant among the downregulated genes were ones that affect DNA replication and repair along with chromosomal segregation. Many of the genes identified in this study have not been previously implicated in the heat stress response. These data extend our understanding of the transcriptome response to heat stress with many of the identified biological processes and pathways likely to function in adapting cells and organisms to hyperthermic stress. Furthermore, this study should provide important insight to future efforts attempting to improve species abilities to withstand heat stress through genome-wide association studies and breeding.

  1. Redox-dependent induction of antioxidant defenses by phenolic diterpenes confers stress tolerance in normal human skin fibroblasts: Insights on replicative senescence.

    Science.gov (United States)

    Carvalho, Ana C; Gomes, Andreia C; Pereira-Wilson, Cristina; Lima, Cristovao F

    2015-06-01

    Mild stress-induced hormesis represents a promising strategy for targeting the age-related accumulation of molecular damage and, therefore, for preventing diseases and achieving healthy aging. Fruits, vegetables, and spices contain a wide variety of hormetic phytochemicals, which may explain the beneficial health effects associated with the consumption of these dietary components. In the present study, the induction of cellular antioxidant defenses by the phenolic diterpenes carnosic acid (CA) and carnosol (CS) were studied in normal human skin fibroblasts, and insights into the aging process at the cellular level investigated. We observed that CA and CS induced several cytoprotective enzymes and antioxidant defenses in human fibroblasts, whose induction was dependent on the cellular redox state for CS and associated with Nrf2 signaling for both compounds. The stress response elicited by preincubation with CS conferred a cytoprotective action against a following oxidant challenge with tert-butyl hydroperoxide, confirming its hormetic effect. Preincubation of normal fibroblasts with CS also protected against hydrogen peroxide-induced premature senescence. Furthermore, cultivation of middle passage normal human skin fibroblasts in the presence of CS ameliorated the physiological state of cells during replicative senescence. Our results support the view that mild stress-induced antioxidant defenses by CS can confer stress tolerance in normal cells and may have important implications in the promotion of healthy aging.

  2. The skin conductance orienting response in neuroleptic-free schizophrenics: replication of the scoring criteria effect.

    Science.gov (United States)

    Levinson, D F; Edelberg, R; Maricq, H R

    1985-06-01

    It has been suggested that the use of invalid scoring criteria might be responsible for the finding of excessive nonhabituation of the skin conductance orienting response (SCOR) in schizophrenia. Certain criteria may confuse SCOR and spontaneous SC activity in subjects with high rates of the latter (Levinson et al. 1984). To replicate this finding, data were reanalyzed from a study of 25 neuroleptic-free schizophrenic patients and 23 normal male subjects. Analysis of response latency and amplitude during a habituation paradigm of 11 78.5-dB tones confirmed the predictions. Broad scoring criteria (SCOR onset 1-5 sec poststimulus, and a three-no-response-trials habituation criterion) produced significantly different habituation scores than more restrictive criteria (1.6-3.0 sec latency window and a two-trials habituation criterion). Nonhabituation was scored in five patients and six normals by the former criteria, but in no patient and one normal by the latter. Nonhabituators, defined by using the broad criteria, had higher rates of spontaneous activity. The narrow latency window contained significantly more responses than could be explained by the spontaneous activity rate, but this was not true for the added time permitted by the broad window. It is concluded that the use of more restrictive scoring criteria may help to clarify the validity of SCOR nonresponse or hyporesponse as a marker for a type of schizophrenic illness.

  3. Physiological Responses to Thermal Stress and Exercise

    Science.gov (United States)

    Iyota, Hiroyuki; Ohya, Akira; Yamagata, Junko; Suzuki, Takashi; Miyagawa, Toshiaki; Kawabata, Takashi

    The simple and noninvasive measuring methods of bioinstrumentation in humans is required for optimization of air conditioning and management of thermal environments, taking into consideration the individual specificity of the human body as well as the stress conditions affecting each. Changes in human blood circulation were induced with environmental factors such as heat, cold, exercise, mental stress, and so on. In this study, the physiological responses of human body to heat stress and exercise were investigated in the initial phase of the developmental research. We measured the body core and skin temperatures, skin blood flow, and pulse wave as the indices of the adaptation of the cardiovascular system. A laser Doppler skin blood flowmetry using an optical-sensor with a small portable data logger was employed for the measurement. These results reveal the heat-stress and exercise-induced circulatory responses, which are under the control of the sympathetic nerve system. Furthermore, it was suggested that the activity of the sympathetic nervous system could be evaluated from the signals of the pulse wave included in the signals derived from skin blood flow by means of heart rate variability assessments and detecting peak heights of velocity-plethysmogram.

  4. Silicon Dioxide Impedes Antiviral Response and Causes Genotoxic Insult During Calicivirus Replication.

    Science.gov (United States)

    Agnihothram, Sudhakar S; Vermudez, Sheryl Anne; Mullis, Lisa; Townsend, Todd A; Manjanatha, Mugimane G; Azevedo, Marli P

    2016-07-01

    Noroviruses (NoV) are the leading cause of nonbacterial gastroenteritis in humans, and replicate extensively in the human gastrointestinal (GI) tract. Silica (also known as silicon dioxide, SiO2) nanoparticles (NPs) used in processed foods, dairy products, and beverages also accumulate in the GI tract. We investigated the effect of silica NPs on NoV replication and host cell response during virus infection, using murine norovirus (MNV-1) infection of RAW 264.7 murine macrophages. Pretreatment with 10 μg/ml silica significantly reduced the viability of macrophages, but no cumulative effects on viability of macrophages were observed with MNV-1 infection. No difference was observed between exposure to control or silica NPs on either the quantity of viral genome copies or the production of infectious virus in macrophages infected with MNV-1. Silica NPs reduced the ability of macrophages to upregulate genes encoding bone morphogenic proteins (BMPs), chemokine ligands and cytokines for which expression levels were otherwise found to be upregulated in response to MNV-1 infection. Furthermore, silica NPs reduced the levels of proinflammatory cytokines secreted by macrophages in response to MNV infection. Finally, silica NPs with MNV-1 infection produced a genotoxic insult to macrophages. Strikingly, this genotoxic insult was also found to occur as a synergistic effect of silica NPs and feline calicivirus infection in feline kidney epithelial cells. Taken together, our study suggests important safety considerations related to reducing exposure to silica NPs affecting the GI tract in individuals infected with NoVs and possibly other foodborne viruses.

  5. The role of APC/C(Cdh1) in replication stress and origin of genomic instability.

    Science.gov (United States)

    Greil, C; Krohs, J; Schnerch, D; Follo, M; Felthaus, J; Engelhardt, M; Wäsch, R

    2016-06-01

    It has been proposed that the APC/C(Cdh1) functions as a tumor suppressor by maintaining genomic stability. However, the exact nature of genomic instability following loss of Cdh1 is unclear. Using biochemistry and live cell imaging of single cells we found that Cdh1 knockdown (kd) leads to strong nuclear stabilization of the substrates cyclin A and B and deregulated kinetics of DNA replication. Restoration of the Cdh1-dependent G2 DNA damage checkpoint did not result in G2 arrest but blocked cells in prometaphase, suggesting that these cells enter mitosis despite incomplete replication. This results in DNA double-strand breaks, anaphase bridges, cytokinesis defects and tetraploidization. Tetraploid cells are the source of supernumerary centrosomes following Cdh1-kd, leading to multipolar mitosis or centrosome clustering, in turn resulting in merotelic attachment and lagging chromosomes. Whereas some of these events cause apoptosis during mitosis, surviving cells may accumulate chromosomal aberrations.

  6. Responses of Multi-Aged Music Students to Mid-20th-Century Art Music: A Replication and Extension

    Science.gov (United States)

    Madsen, Clifford K.; Geringer, John M.

    2015-01-01

    This investigation replicates previous research into K-12 students' responses to mid-20th-century art music. The study extends that research to include undergraduates and graduates as well as an additional group of graduate students who had taken a 20th-century music class. Children's responses showed remarkable consistency and indicated that…

  7. Stress response and apoptosis in pro- and antiinflammatory macrophages.

    Science.gov (United States)

    Malyshev, I Yu; Kruglov, S V; Bakhtina, L Yu; Malysheva, E V; Zubin, M; Norkin, M

    2004-08-01

    We showed that stress response and apoptosis in macrophages depend on the phenotype of their secretory activity and specific biological and physical characteristics of the factor inducing stress-response or apoptosis.

  8. Caregiving and developmental factors differentiating young at-risk urban children showing resilient versus stress-affected outcomes: a replication and extension.

    Science.gov (United States)

    Wyman, P A; Cowen, E L; Work, W C; Hoyt-Meyers, L; Magnus, K B; Fagen, D B

    1999-01-01

    This study tested hypotheses from an organizational-developmental model for childhood resilience. In this model resilience reflects a child's mastery of age-salient objectives, in the face of substantial adversity, by drawing on internal and external resources that enhance processes of adaptation specific to each developmental stage. Interviews were conducted with parents of 122 7- to 9-year-old urban children exposed to multiple risk factors, 69 classified as resilient and 53 as maladjusted. Consistent with predictions generated by the model: (1) characteristics of a child's caregiving system and early development differentiated children with resilient and stress-affected adaptations; and (2) variables reflecting emotionally responsive, competent parenting were direct, proximal predictors of resilient status and mediators of other caregiver resources such as education, mental health, and relational history. Identified predictors of resilient status, including competent parenting and caregiver psychosocial resources, largely replicated findings from a prior study with sociodemographically comparable 9- to 12-year-old children.

  9. An epigenome-wide association meta-analysis of prenatal maternal stress in neonates: A model approach for replication.

    Science.gov (United States)

    Rijlaarsdam, Jolien; Pappa, Irene; Walton, Esther; Bakermans-Kranenburg, Marian J; Mileva-Seitz, Viara R; Rippe, Ralph C A; Roza, Sabine J; Jaddoe, Vincent W V; Verhulst, Frank C; Felix, Janine F; Cecil, Charlotte A M; Relton, Caroline L; Gaunt, Tom R; McArdle, Wendy; Mill, Jonathan; Barker, Edward D; Tiemeier, Henning; van IJzendoorn, Marinus H

    2016-01-01

    Prenatal maternal stress exposure has been associated with neonatal differential DNA methylation. However, the available evidence in humans is largely based on candidate gene methylation studies, where only a few CpG sites were evaluated. The aim of this study was to examine the association between prenatal exposure to maternal stress and offspring genome-wide cord blood methylation using different methods. First, we conducted a meta-analysis and follow-up pathway analyses. Second, we used novel region discovery methods [i.e., differentially methylated regions (DMRs) analyses]. To this end, we used data from two independent population-based studies, the Generation R Study (n = 912) and the Avon Longitudinal Study of Parents and Children (ALSPAC, n = 828), to (i) measure genome-wide DNA methylation in cord blood and (ii) extract a prenatal maternal stress composite. The meta-analysis (ntotal = 1,740) revealed no epigenome-wide (meta P meta-analysis (meta P meta-analysis, the current study indicates that there are no large effects of prenatal maternal stress exposure on neonatal DNA methylation. Such replication efforts are essential in the search for robust associations, whether derived from candidate gene methylation or epigenome-wide studies.

  10. HLA alleles associated with the adaptive immune response to smallpox vaccine: a replication study.

    Science.gov (United States)

    Ovsyannikova, Inna G; Pankratz, V Shane; Salk, Hannah M; Kennedy, Richard B; Poland, Gregory A

    2014-09-01

    We previously reported HLA allelic associations with vaccinia virus (VACV)-induced adaptive immune responses in a cohort of healthy individuals (n = 1,071 subjects) after a single dose of the licensed smallpox (Dryvax) vaccine. This study demonstrated that specific HLA alleles were significantly associated with VACV-induced neutralizing antibody (NA) titers (HLA-B*13:02, *38:02, *44:03, *48:01, and HLA-DQB1*03:02, *06:04) and cytokine (HLA-DRB1*01:03, *03:01, *10:01, *13:01, *15:01) immune responses. We undertook an independent study of 1,053 healthy individuals and examined associations between HLA alleles and measures of adaptive immunity after a single dose of Dryvax-derived ACAM2000 vaccine to evaluate previously discovered HLA allelic associations from the Dryvax study and determine if these associations are replicated with ACAM2000. Females had significantly higher NA titers than male subjects in both study cohorts [median ID50 discovery cohort 159 (93, 256) vs. 125 (75, 186), p smallpox vaccine-induced adaptive immune responses are significantly influenced by HLA gene polymorphisms. These data provide information for functional studies and design of novel candidate smallpox vaccines.

  11. Response to temperature stress in rhizobia.

    Science.gov (United States)

    Alexandre, Ana; Oliveira, Solange

    2013-08-01

    It is well established that soil is a challenging environment for bacteria, where conditions may change rapidly and bacteria have to acclimate and adapt in order to survive. Rhizobia are an important group of soil bacteria due to their ability to establish atmospheric nitrogen-fixing symbioses with many legume species. Some of these legumes are used to feed either humans or cattle and therefore the use of rhizobia can reduce the need for synthetic N-fertilizers. Several environmental factors shape the composition and the activity of rhizobia populations in the rhizosphere. Soil pH and temperature are often considered to be the major abiotic factors in determining the bacterial community diversity. The present review focuses on the current knowledge on the molecular bases of temperature stress response in rhizobia. The effects of temperature stress in the legume-rhizobia symbioses are also addressed.

  12. The early stress responses in fish larvae.

    Science.gov (United States)

    Pederzoli, Aurora; Mola, Lucrezia

    2016-05-01

    During the life cycle of fish the larval stages are the most interesting and variable. Teleost larvae undergo a daily increase in adaptability and many organs differentiate and become active. These processes are concerted and require an early neuro-immune-endocrine integration. In larvae communication among the nervous, endocrine and immune systems utilizes several known signal molecule families which could be different from those of the adult fish. The immune-neuroendocrine system was studied in several fish species, among which in particular the sea bass (Dicentrarchus labrax), that is a species of great commercial interest, very important in aquaculture and thus highly studied. Indeed the immune system of this species is the best known among marine teleosts. In this review the data on main signal molecules of stress carried out on larvae of fish are considered and discussed. For sea bass active roles in the early immunological responses of some well-known molecules involved in the stress, such as ACTH, nitric oxide, CRF, HSP-70 and cortisol have been proposed. These molecules and/or their receptors are biologically active mainly in the gut before complete differentiation of gut-associated lymphoid tissue (GALT), probably acting in an autocrine/paracrine way. An intriguing idea emerges from all results of these researches; the molecules involved in stress responses, expressed in the adult cells of the hypothalamic-pituitary axis, during the larval life of fish are present in several other localizations, where they perform probably the same role. It may be hypothesized that the functions performed by hypothalamic-pituitary system are particularly important for the survival of the larva and therefore they comprises several other localizations of body. Indeed the larval stages of fish are very crucial phases that include many physiological changes and several possible stress both internal and environmental.

  13. Lifestyle, stress and cortisol response: Review I: Mental stress

    OpenAIRE

    Fukuda, Sanae; Morimoto, Kanehisa

    2001-01-01

    The incidences of diseases related to mental stress are increasing in Japan. Mental stress, unacknowledged for long periods, has been shown to lead to the development of a number of diseases. Thus, an index for mental stress is important to induce awareness of its presence. We focused on the relationship between cortisol and mental stress in this review. We will discuss both the usefulness and problems of cortisol as a mental stress index by summarizing the relationship between cortisol and m...

  14. Adaptive evolution of a stress response protein.

    Directory of Open Access Journals (Sweden)

    Tom J Little

    Full Text Available BACKGROUND: Some cancers are mediated by an interplay between tissue damage, pathogens and localised innate immune responses, but the mechanisms that underlie these linkages are only beginning to be unravelled. METHODS AND PRINCIPAL FINDINGS: Here we identify a strong signature of adaptive evolution on the DNA sequence of the mammalian stress response gene SEP53, a member of the epidermal differentiation complex fused-gene family known for its role in suppressing cancers. The SEP53 gene appears to have been subject to adaptive evolution of a type that is commonly (though not exclusively associated with coevolutionary arms races. A similar pattern of molecular evolution was not evident in the p53 cancer-suppressing gene. CONCLUSIONS: Our data thus raises the possibility that SEP53 is a component of the mucosal/epithelial innate immune response engaged in an ongoing interaction with a pathogen. Although the pathogenic stress mediating adaptive evolution of SEP53 is not known, there are a number of well-known candidates, in particular viruses with established links to carcinoma.

  15. Cannibalism stress response in Bacillus subtilis.

    Science.gov (United States)

    Höfler, Carolin; Heckmann, Judith; Fritsch, Anne; Popp, Philipp; Gebhard, Susanne; Fritz, Georg; Mascher, Thorsten

    2016-01-01

    When faced with carbon source limitation, the Gram-positive soil organism Bacillus subtilis initiates a survival strategy called sporulation, which leads to the formation of highly resistant endospores that allow B. subtilis to survive even long periods of starvation. In order to avoid commitment to this energy-demanding and irreversible process, B. subtilis employs another strategy called 'cannibalism' to delay sporulation as long as possible. Cannibalism involves the production and secretion of two cannibalism toxins, sporulation delaying protein (SDP) and sporulation killing factor (SKF), which are able to lyse sensitive siblings. The lysed cells are thought to then provide nutrients for the cannibals to slow down or even prevent them from entering sporulation. In this study, we uncovered the role of the cell envelope stress response (CESR), especially the Bce-like antimicrobial peptide detoxification modules, in the cannibalism stress response during the stationary phase. SDP and SKF specifically induce Bce-like systems and some extracytoplasmic function σ factors in stationary-phase cultures, but only the latter provide some degree of protection. A full Bce response is only triggered by mature toxins, and not by toxin precursors. Our study provides insights into the close relationship between stationary-phase survival and the CESR of B. subtilis.

  16. Combinatorial stress responses: direct coupling of two major stress responses in Escherichia coli

    Directory of Open Access Journals (Sweden)

    Daniel R. Brown

    2014-09-01

    Full Text Available Nitrogen is an essential element for all life, and this is no different for the bacterial cell. Numerous cellular macromolecules contain nitrogen, including proteins, nucleic acids and cell wall components. In Escherichia coli and related bacteria, the nitrogen stress (Ntr response allows cells to rapidly sense and adapt to nitrogen limitation by scavenging for alternative nitrogen sources through the transcriptional activation of transport systems and catabolic and biosynthetic operons by the global transcriptional regulator NtrC. Nitrogen-starved bacterial cells also synthesize the (pppGpp effector molecules of a second global bacterial stress response - the stringent response. Recently, we showed that the transcription of relA, the gene which encodes the major (pppGpp synthetase in E. coli, is activated by NtrC during nitrogen starvation. Our results revealed that in E. coli and related bacteria, NtrC functions in combinatorial stress and serves to couple two major stress responses, the Ntr response and stringent response.

  17. Hepatitis C Virus Infection Induces Autophagy as a Prosurvival Mechanism to Alleviate Hepatic ER-Stress Response

    Directory of Open Access Journals (Sweden)

    Srikanta Dash

    2016-05-01

    Full Text Available Hepatitis C virus (HCV infection frequently leads to chronic liver disease, liver cirrhosis and hepatocellular carcinoma (HCC. The molecular mechanisms by which HCV infection leads to chronic liver disease and HCC are not well understood. The infection cycle of HCV is initiated by the attachment and entry of virus particles into a hepatocyte. Replication of the HCV genome inside hepatocytes leads to accumulation of large amounts of viral proteins and RNA replication intermediates in the endoplasmic reticulum (ER, resulting in production of thousands of new virus particles. HCV-infected hepatocytes mount a substantial stress response. How the infected hepatocyte integrates the viral-induced stress response with chronic infection is unknown. The unfolded protein response (UPR, an ER-associated cellular transcriptional response, is activated in HCV infected hepatocytes. Over the past several years, research performed by a number of laboratories, including ours, has shown that HCV induced UPR robustly activates autophagy to sustain viral replication in the infected hepatocyte. Induction of the cellular autophagy response is required to improve survival of infected cells by inhibition of cellular apoptosis. The autophagy response also inhibits the cellular innate antiviral program that usually inhibits HCV replication. In this review, we discuss the physiological implications of the HCV-induced chronic ER-stress response in the liver disease progression.

  18. Economic Pressure in African American Families: A Replication and Extension of the Family Stress Model.

    Science.gov (United States)

    Conger, Rand D.; Wallace, Lora Ebert; Sun, Yumei; Simons, Ronald L.; McLoyd, Vonnie C.; Brody, Gene H.

    2002-01-01

    Evaluated applicability of family stress model of economic hardship for understanding economic influences on child development among African American families with a 10- or 11-year-old child. Found that economic hardship positively related to economic pressure in families, and to emotional distress of caregivers, which in turn damaged the…

  19. Genotype-specific responses to light stress in eelgrass Zostera marina, a marine foundation plant

    DEFF Research Database (Denmark)

    Salo, Tiina Elina; Reusch, Thorsten B. H.

    2015-01-01

    Within mono-specific meadows of clonal plants, genotypic diversity may functionally replace species diversity. Little is known about the variability in performance and plasticity of different genotypes towards anthropogenically induced stressors. In this field experiment we compared light......-limitation stress responses and recovery of different eelgrass Zostera marina genotypes to assess the variability in phenotypic plasticity and gene expression between different genotypes. Replicated monoculture plots of 4 genotypes were subjected to a simulated turbidity period of 4 wk using shading screens...... remarkable plasticity in their stress responses and all phenotypic variables recovered to the control level within 4 wk. Depletion and subsequent restoration of sucrose levels differed among genotypes. In terms of gene expression, no consistent patterns were observed. Our study confirms that stress responses...

  20. Genetic and biochemical evidences reveal novel insights into the mechanism underlying Saccharomyces cerevisiae Sae2-mediated abrogation of DNA replication stress

    Indian Academy of Sciences (India)

    INDRAJEET GHODKE; K MUNIYAPPA

    2016-12-01

    In Saccharomyces cerevisiae, the Mre11-Rad50-Xrs2 (MRX) protein complex plays pivotal roles in double-strandbreak (DSB) repair, replication stress and telomere length maintenance. Another protein linked to DSB repair is Sae2,which regulates MRX persistence at DSBs. However, very little is known about its role in DNA replication stress andrepair. Here, we reveal a crucial role for Sae2 in DNA replication stress. We show that different mutant alleles of SAE2cause hypersensitivity to genotoxic agents, and when combined with Δmre11 or nuclease-defective mre11 mutantalleles, the double mutants are considerably more sensitive suggesting that the sae2 mutations synergize with mre11mutations. Biochemical studies demonstrate that Sae2 exists as a dimer in solution, associates preferentially withsingle-stranded and branched DNA structures, exhibits structure-specific endonuclease activity and cleaves thesesubstrates from the 5′ end. Furthermore, we show that the nuclease activity is indeed intrinsic to Sae2. Interestingly,sae2G270D protein possesses DNA-binding activity, but lacks detectable nuclease activity. Altogether, our data suggesta direct role for Sae2 nuclease activity in processing of the DNA structures that arise during replication and DNAdamage and provide insights into the mechanism underlying Mre11-Sae2-mediated abrogation of replication stress-relateddefects in S. cerevisiae.

  1. Rad53-Mediated Regulation of Rrm3 and Pif1 DNA Helicases Contributes to Prevention of Aberrant Fork Transitions under Replication Stress

    Directory of Open Access Journals (Sweden)

    Silvia Emma Rossi

    2015-10-01

    Full Text Available Replication stress activates the Mec1ATR and Rad53 kinases. Rad53 phosphorylates nuclear pores to counteract gene gating, thus preventing aberrant transitions at forks approaching transcribed genes. Here, we show that Rrm3 and Pif1, DNA helicases assisting fork progression across pausing sites, are detrimental in rad53 mutants experiencing replication stress. Rrm3 and Pif1 ablations rescue cell lethality, chromosome fragmentation, replisome-fork dissociation, fork reversal, and processing in rad53 cells. Through phosphorylation, Rad53 regulates Rrm3 and Pif1; phospho-mimicking rrm3 mutants ameliorate rad53 phenotypes following replication stress without affecting replication across pausing elements under normal conditions. Hence, the Mec1-Rad53 axis protects fork stability by regulating nuclear pores and DNA helicases. We propose that following replication stress, forks stall in an asymmetric conformation by inhibiting Rrm3 and Pif1, thus impeding lagging strand extension and preventing fork reversal; conversely, under unperturbed conditions, the peculiar conformation of forks encountering pausing sites would depend on active Rrm3 and Pif1.

  2. Single molecule analysis of Trypanosoma brucei DNA replication dynamics.

    Science.gov (United States)

    Calderano, Simone Guedes; Drosopoulos, William C; Quaresma, Marina Mônaco; Marques, Catarina A; Kosiyatrakul, Settapong; McCulloch, Richard; Schildkraut, Carl L; Elias, Maria Carolina

    2015-03-11

    Eukaryotic genome duplication relies on origins of replication, distributed over multiple chromosomes, to initiate DNA replication. A recent genome-wide analysis of Trypanosoma brucei, the etiological agent of sleeping sickness, localized its replication origins to the boundaries of multigenic transcription units. To better understand genomic replication in this organism, we examined replication by single molecule analysis of replicated DNA. We determined the average speed of replication forks of procyclic and bloodstream form cells and we found that T. brucei DNA replication rate is similar to rates seen in other eukaryotes. We also analyzed the replication dynamics of a central region of chromosome 1 in procyclic forms. We present evidence for replication terminating within the central part of the chromosome and thus emanating from both sides, suggesting a previously unmapped origin toward the 5' extremity of chromosome 1. Also, termination is not at a fixed location in chromosome 1, but is rather variable. Importantly, we found a replication origin located near an ORC1/CDC6 binding site that is detected after replicative stress induced by hydroxyurea treatment, suggesting it may be a dormant origin activated in response to replicative stress. Collectively, our findings support the existence of more replication origins in T. brucei than previously appreciated.

  3. Personality traits modulate emotional and physiological responses to stress.

    Science.gov (United States)

    Childs, Emma; White, Tara L; de Wit, Harriet

    2014-09-01

    An individual's susceptibility to psychological and physical disorders associated with chronic stress exposure, for example, cardiovascular and infectious disease, may also be predicted by their reactivity to acute stress. One factor associated with both stress resilience and health outcomes is personality. An understanding of how personality influences responses to acute stress may shed light upon individual differences in susceptibility to chronic stress-linked disease. This study examined the relationships between personality and acute responses to stress in 125 healthy adults, using hierarchical linear regression. We assessed personality traits using the Multidimensional Personality Questionnaire (MPQ-BF), and responses to acute stress (cortisol, heart rate, blood pressure, mood) using a standardized laboratory psychosocial stress task, the Trier Social Stress Test. Individuals with high Negative Emotionality exhibited greater emotional distress and lower blood pressure responses to the Trier Social Stress Test. Individuals with high agentic Positive Emotionality exhibited prolonged heart rate responses to stress, whereas those with high communal Positive Emotionality exhibited smaller cortisol and blood pressure responses. Separate personality traits differentially predicted emotional, cardiovascular, and cortisol responses to a psychosocial stressor in healthy volunteers. Future research investigating the association of personality with chronic stress-related disease may provide further clues to the relationship between acute stress reactivity and susceptibility to disease.

  4. Increasing the Number of Replications in Item Response Theory Simulations: Automation through SAS and Disk Operating System

    Science.gov (United States)

    Gagne, Phill; Furlow, Carolyn; Ross, Terris

    2009-01-01

    In item response theory (IRT) simulation research, it is often necessary to use one software package for data generation and a second software package to conduct the IRT analysis. Because this can substantially slow down the simulation process, it is sometimes offered as a justification for using very few replications. This article provides…

  5. Increasing the Number of Replications in Item Response Theory Simulations: Automation through SAS and Disk Operating System

    Science.gov (United States)

    Gagne, Phill; Furlow, Carolyn; Ross, Terris

    2009-01-01

    In item response theory (IRT) simulation research, it is often necessary to use one software package for data generation and a second software package to conduct the IRT analysis. Because this can substantially slow down the simulation process, it is sometimes offered as a justification for using very few replications. This article provides…

  6. Leaf trait response to nutrients and herbivore exclusion across a globally replicated grassland experiment

    Science.gov (United States)

    Firn, Jennifer

    2017-04-01

    Leaf trait response to nutrients and herbivore exclusion across a globally replicated grassland experiment Jennifer Firn1, James McGree2, Eric Lind3, Elizabeth Borer3, Eric Seabloom3, Lauren Sullivan3, Kimberly Lapierre4 and the Nutrient Network 1Queensland University of Technology (QUT), School of Earth, Environmental and Biological Sciences, Science and Engineering Faculty, Brisbane, QLD, 4001 Australia 2Queensland University of Technology (QUT), School of Mathematical Sciences, Science and Engineering Faculty, Brisbane, QLD, 4001 Australia 3Universtiy of Minnesota, Department of Ecology, Evolution, and Behavior, 1479 Gortner Avenue, 140 Gortner Laboratory, St. Paul, MN 55108 USA 4Department of integrative Biology, University of California, Berkeley, CA 94720 USA Functional trait research has developed with the aim of finding general patterns in how the function of plant assemblages changes with respect to different land-uses. Most studies have compared sites within and across regions with variations in land-use history, but not necessarily with standardized treatments in an experimental framework. The trends that have emerged from this research is that characteristics of leaf traits such as specific leaf area (SLA) correlate with carbon acquisition strategies known to influence ecosystem functioning. SLA has been found to represent a plant's investment in growing light-capturing area per dry mass content. Species with a relatively high SLA tend to have a higher rate of return on the resources invested into making tissue (cheaper leaves in terms of energy and resources needed to produce them) when compared to species with a lower SLA (more expensive leaves to produce). Few studies have examined quantitatively measured traits in an experimental framework. The Nutrient Network experiment, globally distributed experiment, presents a unique opportunity to examine the response of functional traits across grassland ecosystems characterised by a diverse range of

  7. Stress responses in probiotic Lactobacillus casei.

    Science.gov (United States)

    Hosseini Nezhad, Marzieh; Hussain, Malik Altaf; Britz, Margaret Lorraine

    2015-01-01

    Survival in harsh environments is critical to both the industrial performance of lactic acid bacteria (LAB) and their competitiveness in complex microbial ecologies. Among the LAB, members of the Lactobacillus casei group have industrial applications as acid-producing starter cultures for milk fermentations and as specialty cultures for the intensification and acceleration of flavor development in certain bacterial-ripened cheese varieties. They are amongst the most common organisms in the gastrointestinal (GI) tract of humans and other animals, and have the potential to function as probiotics. Whether used in industrial or probiotic applications, environmental stresses will affect the physiological status and properties of cells, including altering their functionality and biochemistry. Understanding the mechanisms of how LAB cope with different environments is of great biotechnological importance, from both a fundamental and applied perspective: hence, interaction between these strains and their environment has gained increased interest in recent years. This paper presents an overview of the important features of stress responses in Lb. casei, and related proteomic or gene expression patterns that may improve their use as starter cultures and probiotics.

  8. Involvement of Differential Relationship between HCV Replication and Hepatic PRR Signaling Gene Expression in Responsiveness to IFN-Based Therapy.

    Science.gov (United States)

    Yuki, Nobukazu; Matsumoto, Shinji; Kato, Michio; Yamaguchi, Toshikazu

    2013-01-01

    Aim. To gain an insight into the effect of HCV replication-associated interference with the IFN system on hepatic mRNA expression involved in IFN production. Methods. Relative mRNA expression of TLR3/RIG-I signaling genes involved in IFN- β production was correlated with positive- and negative-strand HCV RNAs in pretreatment liver tissues responsive and nonresponsive to peginterferon and ribavirin for chronic hepatitis C genotype 1. Treatment response was analyzed for per protocol population at weeks 12 (n = 45) and 24 (n = 40) and at 24 weeks aftertreatment (n = 38). Results. HCV replication had no relation to the expression of TLR3, RIG-I, TRIF, IPS-1, IRF3, and IFN- β mRNAs in responders. In striking contrast, positive- and/or negative-strand HCV showed positive correlations with TLR3, RIG-I, TRIF, IPS-1, and IRF3 mRNAs in week-12 nonresponders; with RIG-I, TRIF, IPS-1, and IRF3 mRNAs in week-24 nonresponders; and with TLR3, RIG-I, and IRF3 mRNAs in posttreatment nonresponders. Thus mRNA expression of TLR3/RIG-I signaling genes was increased in relation to viral replication in nonresponders. Conclusions. The findings in IFN nonresponders may imply a host feedback response to severe impairment of the IFN system associated with HCV replication.

  9. The Plant Heat Stress Transcription Factors (HSFs): Structure, Regulation, and Function in Response to Abiotic Stresses.

    Science.gov (United States)

    Guo, Meng; Liu, Jin-Hong; Ma, Xiao; Luo, De-Xu; Gong, Zhen-Hui; Lu, Ming-Hui

    2016-01-01

    Abiotic stresses such as high temperature, salinity, and drought adversely affect the survival, growth, and reproduction of plants. Plants respond to such unfavorable changes through developmental, physiological, and biochemical ways, and these responses require expression of stress-responsive genes, which are regulated by a network of transcription factors (TFs), including heat stress transcription factors (HSFs). HSFs play a crucial role in plants response to several abiotic stresses by regulating the expression of stress-responsive genes, such as heat shock proteins (Hsps). In this review, we describe the conserved structure of plant HSFs, the identification of HSF gene families from various plant species, their expression profiling under abiotic stress conditions, regulation at different levels and function in abiotic stresses. Despite plant HSFs share highly conserved structure, their remarkable diversification across plants reflects their numerous functions as well as their integration into the complex stress signaling and response networks, which can be employed in crop improvement strategies via biotechnological intervention.

  10. The plant heat stress transcription factors (HSFs: structure, regulation and function in response to abiotic stresses

    Directory of Open Access Journals (Sweden)

    Meng eGuo

    2016-02-01

    Full Text Available Abiotic stresses such as high temperature, salinity and drought adversely affect the survival, growth and reproduction of plants. Plants respond to such unfavorable changes through developmental, physiological and biochemical ways, and these responses require expression of stress-responsive genes, which are regulated by a network of transcription factors (TFs, including heat stress transcription factors (HSFs. HSFs play a crucial role in plants response to several abiotic stresses by regulating the expression of stress-responsive genes, such as heat shock proteins (Hsps. In this review, we describe the conserved structure of plant HSFs, the identification of HSF gene families from various plant species, their expression profiling under abiotic stress conditions, regulation at different levels and function in abiotic stresses. Despite plant HSFs share highly conserved structure, their remarkable diversification across plants reflects their numerous functions as well as their integration into the complex stress signaling and response networks, which can be employed in crop improvement strategies via biotechnological intervention.

  11. Personality traits modulate emotional and physiological responses to stress

    OpenAIRE

    2014-01-01

    An individual’s susceptibility to psychological and physical disorders associated with chronic stress exposure e.g., cardiovascular and infectious disease, may also be predicted by their reactivity to acute stress. One factor associated with both stress resilience and health outcomes is personality. An understanding of how personality influences responses to acute stress may shed light upon individual differences in susceptibility to chronic stress-linked disease.

  12. The role of mindfulness in romantic relationship satisfaction and responses to relationship stress.

    Science.gov (United States)

    Barnes, Sean; Brown, Kirk Warren; Krusemark, Elizabeth; Campbell, W Keith; Rogge, Ronald D

    2007-10-01

    Two studies examined the role of mindfulness in romantic relationship satisfaction and in responses to relationship stress. Using a longitudinal design, Study 1 found that higher trait mindfulness predicted higher relationship satisfaction and greater capacities to respond constructively to relationship stress. Study 2 replicated and extended these findings. Mindfulness was again shown to relate to relationship satisfaction; then, using a conflict discussion paradigm, trait mindfulness was found to predict lower emotional stress responses and positive pre- and postconflict change in perception of the relationship. State mindfulness was related to better communication quality during the discussion. Both studies indicated that mindfulness may play an influential role in romantic relationship well-being. Discussion highlights future research directions for this new area of inquiry.

  13. Alpha interferon-induced antiviral response noncytolytically reduces replication defective adenovirus DNA in MDBK cells.

    Science.gov (United States)

    Guo, Ju-Tao; Zhou, Tianlun; Guo, Haitao; Block, Timothy M

    2007-12-01

    Although alpha interferon (IFN-alpha) is of benefit in the treatment of viral hepatitis B, HBV replication has been refractory to the cytokine in commonly used hepatocyte-derived cell lines. In search for a cell culture system to study the mechanism by which IFN-alpha inhibits HBV replication, we infected a variety of cell lines with an adenoviral vector containing a replication competent 1.3-fold genome length HBV DNA (AdHBV) and followed by incubation with IFN-alpha. We found that IFN-alpha efficiently decreased the level of HBV DNA replicative intermediates in AdHBV infected Madin-Darby bovine kidney (MDBK) cells. Further analysis revealed, surprisingly, that IFN-alpha did not directly inhibit HBV replication, rather the amount of adenovirus DNA in the nuclei of MDBK cells was reduced. As a consequence, HBV RNA transcription and DNA replication were inhibited. Experiments with adenoviral vector expressing a green fluorescent protein (GFP) further supported the notion that IFN-alpha treatment noncytolytically eliminated adenovirus DNA, but did not kill the vector infected MDBK cells. Our data suggest that IFN-alpha-induced antiviral program is able to discriminate host cellular DNA from episomal viral DNA and might represent a novel pathway of interferon mediate innate defense against DNA virus infections.

  14. FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress

    DEFF Research Database (Denmark)

    Fugger, Kasper; Chu, Wai Kit; Haahr, Peter

    2013-01-01

    The molecular events occurring following the disruption of DNA replication forks are poorly characterized, despite extensive use of replication inhibitors such as hydroxyurea in the treatment of malignancies. Here, we identify a key role for the FBH1 helicase in mediating DNA double-strand break...... formation following replication inhibition. We show that FBH1-deficient cells are resistant to killing by hydroxyurea, and exhibit impaired activation of the pro-apoptotic factor p53, consistent with decreased DNA double-strand break formation. Similar findings were obtained in murine ES cells carrying...... disrupted alleles of Fbh1. We also show that FBH1 through its helicase activity co-operates with the MUS81 nuclease in promoting the endonucleolytic DNA cleavage following prolonged replication stress. Accordingly, MUS81 and EME1-depleted cells show increased resistance to the cytotoxic effects...

  15. Role of shame and body esteem in cortisol stress responses.

    Science.gov (United States)

    Lupis, Sarah B; Sabik, Natalie J; Wolf, Jutta M

    2016-04-01

    Studies assessing the role of shame in HPA axis reactivity report mixed findings. Discrepancies may be due to methodological difficulties and inter-individual differences in the propensity to experience shame in a stressful situation. Hence, the current study combined self-report of shame and facial coding of shame expressions and assessed the role of body esteem as a moderator of the shame-stress link. For this, 44 healthy students (24F, age 20.5 ± 2.1 years) were exposed to an acute psychosocial stress paradigm (Trier Social Stress Test: TSST). Salivary cortisol levels were measured throughout the protocol. Trait shame was measured before the stress test, and state shame immediately afterwards. Video recordings of the TSST were coded to determine emotion expressions. State shame was neither associated with cortisol stress responses nor with body esteem (self-report: all ps ≥ .24; expression: all ps ≥ .31). In contrast, higher trait shame was associated with both negative body esteem (p = .049) and stronger cortisol stress responses (p = .013). Lastly, having lower body esteem predicted stronger cortisol stress responses (p = .022); however, it did not significantly moderate the association between shame indices and cortisol stress responses (all ps ≥ .94). These findings suggest that body esteem and trait shame independently contribute to strength of cortisol stress responses. Thus, in addition to trait shame, body esteem emerged as an important predictor of cortisol stress responses and as such, a potential contributor to stress-related negative health outcomes.

  16. ATR-Chk1-APC/C-dependent stabilization of Cdc7-ASK (Dbf4) kinase is required for DNA lesion bypass under replication stress

    DEFF Research Database (Denmark)

    Yamada, M.; Watanabe, K.; Mistrik, M.

    2013-01-01

    Cdc7 kinase regulates DNA replication. However, its role in DNA repair and recombination is poorly understood. Here we describe a pathway that stabilizes the human Cdc7-ASK (activator of S-phase kinase; also called Dbf4), its regulation, and its function in cellular responses to compromised DNA...... replication. Stalled DNA replication evoked stabilization of the Cdc7-ASK (Dbf4) complex in a manner dependent on ATR-Chk1-mediated checkpoint signaling and its interplay with the anaphase-promoting complex/cyclosomeCdh1 (APC/C) ubiquitin ligase. Mechanistically, Chk1 kinase inactivates APC/C through......) with RAD18 disables foci formation by RAD18 and hinders chromatin loading of translesion DNA polymerase h. These findings define a novel mechanism that orchestrates replication checkpoint signaling and ubiquitin-proteasome machinery with the DNA damage bypass pathway to guard against replication collapse...

  17. Biological stress response terminology: Integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework.

    Science.gov (United States)

    Calabrese, Edward J; Bachmann, Kenneth A; Bailer, A John; Bolger, P Michael; Borak, Jonathan; Cai, Lu; Cedergreen, Nina; Cherian, M George; Chiueh, Chuang C; Clarkson, Thomas W; Cook, Ralph R; Diamond, David M; Doolittle, David J; Dorato, Michael A; Duke, Stephen O; Feinendegen, Ludwig; Gardner, Donald E; Hart, Ronald W; Hastings, Kenneth L; Hayes, A Wallace; Hoffmann, George R; Ives, John A; Jaworowski, Zbigniew; Johnson, Thomas E; Jonas, Wayne B; Kaminski, Norbert E; Keller, John G; Klaunig, James E; Knudsen, Thomas B; Kozumbo, Walter J; Lettieri, Teresa; Liu, Shu-Zheng; Maisseu, Andre; Maynard, Kenneth I; Masoro, Edward J; McClellan, Roger O; Mehendale, Harihara M; Mothersill, Carmel; Newlin, David B; Nigg, Herbert N; Oehme, Frederick W; Phalen, Robert F; Philbert, Martin A; Rattan, Suresh I S; Riviere, Jim E; Rodricks, Joseph; Sapolsky, Robert M; Scott, Bobby R; Seymour, Colin; Sinclair, David A; Smith-Sonneborn, Joan; Snow, Elizabeth T; Spear, Linda; Stevenson, Donald E; Thomas, Yolene; Tubiana, Maurice; Williams, Gary M; Mattson, Mark P

    2007-07-01

    Many biological subdisciplines that regularly assess dose-response relationships have identified an evolutionarily conserved process in which a low dose of a stressful stimulus activates an adaptive response that increases the resistance of the cell or organism to a moderate to severe level of stress. Due to a lack of frequent interaction among scientists in these many areas, there has emerged a broad range of terms that describe such dose-response relationships. This situation has become problematic because the different terms describe a family of similar biological responses (e.g., adaptive response, preconditioning, hormesis), adversely affecting interdisciplinary communication, and possibly even obscuring generalizable features and central biological concepts. With support from scientists in a broad range of disciplines, this article offers a set of recommendations we believe can achieve greater conceptual harmony in dose-response terminology, as well as better understanding and communication across the broad spectrum of biological disciplines.

  18. Stressors, Resources, and Stress Responses in Pregnant African American Women

    Science.gov (United States)

    Giurgescu, Carmen; Kavanaugh, Karen; Norr, Kathleen F.; Dancy, Barbara L.; Twigg, Naomi; McFarlin, Barbara L.; Engeland, Christopher G.; Hennessy, Mary Dawn; White-Traut, Rosemary C.

    2013-01-01

    This research aimed to develop an initial understanding of the stressors, stress responses, and personal resources that impact African American women during pregnancy, potentially leading to preterm birth. Guided by the ecological model, a prospective, mixed-methods, complementarity design was used with 11 pregnant women and 8 of their significant others. Our integrated analysis of quantitative and qualitative data revealed 2 types of stress responses: high stress responses (7 women) and low stress responses (4 women). Patterns of stress responses were seen in psychological stress and cervical remodeling (attenuation or cervical length). All women in the high stress responses group had high depression and/or low psychological well-being and abnormal cervical remodeling at one or both data collection times. All but 1 woman had at least 3 sources of stress (racial, neighborhood, financial, or network). In contrast, 3 of the 4 women in the low stress responses group had only 2 sources of stress (racial, neighborhood, financial, or network) and 1 had none; these women also reported higher perceived support. The findings demonstrate the importance of periodically assessing stress in African American women during pregnancy, particularly related to their support network as well as the positive supports they receive. PMID:23360946

  19. Ubiquitin-dependent recruitment of the Bloom syndrome helicase upon replication stress is required to suppress homologous recombination.

    Science.gov (United States)

    Tikoo, Shweta; Madhavan, Vinoth; Hussain, Mansoor; Miller, Edward S; Arora, Prateek; Zlatanou, Anastasia; Modi, Priyanka; Townsend, Kelly; Stewart, Grant S; Sengupta, Sagar

    2013-06-12

    Limiting the levels of homologous recombination (HR) that occur at sites of DNA damage is a major role of BLM helicase. However, very little is known about the mechanisms dictating its relocalization to these sites. Here, we demonstrate that the ubiquitin/SUMO-dependent DNA damage response (UbS-DDR), controlled by the E3 ligases RNF8/RNF168, triggers BLM recruitment to sites of replication fork stalling via ubiquitylation in the N-terminal region of BLM and subsequent BLM binding to the ubiquitin-interacting motifs of RAP80. Furthermore, we show that this mechanism of BLM relocalization is essential for BLM's ability to suppress excessive/uncontrolled HR at stalled replication forks. Unexpectedly, we also uncovered a requirement for RNF8-dependent ubiquitylation of BLM and PML for maintaining the integrity of PML-associated nuclear bodies and as a consequence the localization of BLM to these structures. Lastly, we identified a novel role for RAP80 in preventing proteasomal degradation of BLM in unstressed cells. Taken together, these data highlight an important biochemical link between the UbS-DDR and BLM-dependent pathways involved in maintaining genome stability.

  20. Delayed IFN response differentiates replication of West Nile virus and Japanese encephalitis virus in human neuroblastoma and glioblastoma cells.

    Science.gov (United States)

    Takamatsu, Yuki; Uchida, Leo; Morita, Kouichi

    2015-08-01

    West Nile virus (WNV) and Japanese encephalitis virus (JEV) are important causes of human encephalitis cases, which result in a high mortality ratio and neurological sequelae after recovery. Understanding the mechanism of neuropathogenicity in these viral infections is important for the development of specific antiviral therapy. Here, we focused on human-derived neuronal and glial cells to understand the cellular responses against WNV and JEV infection. It was demonstrated that early IFN-β induction regulated virus replication in glioblastoma tbl98G cells, whereas delayed IFN-β induction resulted in efficient virus replication in neuroblastoma SK-N-SH cells. Moreover, the concealing of viral dsRNA in the intracellular membrane resulted in the delayed IFN response in SK-N-SH cells. These results, which showed different IFN responses between human neuronal and glial cells after WNV or JEV infection, are expected to contribute to our understanding of the molecular mechanisms for neuropathology in these viral infections.

  1. Rethinking stress: the role of mindsets in determining the stress response.

    Science.gov (United States)

    Crum, Alia J; Salovey, Peter; Achor, Shawn

    2013-04-01

    This article describes 3 studies that explore the role of mindsets in the context of stress. In Study 1, we present data supporting the reliability and validity of an 8-item instrument, the Stress Mindset Measure (SMM), designed to assess the extent to which an individual believes that the effects of stress are either enhancing or debilitating. In Study 2, we demonstrate that stress mindsets can be altered by watching short, multimedia film clips presenting factual information biased toward defining the nature of stress in 1 of 2 ways (stress-is-enhancing vs. stress-is-debilitating). In Study 3, we demonstrate the effect of stress mindset on physiological and behavioral outcomes, showing that a stress-is-enhancing mindset is associated with moderate cortisol reactivity and high desire for feedback under stress. Together, these 3 studies suggest that stress mindset is a distinct and meaningful variable in determining the stress response.

  2. DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes ubiquitin-dependent responses to replication blocks

    DEFF Research Database (Denmark)

    Mosbech, Anna; Gibbs-Seymour, Ian; Kagias, Konstantinos;

    2012-01-01

    Ubiquitin-mediated processes orchestrate critical DNA-damage signaling and repair pathways. We identify human DVC1 (C1orf124; Spartan) as a cell cycle-regulated anaphase-promoting complex (APC) substrate that accumulates at stalled replication forks. DVC1 recruitment to sites of replication stress...... synthesis (TLS) DNA polymerase η (Pol η) from monoubiquitylated PCNA. DVC1 knockdown enhances UV light-induced mutagenesis, and depletion of human DVC1 or the Caenorhabditis elegans ortholog DVC-1 causes hypersensitivity to replication stress-inducing agents. Our findings establish DVC1 as a DNA damage...

  3. Waterborne aripiprazole blunts the stress response in zebrafish

    Science.gov (United States)

    Barcellos, Heloísa Helena De Alcantara; Kalichak, Fabiana; da Rosa, João Gabriel Santos; Oliveira, Thiago Acosta; Koakoski, Gessi; Idalencio, Renan; de Abreu, Murilo Sander; Giacomini, Ana Cristina Varrone; Fagundes, Michele; Variani, Cristiane; Rossini, Mainara; Piato, Angelo L.; Barcellos, Leonardo José Gil

    2016-11-01

    Here we provide, at least to our knowledge, the first evidence that aripiprazole (APPZ) in the water blunts the stress response of exposed fish in a concentration ten times lower than the concentration detected in the environment. Although the mechanism of APPZ in the neuroendocrine axis is not yet determined, our results highlight that the presence of APPZ residues in the environment may interfere with the stress responses in fish. Since an adequate stress response is crucial to restore fish homeostasis after stressors, fish with impaired stress response may have trouble to cope with natural and/or imposed stressors with consequences to their welfare and survival.

  4. Activation of nucleotide oligomerization domain 2 (NOD2 by human cytomegalovirus initiates innate immune responses and restricts virus replication.

    Directory of Open Access Journals (Sweden)

    Arun Kapoor

    Full Text Available Nucleotide-binding oligomerization domain 2 (NOD2 is an important innate immune sensor of bacterial pathogens. Its induction results in activation of the classic NF-κB pathway and alternative pathways including type I IFN and autophagy. Although the importance of NOD2 in recognizing RNA viruses has recently been identified, its role in sensing DNA viruses has not been studied. We report that infection with human cytomegalovirus (HCMV results in significant induction of NOD2 expression, beginning as early as 2 hours post infection and increasing steadily 24 hours post infection and afterwards. Infection with human herpesvirus 1 and 2 does not induce NOD2 expression. While the HCMV-encoded glycoprotein B is not required for NOD2 induction, a replication competent virion is necessary. Lentivirus-based NOD2 knockdown in human foreskin fibroblasts (HFFs and U373 glioma cells leads to enhanced HCMV replication along with decreased levels of interferon beta (IFN-β and the pro-inflammatory cytokine, IL8. NOD2 induction in HCMV-infected cells activates downstream NF-κB and interferon pathways supported by reduced nuclear localization of NF-κB and pIRF3 in NOD2 knockdown HFFs. Stable overexpression of NOD2 in HFFs restricts HCMV replication in association with increased levels of IFN-β and IL8. Similarly, transient overexpression of NOD2 in U373 cells or its downstream kinase, RIPK2, results in decreased HCMV replication and enhanced cytokine responses. However, overexpression of a mutant NOD2, 3020insC, associated with severe Crohn's disease, results in enhanced HCMV replication and decreased levels of IFN-β in U373 cells. These results show for the first time that NOD2 plays a significant role in HCMV replication and may provide a model for studies of HCMV recognition by the host cell and HCMV colitis in Crohn's disease.

  5. Response of vegetation indices to changes in three measures of leaf water stress

    Science.gov (United States)

    Cohen, Warren B.

    1991-01-01

    The responses of vegetation indices to changes in water stress were evaluated in two separate laboratory experiments. In one experiment the normalized difference vegetation index (NDVI), the near-IR to red ratio (near-IR/red), the Infrared Index (II), and the Moisture Stress Index (MSI) were more highly correlated to leaf water potential in lodgepole pine branches than were the Leaf Water Content Index (LWCI), the mid-IR ratio (Mid-IR), or any of the single Thematic Mapper (TM) bands. In the other experiment, these six indices and the TM Tasseled Cap brightness, greenness, and wetness indices responded to changes in leaf relative water content (RWC) differently than they responded to changes in leaf water content (WC) of three plant species, and the responses were dependent on how experimental replicates were pooled. With no pooling, the LWCI was the most highly correlated index to both RWC and WC among replications, followed by the II, MSI, and wetness. Only the LWCI was highly correlated to RWC and WC when replications were pooled within species. With among species pooling the LWCI was the only index highly correlated with RWC, while the II, MSI, Mid-IR, and wetness were most highly correlated with WC.

  6. Transcriptomic responses to heat stress and bleaching in the elkhorn coral Acropora palmata

    KAUST Repository

    DeSalvo, MK

    2010-03-08

    The emergence of genomic tools for reef-building corals and symbiotic anemones comes at a time when alarming losses in coral cover are being observed worldwide. These tools hold great promise in elucidating novel and unforeseen cellular processes underlying the successful mutualism between corals and their dinoflagellate endosymbionts Symbiodinium spp. Since thermal stress triggers a breakdown in the symbiosis (coral bleaching), measuring the transcriptomic response to thermal stress-induced bleaching offers an extraordinary view of cellular processes that are specific to coral–algal symbioses. In the present study, we utilized a cDNA microarray containing 2059 genes of the threatened Caribbean elkhorn coral Acropora palmata to identify genes that are differentially expressed upon thermal stress. Fragments from replicate colonies were exposed to elevated temperature for 2 d, and samples were frozen for microarray analysis after 24 and 48 h. Totals of 204 and 104 genes were differentially expressed in samples that were collected 1 and 2 d after thermal stress, respectively. Analysis of the differentially expressed genes indicates a cellular stress response in A. palmata involving (1) growth arrest, (2) chaperone activity, (3) nucleic acid stabilization and repair, and (4) removal of damaged macromolecules. Other differentially expressed processes include sensory perception, metabolite transfer between host and endosymbiont, nitric oxide signaling, and modifications to the actin cytoskeleton and extracellular matrix. The results are compared with those from a previous coral microarray study of thermal stress in Montastraea faveolata, and point to an overall evolutionary conserved bleaching response in scleractinian corals.

  7. Origins of asymmetric stress-strain response in phase transformations

    Energy Technology Data Exchange (ETDEWEB)

    Sehitoglu, H.; Gall, K. [Univ. of Illinois, Urbana, IL (United States)

    1997-12-31

    It has been determined that the transformation stress-strain behavior of CuZnAl and NiTi shape memory alloys is dependent on the applied stress state. The uniaxial compressive stress necessary to macroscopically trigger the transformation is approximately 34% (CuZnAl) and 26% (NiTi) larger than the required uniaxial tensile stress. For three dimensional stress states, the response of either alloy system is dependent on the directions of the dominant principal stresses along with the hydrostatic stress component of the stress state. The stress state effects are dominated by the favored growth and nucleation of more martensite plates in tension versus compression. The effect of different hydrostatic pressure levels between stress states on martensite plates volume change is considered small.

  8. Temporal profiling of the chromatin proteome reveals system-wide responses to replication inhibition

    DEFF Research Database (Denmark)

    Khoudoli, Guennadi A; Gillespie, Peter J; Stewart, Graeme

    2008-01-01

    Although the replication, expression, and maintenance of DNA are well-studied processes, the way that they are coordinated is poorly understood. Here, we report an analysis of the changing association of proteins with chromatin (the chromatin proteome) during progression through interphase...... of the cell cycle. Sperm nuclei were incubated in Xenopus egg extracts, and chromatin-associated proteins were analyzed by mass spectrometry at different times. Approximately 75% of the proteins varied in abundance on chromatin by more than 15%, suggesting that the chromatin proteome is highly dynamic...... to replication inhibition (including nuclear pore proteins) coprecipitated with the Mcm2-7 licensing complex on chromatin, suggesting that Mcm2-7 play a central role in coordinating nuclear structure with DNA replication....

  9. Adulthood stress responses in rats are variably altered as a factor of adolescent stress exposure.

    Science.gov (United States)

    Moore, Nicole L T; Altman, Daniel E; Gauchan, Sangeeta; Genovese, Raymond F

    2016-05-01

    Stress exposure during development may influence adulthood stress response severity. The present study investigates persisting effects of two adolescent stressors upon adulthood response to predator exposure (PE). Rats were exposed to underwater trauma (UWT) or PE during adolescence, then to PE after reaching adulthood. Rats were then exposed to predator odor (PO) to test responses to predator cues alone. Behavioral and neuroendocrine assessments were conducted to determine acute effects of each stress experience. Adolescent stress altered behavioral response to adulthood PE. Acoustic startle response was blunted. Bidirectional changes in plus maze exploration were revealed as a factor of adolescent stress type. Neuroendocrine response magnitude did not predict severity of adolescent or adult stress response, suggesting that different adolescent stress events may differentially alter developmental outcomes regardless of acute behavioral or neuroendocrine response. We report that exposure to two different stressors in adolescence may differentially affect stress response outcomes in adulthood. Acute response to an adolescent stressor may not be consistent across all stressors or all dependent measures, and may not predict alterations in developmental outcomes pertaining to adulthood stress exposure. Further studies are needed to characterize factors underlying long-term effects of a developmental stressor.

  10. Immune responses to stress in rheumatoid arthritis and psoriasis

    NARCIS (Netherlands)

    Brouwer, S.J. dr; Middendorp, H. van; Stormink, C.; Kraaimaat, F.W.; Joosten, I.; Radstake, T.R.; Jong, E.M. de; Schalkwijk, J.; Donders, A.R.; Eijsbouts, A.M.M.; Kerkhof, P.C.M. van de; Riel, P.L.C.M. van; Evers, A.W.

    2014-01-01

    OBJECTIVE: Stress is one of the factors that may exacerbate the progression of chronic inflammatory diseases such as RA and psoriasis. We exploratively compared the effects of acute stress on levels of circulating cytokines involved in disease progression and/or the stress response in patients with

  11. Wolbachia Blocks Viral Genome Replication Early in Infection without a Transcriptional Response by the Endosymbiont or Host Small RNA Pathways.

    Directory of Open Access Journals (Sweden)

    Stephanie M Rainey

    2016-04-01

    Full Text Available The intracellular endosymbiotic bacterium Wolbachia can protect insects against viral infection, and is being introduced into mosquito populations in the wild to block the transmission of arboviruses that infect humans and are a major public health concern. To investigate the mechanisms underlying this antiviral protection, we have developed a new model system combining Wolbachia-infected Drosophila melanogaster cell culture with the model mosquito-borne Semliki Forest virus (SFV; Togaviridae, Alphavirus. Wolbachia provides strong antiviral protection rapidly after infection, suggesting that an early stage post-infection is being blocked. Wolbachia does appear to have major effects on events distinct from entry, assembly or exit as it inhibits the replication of an SFV replicon transfected into the cells. Furthermore, it causes a far greater reduction in the expression of proteins from the 3' open reading frame than the 5' non-structural protein open reading frame, indicating that it is blocking the replication of viral RNA. Further to this separation of the replicase proteins and viral RNA in transreplication assays shows that uncoupling of viral RNA and replicase proteins does not overcome Wolbachia's antiviral activity. This further suggests that replicative processes are disrupted, such as translation or replication, by Wolbachia infection. This may occur by Wolbachia mounting an active antiviral response, but the virus did not cause any transcriptional response by the bacterium, suggesting that this is not the case. Host microRNAs (miRNAs have been implicated in protection, but again we found that host cell miRNA expression was unaffected by the bacterium and neither do our findings suggest any involvement of the antiviral siRNA pathway. We conclude that Wolbachia may directly interfere with early events in virus replication such as translation of incoming viral RNA or RNA transcription, and this likely involves an intrinsic (as opposed to

  12. Wolbachia Blocks Viral Genome Replication Early in Infection without a Transcriptional Response by the Endosymbiont or Host Small RNA Pathways.

    Science.gov (United States)

    Rainey, Stephanie M; Martinez, Julien; McFarlane, Melanie; Juneja, Punita; Sarkies, Peter; Lulla, Aleksei; Schnettler, Esther; Varjak, Margus; Merits, Andres; Miska, Eric A; Jiggins, Francis M; Kohl, Alain

    2016-04-01

    The intracellular endosymbiotic bacterium Wolbachia can protect insects against viral infection, and is being introduced into mosquito populations in the wild to block the transmission of arboviruses that infect humans and are a major public health concern. To investigate the mechanisms underlying this antiviral protection, we have developed a new model system combining Wolbachia-infected Drosophila melanogaster cell culture with the model mosquito-borne Semliki Forest virus (SFV; Togaviridae, Alphavirus). Wolbachia provides strong antiviral protection rapidly after infection, suggesting that an early stage post-infection is being blocked. Wolbachia does appear to have major effects on events distinct from entry, assembly or exit as it inhibits the replication of an SFV replicon transfected into the cells. Furthermore, it causes a far greater reduction in the expression of proteins from the 3' open reading frame than the 5' non-structural protein open reading frame, indicating that it is blocking the replication of viral RNA. Further to this separation of the replicase proteins and viral RNA in transreplication assays shows that uncoupling of viral RNA and replicase proteins does not overcome Wolbachia's antiviral activity. This further suggests that replicative processes are disrupted, such as translation or replication, by Wolbachia infection. This may occur by Wolbachia mounting an active antiviral response, but the virus did not cause any transcriptional response by the bacterium, suggesting that this is not the case. Host microRNAs (miRNAs) have been implicated in protection, but again we found that host cell miRNA expression was unaffected by the bacterium and neither do our findings suggest any involvement of the antiviral siRNA pathway. We conclude that Wolbachia may directly interfere with early events in virus replication such as translation of incoming viral RNA or RNA transcription, and this likely involves an intrinsic (as opposed to an induced

  13. The stress response system of proteins: Implications for bioreactor scaleup

    Science.gov (United States)

    Goochee, Charles F.

    1988-01-01

    Animal cells face a variety of environmental stresses in large scale bioreactors, including periodic variations in shear stress and dissolved oxygen concentration. Diagnostic techniques were developed for identifying the particular sources of environmental stresses for animal cells in a given bioreactor configuration. The mechanisms by which cells cope with such stresses was examined. The individual concentrations and synthesis rates of hundreds of intracellular proteins are affected by the extracellular environment (medium composition, dissolved oxygen concentration, ph, and level of surface shear stress). Techniques are currently being developed for quantifying the synthesis rates and concentrations of the intracellular proteins which are most sensitive to environmental stress. Previous research has demonstrated that a particular set of stress response proteins are synthesized by mammalian cells in response to temperature fluctuations, dissolved oxygen deprivation, and glucose deprivation. Recently, it was demonstrated that exposure of human kidney cells to high shear stress results in expression of a completely distinct set of intracellular proteins.

  14. Expression of Raf kinase inhibitor protein is downregulated in response to Newcastle disease virus infection to promote viral replication.

    Science.gov (United States)

    Yin, Renfu; Liu, Xinxin; Bi, Yuhai; Xie, Guangyao; Zhang, Pingze; Meng, Xin; Ai, Lili; Xu, Rongyi; Sun, Yuzhang; Stoeger, Tobias; Ding, Zhuang

    2015-09-01

    Newcastle disease virus (NDV) causes a severe and economically significant disease affecting almost the entire poultry industry worldwide. However, factors that affect NDV replication in host cells are poorly understood. Raf kinase inhibitory protein (RKIP) is a physiological inhibitor of c-RAF kinase and NF-κB signalling, known for their functions in the control of immune response as well as tumour invasion and metastasis. In the present study, we investigated the consequences of overexpression of host RKIP during viral infection. We demonstrate that NDV infection represses RKIP expression thereby promoting virus replication. Experimental upregulation of RKIP in turn acts as a potential antiviral defence mechanism in host cells that restricts NDV replication by repressing the activation of Raf/MEK/ERK and IκBα/NF-κB signalling pathways. Our results not only extend the concept of linking NDV-host interactions, but also reveal RKIP as a new class of protein-kinase-inhibitor protein that affects NDV replication with therapeutic potential.

  15. Acute MUS81 depletion leads to replication fork slowing and a constitutive DNA damage response

    DEFF Research Database (Denmark)

    Xing, Meichun; Wang, Xiaohui; Palmai-Pallag, Timea

    2015-01-01

    The MUS81 protein belongs to a conserved family of DNA structure-specific nucleases that play important roles in DNA replication and repair. Inactivation of the Mus81 gene in mice has no major deleterious consequences for embryonic development, although cancer susceptibility has been reported. We...

  16. Intracellular dynamics of archaeal FANCM homologue Hef in response to halted DNA replication

    NARCIS (Netherlands)

    Lestini, R.; Laptenok, S.P.; Kühn, J.; Hink, M.A.; Schanne-Klein, M.C.; Liebl, U.; Myllykallio, H.

    2013-01-01

    Hef is an archaeal member of the DNA repair endonuclease XPF (XPF)/Crossover junction endonuclease MUS81 (MUS81)/Fanconi anemia, complementation group M (FANCM) protein family that in eukaryotes participates in the restart of stalled DNA replication forks. To investigate the physiological roles of H

  17. Proteomic studies of drought stress response in Fabaceae

    Directory of Open Access Journals (Sweden)

    Tanja ZADRAŽNIK

    2015-11-01

    Full Text Available Drought stress is a serious threat to crop production that influences plant growth and development and subsequently causes reduced quantity and quality of the yield. Plant stress induces changes in cell metabolism, which includes differential expression of proteins. Proteomics offer a powerful approach to analyse proteins involved in drought stress response of plants. Analyses of changes in protein abundance of legumes under drought stress are very important, as legumes play an important role in human and animal diet and are often exposed to drought. The presented results of proteomic studies of selected legumes enable better understanding of molecular mechanisms of drought stress response. The study of drought stress response of plants with proteomic approach may contribute to the development of potential drought-response markers and to the development of drought-tolerant cultivars of different legume crop species.

  18. Stress in university students and cardiovascular response to academic stressors

    OpenAIRE

    Guimarães,Teresa; Silva, Ana Patrícia; Monteiro, Iolanda; Gomes, Rui

    2014-01-01

    Introduction: University students are frequently exposed to events that can cause stress and anxiety, producing elevated cardiovascular responses. Repeated exposure to academic stress has implications to students’ success and well-being and may contribute to the development of long-term health problems. Objective: To identify stress levels and coping strategies in university students and assess the impact of stress experience in heart rate variability (HRV). Methods: 17 university students, 1...

  19. Perceived stress at work is associated with attenuated DHEA-S response during acute psychosocial stress.

    Science.gov (United States)

    Lennartsson, Anna-Karin; Theorell, Töres; Kushnir, Mark M; Bergquist, Jonas; Jonsdottir, Ingibjörg H

    2013-09-01

    Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) have been suggested to play a protective role during acute psychosocial stress, because they act as antagonists to the effects of the stress hormone cortisol. This study aims to investigate whether prolonged psychosocial stress, measured as perceived stress at work during the past week, is related to the capacity to produce DHEA and DHEA-S during acute psychosocial stress. It also aims to investigate whether prolonged perceived stress affects the balance between production of cortisol and DHEA-S during acute psychosocial stress. Thirty-six healthy subjects (19 men and 17 women, mean age 37 years, SD 5 years), were included. Perceived stress at work during the past week was measured by using the Stress-Energy (SE) Questionnaire. The participants were divided into three groups based on their mean scores; Low stress, Medium stress and High stress. The participants underwent the Trier Social Stress Test (TSST) and blood samples were collected before, directly after the stress test, and after 30 min of recovery. General Linear Models were used to investigate if the Medium stress group and the High stress group differ regarding stress response compared to the Low stress group. Higher perceived stress at work was associated with attenuated DHEA-S response during acute psychosocial stress. Furthermore, the ratio between the cortisol production and the DHEA-S production during the acute stress test were higher in individuals reporting higher perceived stress at work compared to individuals reporting low perceived stress at work. There was no statistical difference in DHEA response between the groups. This study shows that prolonged stress, measured as perceived stress at work during the past week, seems to negatively affect the capacity to produce DHEA-S during acute stress. Given the protective functions of DHEA-S, attenuated DHEA-S production during acute stress may lead to higher risk for adverse

  20. Hormonal modulation of the heat shock response: insights from fish with divergent cortisol stress responses

    DEFF Research Database (Denmark)

    LeBlanc, Sacha; Höglund, Erik; Gilmour, Kathleen M.;

    2012-01-01

    shock response, we capitalized on two lines of rainbow trout specifically bred for their high (HR) and low (LR) cortisol response to stress. We predicted that LR fish, with a low cortisol but high catecholamine response to stress, would induce higher levels of HSPs after acute heat stress than HR trout......Acute temperature stress in animals results in increases in heat shock proteins (HSPs) and stress hormones. There is evidence that stress hormones influence the magnitude of the heat shock response; however, their role is equivocal. To determine whether and how stress hormones may affect the heat....... We found that HR fish have significantly higher increases in both catecholamines and cortisol compared with LR fish, and LR fish had no appreciable stress hormone response to heat shock. This unexpected finding prevented further interpretation of the hormonal modulation of the heat shock response...

  1. FBH1 Catalyzes Regression of Stalled Replication Forks

    DEFF Research Database (Denmark)

    Fugger, Kasper; Mistrik, Martin; Neelsen, Kai J

    2015-01-01

    DNA replication fork perturbation is a major challenge to the maintenance of genome integrity. It has been suggested that processing of stalled forks might involve fork regression, in which the fork reverses and the two nascent DNA strands anneal. Here, we show that FBH1 catalyzes regression...... a model whereby FBH1 promotes early checkpoint signaling by remodeling of stalled DNA replication forks....... of a model replication fork in vitro and promotes fork regression in vivo in response to replication perturbation. Cells respond to fork stalling by activating checkpoint responses requiring signaling through stress-activated protein kinases. Importantly, we show that FBH1, through its helicase activity...

  2. T cells detect intracellular DNA but fail to induce type I IFN responses: implications for restriction of HIV replication.

    Directory of Open Access Journals (Sweden)

    Randi K Berg

    Full Text Available HIV infects key cell types of the immune system, most notably macrophages and CD4+ T cells. Whereas macrophages represent an important viral reservoir, activated CD4+ T cells are the most permissive cell types supporting high levels of viral replication. In recent years, it has been appreciated that the innate immune system plays an important role in controlling HIV replication, e.g. via interferon (IFN-inducible restriction factors. Moreover, innate immune responses are involved in driving chronic immune activation and the pathogenesis of progressive immunodeficiency. Several pattern recognition receptors detecting HIV have been reported, including Toll-like receptor 7 and Retinoic-inducible gene-I, which detects viral RNA. Here we report that human primary T cells fail to induce strong IFN responses, despite the fact that this cell type does express key molecules involved in DNA signaling pathways. We demonstrate that the DNA sensor IFI16 migrates to sites of foreign DNA localization in the cytoplasm and recruits the signaling molecules stimulator of IFN genes and Tank-binding kinase, but this does not result in expression of IFN and IFN-stimulated genes. Importantly, we show that cytosolic DNA fails to affect HIV replication. However, exogenous treatment of activated T cells with type I IFN has the capacity to induce expression of IFN-stimulated genes and suppress HIV replication. Our data suggest the existence of an impaired DNA signaling machinery in T cells, which may prevent this cell type from activating cell-autonomous anti-HIV responses. This phenomenon could contribute to the high permissiveness of CD4+ T cells for HIV-1.

  3. Mechanical stress induces biotic and abiotic stress responses via a novel cis-element.

    Directory of Open Access Journals (Sweden)

    Justin W Walley

    2007-10-01

    Full Text Available Plants are continuously exposed to a myriad of abiotic and biotic stresses. However, the molecular mechanisms by which these stress signals are perceived and transduced are poorly understood. To begin to identify primary stress signal transduction components, we have focused on genes that respond rapidly (within 5 min to stress signals. Because it has been hypothesized that detection of physical stress is a mechanism common to mounting a response against a broad range of environmental stresses, we have utilized mechanical wounding as the stress stimulus and performed whole genome microarray analysis of Arabidopsis thaliana leaf tissue. This led to the identification of a number of rapid wound responsive (RWR genes. Comparison of RWR genes with published abiotic and biotic stress microarray datasets demonstrates a large overlap across a wide range of environmental stresses. Interestingly, RWR genes also exhibit a striking level and pattern of circadian regulation, with induced and repressed genes displaying antiphasic rhythms. Using bioinformatic analysis, we identified a novel motif overrepresented in the promoters of RWR genes, herein designated as the Rapid Stress Response Element (RSRE. We demonstrate in transgenic plants that multimerized RSREs are sufficient to confer a rapid response to both biotic and abiotic stresses in vivo, thereby establishing the functional involvement of this motif in primary transcriptional stress responses. Collectively, our data provide evidence for a novel cis-element that is distributed across the promoters of an array of diverse stress-responsive genes, poised to respond immediately and coordinately to stress signals. This structure suggests that plants may have a transcriptional network resembling the general stress signaling pathway in yeast and that the RSRE element may provide the key to this coordinate regulation.

  4. Response Inhibition and Cognitive Appraisal in Clients with Acute Stress Disorder and Posttraumatic Stress Disorder

    Directory of Open Access Journals (Sweden)

    Abass Abolghasemi

    2013-09-01

    Full Text Available Objective: The purpose of the present study was to compare response inhibition and cognitive appraisal in clients with acute stress disorder, clients with posttraumatic stress disorder, and normal individuals .Method:This was a comparative study. The sample consisted of 40 clients with acute stress disorder, 40 patients with posttraumatic stress disorder, and 40 normal individuals from Mazandaran province selected through convenience sampling method. Data were collected using Composite International Diagnostic Interview, Stroop Color-Word Test, Posttraumatic Cognitions Inventory, and the Impact of Event Scale. Results:Results showed that individuals with acute stress disorder are less able to inhibit inappropriate responses and have more impaired cognitive appraisals compared to those with posttraumatic stress disorder. Moreover, results showed that response inhibition and cognitive appraisal explain 75% of the variance in posttraumatic stress disorder symptoms and 38% of the variance in posttraumatic stress disorder symptoms .Conclusion:The findings suggest that response inhibition and cognitive appraisal are two variables that influence the severity of posttraumatic stress disorder and acute stress disorder symptoms. Also, these results have important implications for pathology, prevention, and treatment of posttraumatic stress disorder and acute stress disorder

  5. Effects of orthostasis on endocrine responses to psychosocial stress.

    Science.gov (United States)

    Nater, Urs M; Ditzen, Beate; Strahler, Jana; Ehlert, Ulrike

    2013-12-01

    Standardized psychological procedures have been designed to induce physiological stress responses. However, the impact of standing (orthostasis) on the physiological reaction after psychological stress remains unclear. The purpose of the current analysis was to examine and quantify the relative contribution of orthostasis to the physiological stress response by comparing a "standing with stress" to a "standing without stress" condition. We investigated the effect of standing with and without stress on responses of the sympathetic-adrenomedullary (SAM) system and the hypothalamic-pituitary-adrenal (HPA) axis using a standardized psychosocial stress protocol (Trier Social Stress Test) and a non-stress condition in a repeated measures design. Subjects (N=30) were exposed to both conditions in randomized order and had to maintain a standing, upright position for 10minutes. In the "standing with stress" condition, significant increases in repeatedly assessed plasma norepinephrine (NE) and epinephrine (EP), as well as in saliva cortisol were found, while in the "standing without stress" condition, no significant changes in plasma epinephrine and saliva cortisol were observed. Calculations of the relative contribution of orthostasis to physiological stress responses revealed that 25.61% of the NE increase, 82.94% of the EP increase, and 68.91% of the cortisol increase, could be attributed to psychosocial stress adjusted for the effects of orthostasis and basal endocrine output. Although these results are indicative for a marked endocrine reaction that is caused by psychosocial stress alone, our findings show that the contribution of orthostasis must be taken into account when interpreting endocrine data collected in a psychosocial stress test.

  6. Phosphate-dependent root system architecture responses to salt stress

    KAUST Repository

    Kawa, Dorota

    2016-05-20

    Nutrient availability and salinity of the soil affect growth and development of plant roots. Here, we describe how phosphate availability affects root system architecture (RSA) of Arabidopsis and how phosphate levels modulate responses of the root to salt stress. Phosphate (Pi) starvation reduced main root length and increased the number of lateral roots of Arabidopsis Col-0 seedlings. In combination with salt, low Pi dampened the inhibiting effect of mild salt stress (75mM) on all measured RSA components. At higher NaCl concentrations, the Pi deprivation response prevailed over the salt stress only for lateral root elongation. The Pi deprivation response of lateral roots appeared to be oppositely affected by abscisic acid (ABA) signaling compared to the salt stress response. Natural variation in the response to the combination treatment of salt and Pi starvation within 330 Arabidopsis accessions could be grouped into four response patterns. When exposed to double stress, in general lateral roots prioritized responses to salt, while the effect on main root traits was additive. Interestingly, these patterns were not identical for all accessions studied and multiple strategies to integrate the signals from Pi deprivation and salinity were identified. By Genome Wide Association Mapping (GWAS) 13 genomic loci were identified as putative factors integrating responses to salt stress and Pi starvation. From our experiments, we conclude that Pi starvation interferes with salt responses mainly at the level of lateral roots and that large natural variation exists in the available genetic repertoire of accessions to handle the combination of stresses.

  7. 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.

  8. Disrupted glucocorticoid--Immune interactions during stress response in schizophrenia.

    Science.gov (United States)

    Chiappelli, Joshua; Shi, Qiaoyun; Kodi, Priyadurga; Savransky, Anya; Kochunov, Peter; Rowland, Laura M; Nugent, Katie L; Hong, L Elliot

    2016-01-01

    Glucocorticoid and immune pathways typically interact dynamically to optimize adaptation to stressful environmental challenges. We tested the hypothesis that a dysfunctional glucocorticoid-immune relationship contributes to abnormal stress response in schizophrenia. Saliva samples from 34 individuals with schizophrenia (20 male, 14 female) and 40 healthy controls (20 male, 20 female) were collected prior to and at 3 time points following completion of a computerized psychological challenge meant to be frustrating. Salivary concentrations of cortisol and interleukin-6 (IL-6) and their response to the challenge were examined. Both cortisol and IL-6 significantly increased in response to stress in the combined sample (both pschizophrenia patients (r=.379, p=.027). The trends were significantly different (Z=3.7, p=.0002). This stress paradigm induces a rise in both cortisol and IL-6. In healthy controls, a more robust acute cortisol response was associated with a steeper decline of IL-6 levels following stress, corresponding to the expected anti-inflammatory effects of cortisol. Patients exhibited the opposite relationship, suggesting an inability to down-regulate inflammatory responses to psychological stress in schizophrenia; or even a paradoxical increase of IL-6 response. This finding may partially underlie abnormalities in inflammatory and stress pathways previously found in the illness, implicating dysregulated stress response in the chronic inflammatory state in schizophrenia.

  9. Stretching the Stress Boundary: Linking Air Pollution Health Effects to a Neurohormonal Stress Response

    Science.gov (United States)

    Inhaled pollutants produce effects in virtually all organ systems in our body and have been linked to chronic diseases including hypertension, atherosclerosis, Alzheimer’s and diabetes. A neurohormonal stress response (referred here as a systemic response produced by activ...

  10. Stretching the Stress Boundary: Linking Air Pollution Health Effects to a Neurohormonal Stress Response

    Science.gov (United States)

    Inhaled pollutants produce effects in virtually all organ systems in our body and have been linked to chronic diseases including hypertension, atherosclerosis, Alzheimer’s and diabetes. A neurohormonal stress response (referred here as a systemic response produced by activ...

  11. Stress Response and Perinatal Reprogramming: Unraveling (Maladaptive Strategies

    Directory of Open Access Journals (Sweden)

    Laura Musazzi

    2016-01-01

    Full Text Available Environmental stressors induce coping strategies in the majority of individuals. The stress response, involving the activation of the hypothalamic-pituitary-adrenocortical axis and the consequent release of corticosteroid hormones, is indeed aimed at promoting metabolic, functional, and behavioral adaptations. However, behavioral stress is also associated with fast and long-lasting neurochemical, structural, and behavioral changes, leading to long-term remodeling of glutamate transmission, and increased susceptibility to neuropsychiatric disorders. Of note, early-life events, both in utero and during the early postnatal life, trigger reprogramming of the stress response, which is often associated with loss of stress resilience and ensuing neurobehavioral (maladaptations. Indeed, adverse experiences in early life are known to induce long-term stress-related neuropsychiatric disorders in vulnerable individuals. Here, we discuss recent findings about stress remodeling of excitatory neurotransmission and brain morphology in animal models of behavioral stress. These changes are likely driven by epigenetic factors that lie at the core of the stress-response reprogramming in individuals with a history of perinatal stress. We propose that reprogramming mechanisms may underlie the reorganization of excitatory neurotransmission in the short- and long-term response to stressful stimuli.

  12. Morphologic effects of the stress response in fish.

    Science.gov (United States)

    Harper, Claudia; Wolf, Jeffrey C

    2009-01-01

    Fish and other aquatic animals are subject to a broad variety of stressors because their homeostatic mechanisms are highly dependent on prevailing conditions in their immediate surroundings. Yet few studies have addressed stress as a potential confounding factor for bioassays that use fish as test subjects. Common stressors encountered by captive fish include physical and mental trauma associated with capture, transport, handling, and crowding; malnutrition; variations in water temperature, oxygen, and salinity; and peripheral effects of contaminant exposure or infectious disease. Some stress responses are detectable through gross or microscopic examination of various organs or tissues; as reported in the literature, stress responses are most consistently observed in the gills, liver, skin, and components of the urogenital tract. In addition to presenting examples of various stressors and corresponding morphologic effects, this review highlights certain challenges of evaluating stress in fish: (1) stress is an amorphous term that does not have a consistently applied definition; (2) procedures used to determine or measure stress can be inherently stressful; (3) interactions between stressors and stress responses are highly complex; and (4) morphologically, stress responses are often difficult to distinguish from tissue damage or compensatory adaptations induced specifically by the stressor. Further investigations are necessary to more precisely define the role of stress in the interpretation of fish research results.

  13. Responses of Cymbopogon schoenanthus to salt stress

    African Journals Online (AJOL)

    Yomi

    2012-03-27

    Mar 27, 2012 ... dered as one of the major factors affecting plant growth and crop yield (Zid and ... osmotic stress that reduces its growth rate, second, when salt reaches toxic levels in leaves, photosynthetic activity decreases in sensitive ...

  14. Worms under stress: C. elegans stress response and its relevance to complex human disease and aging

    NARCIS (Netherlands)

    Rodriguez Sanchez, M.; Snoek, L.B.; Bono, de M.; Kammenga, J.E.

    2013-01-01

    Many organisms have stress response pathways, components of which share homology with players in complex human disease pathways. Research on stress response in the nematode worm Caenorhabditis elegans has provided detailed insights into the genetic and molecular mechanisms underlying complex human d

  15. Involvement of Histone Modifications in Plant Abiotic Stress Responses

    Institute of Scientific and Technical Information of China (English)

    Lianyu Yuan; Xuncheng Liu; Ming Luo; Songguang Yang; Keqiang Wu

    2013-01-01

    As sessile organisms, plants encounter various environmental stimuli including abiotic stresses during their lifecycle. To survive under adverse conditions, plants have evolved intricate mechanisms to perceive external signals and respond accordingly. Responses to various stresses largely depend on the plant capacity to modulate the transcriptome rapidly and specifically. A number of studies have shown that the molecular mechanisms driving the responses of plants to environmental stresses often depend on nucleosome histone post-translational modifications including histone acetylation, methylation, ubiquitination, and phosphorylation. The combined effects of these modifications play an essential role in the regulation of stress responsive gene expression. In this review, we highlight our current understanding of the epigenetic mechanisms of histone modifications and their roles in plant abiotic stress response.

  16. Post-stress rumination predicts HPA axis responses to repeated acute stress.

    Science.gov (United States)

    Gianferante, Danielle; Thoma, Myriam V; Hanlin, Luke; Chen, Xuejie; Breines, Juliana G; Zoccola, Peggy M; Rohleder, Nicolas

    2014-11-01

    Failure of the hypothalamus-pituitary-adrenal (HPA) axis to habituate to repeated stress exposure is related with adverse health outcomes, but our knowledge of predictors of non-habituation is limited. Rumination, defined as repetitive and unwanted past-centered negative thinking, is related with exaggerated HPA axis stress responses and poor health outcomes. The aim of this study was to test whether post-stress rumination was related with non-habituation of cortisol to repeated stress exposure. Twenty-seven participants (n=13 females) were exposed to the Trier Social Stress Test (TSST) twice on consecutive afternoons. Post-stress rumination was measured after the first TSST, and HPA axis responses were assessed by measuring salivary cortisol 1 min before, and 1, 10, 20, 60, and 120 min after both TSSTs. Stress exposure induced HPA axis activation on both days, and this activation showed habituation indicated by lower responses to the second TSST (F=3.7, p=0.015). Post-stress rumination after the first TSST was associated with greater cortisol reactivity after the initial stress test (r=0.45, pHPA axis responses. This finding implicates rumination as one possible mechanism mediating maladaptive stress response patterns, and it might also offer a pathway through which rumination might lead to negative health outcomes.

  17. Entropy Generation Analysis of Human Thermal Stress Responses

    OpenAIRE

    Boregowda, Satish C.; Choate, Robert E.; Rodney Handy

    2012-01-01

    The present study involves application of an open system entropy generation formulation to analyze human thermal stress responses. The time-series human thermal stress response data are obtained by conducting a simulation using a validated finite-element human thermal model (FEHTM). These simulated human thermal response data are used as an input to the entropy generation expression to obtain human entropy generation (HEG) values. The effects of variables such as air temperature, relative hum...

  18. Nitric Oxide Signaling in Plant Responses to Abiotic Stresses

    Institute of Scientific and Technical Information of China (English)

    Weihua Qiao; LiuMin Fan

    2008-01-01

    Nitric oxide (NO) plays important roles in diverse physiological processes In plants. NO can provoke both beneficial and harmful effects, which depend on the concentration and location of NO in plant cells. This review is focused on NO synthesis and the functions of NO in plant responses to abiotic environmental stresses. Abiotic stresses mostly induce NO production in plants. NO alleviates the harmfulness of reactive oxygen species, and reacts with other target molecules, and regulates the expression of stress responsive genes under various stress conditions.

  19. New World and Old World Alphaviruses Have Evolved to Exploit Different Components of Stress Granules, FXR and G3BP Proteins, for Assembly of Viral Replication Complexes

    Science.gov (United States)

    Kim, Dal Young; Reynaud, Josephine M.; Rasalouskaya, Aliaksandra; Akhrymuk, Ivan; Mobley, James A.; Frolov, Ilya; Frolova, Elena I.

    2016-01-01

    The positive-strand RNA viruses initiate their amplification in the cell from a single genome delivered by virion. This single RNA molecule needs to become involved in replication process before it is recognized and degraded by cellular machinery. In this study, we show that distantly related New World and Old World alphaviruses have independently evolved to utilize different cellular stress granule-related proteins for assembly of complexes, which recruit viral genomic RNA and facilitate formation of viral replication complexes (vRCs). Venezuelan equine encephalitis virus (VEEV) utilizes all members of the Fragile X syndrome (FXR) family, while chikungunya and Sindbis viruses exploit both members of the G3BP family. Despite being in different families, these proteins share common characteristics, which determine their role in alphavirus replication, namely, the abilities for RNA-binding and for self-assembly into large structures. Both FXR and G3BP proteins interact with virus-specific, repeating amino acid sequences located in the C-termini of hypervariable, intrinsically disordered domains (HVDs) of viral nonstructural protein nsP3. We demonstrate that these host factors orchestrate assembly of vRCs and play key roles in RNA and virus replication. Only knockout of all of the homologs results in either pronounced or complete inhibition of replication of different alphaviruses. The use of multiple homologous proteins with redundant functions mediates highly efficient recruitment of viral RNA into the replication process. This independently evolved acquisition of different families of cellular proteins by the disordered protein fragment to support alphavirus replication suggests that other RNA viruses may utilize a similar mechanism of host factor recruitment for vRC assembly. The use of different host factors by alphavirus species may be one of the important determinants of their pathogenesis. PMID:27509095

  20. Dynamical theory of active cellular response to external stress

    Science.gov (United States)

    de, Rumi; Safran, Samuel A.

    2008-09-01

    We present a comprehensive, theoretical treatment of the orientational response to external stress of active, contractile cells embedded in a gel-like elastic medium. The theory includes both the forces that arise from the deformation of the matrix as well as forces due to the internal regulation of the stress fibers and focal adhesions of the cell. We calculate the time-dependent response of both the magnitude and the direction of the elastic dipole that characterizes the active forces exerted by the cell, for various situations. For static or quasistatic external stress, cells orient parallel to the stress while for high frequency dynamic external stress, cells orient nearly perpendicular. Both numerical and analytical calculations of these effects are presented. In addition we predict the relaxation time for the cellular response for both slowly and rapidly varying external stresses; several characteristic scaling regimes for the relaxation time as a function of applied frequency are predicted. We also treat the case of cells for which the regulation of the stress fibers and focal adhesions is controlled by strain (instead of stress) and show that the predicted dependence of the cellular orientation on the Poisson ratio of the matrix can differentiate strain vs stress regulation of cellular response.

  1. Dynamical theory of active cellular response to external stress.

    Science.gov (United States)

    De, Rumi; Safran, Samuel A

    2008-09-01

    We present a comprehensive, theoretical treatment of the orientational response to external stress of active, contractile cells embedded in a gel-like elastic medium. The theory includes both the forces that arise from the deformation of the matrix as well as forces due to the internal regulation of the stress fibers and focal adhesions of the cell. We calculate the time-dependent response of both the magnitude and the direction of the elastic dipole that characterizes the active forces exerted by the cell, for various situations. For static or quasistatic external stress, cells orient parallel to the stress while for high frequency dynamic external stress, cells orient nearly perpendicular. Both numerical and analytical calculations of these effects are presented. In addition we predict the relaxation time for the cellular response for both slowly and rapidly varying external stresses; several characteristic scaling regimes for the relaxation time as a function of applied frequency are predicted. We also treat the case of cells for which the regulation of the stress fibers and focal adhesions is controlled by strain (instead of stress) and show that the predicted dependence of the cellular orientation on the Poisson ratio of the matrix can differentiate strain vs stress regulation of cellular response.

  2. Influence of surface stresses on indentation response

    Science.gov (United States)

    Buchwald, J.; Mayr, S. G.

    2015-03-01

    Surface stresses lead to an effective change in the elastic constants of thin films and at surfaces. The development of modern scanning probe techniques like contact resonance atomic force microscopy empowers the experimenter to measure at scales where these effects become increasingly relevant. In this paper we employ a computational multiscale approach where we compare density functional theory (DFT) and molecular dynamics simulations as tools to calculate the thin-film/surface elastic behavior for silicon and strontiumtitanate. From the surface elastic constants gained by DFT calculations we develop a continuum finite-element multilayer model to study the impact of surface stresses on indentation experiments. In general the stress field of an indenter and thus the impact of surface stresses on the indentation modulus depends on its contact radius and on its particular shape. We propose an analytical model that describes the behavior of the indentation modulus as a function of the contact radius. We show that this model fits well to simulation results gained for a spherical and a flat punch indenter. Our results demonstrate a surface-stress-induced reduction of the indentation modulus of about 5% for strontiumtitanate and 6% for silicon for a contact radius of {{r}c}=5 \\text{nm}, irrespective of the indenter shape.

  3. Association between neuroticism and amygdala responsivity emerges under stressful conditions.

    Science.gov (United States)

    Everaerd, Daphne; Klumpers, Floris; van Wingen, Guido; Tendolkar, Indira; Fernández, Guillén

    2015-05-15

    Increased amygdala reactivity in response to salient stimuli is seen in patients with affective disorders, in healthy subjects at risk for these disorders, and in stressed individuals, making it a prime target for mechanistic studies into the pathophysiology of affective disorders. However, whereas individual differences in neuroticism are thought to modulate the effect of stress on mental health, the mechanistic link between stress, neuroticism and amygdala responsivity is unknown. Thus, we studied the relationship between experimentally induced stress, individual differences in neuroticism, and amygdala responsivity. To this end, fearful and happy faces were presented to a large cohort of young, healthy males (n=120) in two separate functional MRI sessions (stress versus control) in a randomized, controlled cross-over design. We revealed that amygdala reactivity was modulated by an interaction between the factors of stress, neuroticism, and the emotional valence of the facial stimuli. Follow-up analysis showed that neuroticism selectively enhanced amygdala responses to fearful faces in the stress condition. Thus, we show that stress unmasks an association between neuroticism and amygdala responsivity to potentially threatening stimuli. This effect constitutes a possible mechanistic link within the complex pathophysiology of affective disorders, and our novel approach appears suitable for further studies targeting the underlying mechanisms.

  4. Ethylene Responsive Factors (ERFs in the orchestration of stress responses in monocotyledonous plants

    Directory of Open Access Journals (Sweden)

    Sanjukta eDey

    2015-08-01

    Full Text Available The APETALA2/Ethylene-Responsive Factor (AP2/ERF superfamily of transcription factors regulates physiological, developmental and stress responses. Most of the AP2/ERF transcription factors belong to the ERF family in both dicotyledonous and monocotyledonous plants. ERFs are implicated in the responses to both biotic and abiotic stress and occasionally impart multiple stress tolerance. Studies have revealed that ERF gene function is conserved in dicots and monocots. Moreover, successful stress tolerant phenotypes are observed on expression in heterologous systems, making ERFs promising candidates for engineering stress tolerance in plants. In this review, we summarize the role of ERFs in general stress tolerance, including responses to biotic and abiotic stress factors, and endeavor to understand the cascade of ERF regulation resulting in successful signal-to-response translation in monocotyledonous plants.

  5. Stress Generation and Adolescent Depression: Contribution of Interpersonal Stress Responses

    Science.gov (United States)

    Flynn, Megan; Rudolph, Karen D.

    2011-01-01

    This research examined the proposal that ineffective responses to common interpersonal problems disrupt youths' relationships, which, in turn, contributes to depression during adolescence. Youth (86 girls, 81 boys; M age = 12.41, SD = 1.19) and their primary female caregivers participated in a three-wave longitudinal study. Youth completed a…

  6. Stress Generation and Adolescent Depression: Contribution of Interpersonal Stress Responses

    Science.gov (United States)

    Flynn, Megan; Rudolph, Karen D.

    2011-01-01

    This research examined the proposal that ineffective responses to common interpersonal problems disrupt youths' relationships, which, in turn, contributes to depression during adolescence. Youth (86 girls, 81 boys; M age = 12.41, SD = 1.19) and their primary female caregivers participated in a three-wave longitudinal study. Youth completed a…

  7. Oxidative stress response after laparoscopic versus conventional sigmoid resection

    DEFF Research Database (Denmark)

    Madsen, Michael Tvilling; Kücükakin, Bülent; Lykkesfeldt, Jens;

    2012-01-01

    Surgery is accompanied by a surgical stress response, which results in increased morbidity and mortality. Oxidative stress is a part of the surgical stress response. Minimally invasive laparoscopic surgery may result in reduced oxidative stress compared with open surgery. Nineteen patients...... scheduled for sigmoid resection were randomly allocated to open or laparoscopic sigmoid resection in a double-blind, prospective clinical trial. Three biochemical markers of oxidative stress (malondialdehyde, ascorbic acid, and dehydroascorbic acid) were measured at 6 different time points (preoperatively......, 1 h, 6 h, 24 h, 48 h, and 72 h postoperatively). There were no statistical significant differences between laparoscopic and open surgery for any of the 3 oxidative stress parameters. Malondialdehyde was reduced 1 hour postoperatively (P...

  8. Disruption of GluA2 phosphorylation potentiates stress responsivity.

    Science.gov (United States)

    Ellis, Alexandra S; Fosnocht, Anne Q; Lucerne, Kelsey E; Briand, Lisa A

    2017-08-30

    Cocaine addiction is characterized by persistent craving and addicts frequently relapse even after long periods of abstinence. Exposure to stress can precipitate relapse in humans and rodents. Stress and drug use can lead to common alterations in synaptic plasticity and these commonalities may contribute to the ability of stress to elicit relapse. These common changes in synaptic plasticity are mediated, in part, by alterations in the trafficking and stabilization of AMPA receptors. Exposure to both cocaine and stress can lead to alterations in protein kinase C-mediated phosphorylation of GluA2 AMPA subunits and thus alter the trafficking of GluA2-containing AMPARs. However, it is not clear what role AMPAR trafficking plays in the interactions between stress and cocaine. The current study utilized a mouse with a point mutation within the GluA2 subunit c-terminus resulting in a disruption of PKC-mediated GluA2 phosphorylation to examine stress responsivity. Although no differences were seen in the response to a forced swim stress in naïve mice, GluA2 K882A knock-in mice exhibited an increased stress response following cocaine self-administration. Furthermore, we demonstrated that disrupting GluA2 phosphorylation increases vulnerability to stress-induced reinstatement of both cocaine seeking and cocaine-conditioned reward. Finally, GluA2 K882A knock-in mice exhibit an increased vulnerability to social defeat as indicated by increased social avoidance. Taken together these results indicate that disrupting GluA2 phosphorylation leads to increased responsivity to acute stress following cocaine exposure and increased vulnerability to chronic stress. These results highlight the GluA2 phosphorylation site as a novel target for the stress-related disorders. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Gene Expression Profile in the Long-Living Lotus: Insights into the Heat Stress Response Mechanism.

    Science.gov (United States)

    Liu, Xiaojing; Du, Fengfeng; Li, Naiwei; Chang, Yajun; Yao, Dongrui

    2016-01-01

    Lotus (Nelumbo Adans) is an aquatic perennial plant that flourished during the middle Albian stage. In this study, we characterized the digital gene expression signatures for China Antique lotus under conditions of heat shock stress. Using RNA-seq technology, we sequenced four libraries, specifically, two biological replicates for control plant samples and two for heat stress samples. As a result, 6,528,866 to 8,771,183 clean reads were mapped to the reference genome, accounting for 92-96% total clean reads. A total of 396 significantly altered genes were detected across the genome, among which 315 were upregulated and 81 were downregulated by heat shock stress. Gene ontology (GO) enrichment of differentially expressed genes revealed protein folding, cell morphogenesis and cellular component morphogenesis as the top three functional terms under heat shock stress. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis led to the identification of protein processing in endoplasmic reticulum, plant-pathogen interactions, spliceosome, endocytosis, and protein export as significantly enriched pathways. Among the upregulated genes, small heat shock proteins (sHsps) and genes related to cell morphogenesis were particularly abundant under heat stress. Data from the current study provide valuable clues that may help elucidate the molecular events underlying heat stress response in China Antique lotus.

  10. Gene Expression Profile in the Long-Living Lotus: Insights into the Heat Stress Response Mechanism.

    Directory of Open Access Journals (Sweden)

    Xiaojing Liu

    Full Text Available Lotus (Nelumbo Adans is an aquatic perennial plant that flourished during the middle Albian stage. In this study, we characterized the digital gene expression signatures for China Antique lotus under conditions of heat shock stress. Using RNA-seq technology, we sequenced four libraries, specifically, two biological replicates for control plant samples and two for heat stress samples. As a result, 6,528,866 to 8,771,183 clean reads were mapped to the reference genome, accounting for 92-96% total clean reads. A total of 396 significantly altered genes were detected across the genome, among which 315 were upregulated and 81 were downregulated by heat shock stress. Gene ontology (GO enrichment of differentially expressed genes revealed protein folding, cell morphogenesis and cellular component morphogenesis as the top three functional terms under heat shock stress. Kyoto Encyclopedia of Genes and Genomes (KEGG analysis led to the identification of protein processing in endoplasmic reticulum, plant-pathogen interactions, spliceosome, endocytosis, and protein export as significantly enriched pathways. Among the upregulated genes, small heat shock proteins (sHsps and genes related to cell morphogenesis were particularly abundant under heat stress. Data from the current study provide valuable clues that may help elucidate the molecular events underlying heat stress response in China Antique lotus.

  11. Quantification of Bacillus cereus stress responses

    NARCIS (Netherlands)

    Besten, den H.M.W.

    2010-01-01

    The microbial stability and safety of minimally processed foods is controlled by a deliberate combination of preservation hurdles. However, this preservation strategy is challenged by the ability of spoilage bacteria and food-borne pathogens to adapt to stressing environments providing cell robustne

  12. Acute Stress Response in Critically Ill Children

    NARCIS (Netherlands)

    M. den Brinker (Marieke)

    2006-01-01

    textabstractThe understanding of the endocrine changes in critically ill children is important, as it provides insights in the pathophysiology of the acute stress in children and its differences compared with adults. Furthermore, it delineates prognostic factors for survival and supports the rati

  13. Cell Wall Metabolism in Response to Abiotic Stress

    Directory of Open Access Journals (Sweden)

    Hyacinthe Le Gall

    2015-02-01

    Full Text Available This review focuses on the responses of the plant cell wall to several abiotic stresses including drought, flooding, heat, cold, salt, heavy metals, light, and air pollutants. The effects of stress on cell wall metabolism are discussed at the physiological (morphogenic, transcriptomic, proteomic and biochemical levels. The analysis of a large set of data shows that the plant response is highly complex. The overall effects of most abiotic stress are often dependent on the plant species, the genotype, the age of the plant, the timing of the stress application, and the intensity of this stress. This shows the difficulty of identifying a common pattern of stress response in cell wall architecture that could enable adaptation and/or resistance to abiotic stress. However, in most cases, two main mechanisms can be highlighted: (i an increased level in xyloglucan endotransglucosylase/hydrolase (XTH and expansin proteins, associated with an increase in the degree of rhamnogalacturonan I branching that maintains cell wall plasticity and (ii an increased cell wall thickening by reinforcement of the secondary wall with hemicellulose and lignin deposition. Taken together, these results show the need to undertake large-scale analyses, using multidisciplinary approaches, to unravel the consequences of stress on the cell wall. This will help identify the key components that could be targeted to improve biomass production under stress conditions.

  14. Cellular stress responses for monitoring and modulating ageing

    DEFF Research Database (Denmark)

    Demirovic, Dino; Schnebert, Sylvianne; Nizard, Carine

    2013-01-01

    Cellular stress response is a crucial factor in maintaining efficient homeodynamics for survival, health and longevity. Both the immediate and delayed responses to external and internal stressors effectively determine the molecular biochemical and physiological stability in a dynamic and interact......Cellular stress response is a crucial factor in maintaining efficient homeodynamics for survival, health and longevity. Both the immediate and delayed responses to external and internal stressors effectively determine the molecular biochemical and physiological stability in a dynamic...... and interactive manner. There are three main aspects of stress responses: (i) immediate stress response involving extra- and intra-cellular signaling during the period of disturbance and exposure to the stressors; (ii) delayed stress response involving sensors and modulators in the presence of stressors or after......, development and ageing. Our aim is to define and establish the immediate and delayed stress profiles of normal human skin fibroblasts undergoing ageing in vitro. This is done efficiently by using various cellular, molecular and antibody-based detection methods, combined with functional assays, such as wound...

  15. Differentiating anticipatory from reactive cortisol responses to psychosocial stress

    NARCIS (Netherlands)

    Engert, V.; Efanov, S.I.; Duchesne, A.; Vogel, S.; Corbo, V.; Pruessner, J.C.

    2013-01-01

    Most psychosocial stress studies assess the overall cortisol response without further identifying the temporal dynamics within hormone levels. It has been shown, however, that the amplitude of anticipatory cortisol stress levels has a unique predictive value for psychological health. So far, no "bes

  16. The psychophysiological stress response in psoriasis and rheumatoid arthritis

    NARCIS (Netherlands)

    Brouwer, S.J.M. de; Middendorp, H. van; Stormink, C.; Kraaimaat, F.W.; Sweep, F.C.; Jong, E.M.G.J. de; Schalkwijk, J.; Eijsbouts, A.M.M.; Donders, A.R.T.; Kerkhof, P.C.M. van de; Riel, P.L.C.M. van; Evers, A.W.M.

    2014-01-01

    BACKGROUND: Psychosocial stress can be a risk factor for the maintenance and exacerbation of chronic inflammatory diseases, such as psoriasis and rheumatoid arthritis (RA). OBJECTIVES: To gain insight into the specificity of the psychophysiological stress response during chronic inflammation, we ass

  17. Personality, Stressful Life Events, and Treatment Response in Major Depression

    Science.gov (United States)

    Bulmash, Eric; Harkness, Kate L.; Stewart, Jeremy G.; Bagby, R. Michael

    2009-01-01

    The current study examined whether the personality traits of self-criticism or dependency moderated the effect of stressful life events on treatment response. Depressed outpatients (N = 113) were randomized to 16 weeks of cognitive-behavioral therapy, interpersonal psychotherapy, or antidepressant medication (ADM). Stressful life events were…

  18. Cortisol stress responses and children's behavioral functioning at school

    NARCIS (Netherlands)

    Simons, S.S.H.; Cillessen, A.H.N.; Weerth, C. de

    2017-01-01

    The present study investigated whether cortisol stress responses of 6-year-olds were associated with their behavioral functioning at school. Additionally, the moderating role of stress in the family environment was examined. To this end, 149 healthy children (Magen=n6.09 years; 70 girls) participate

  19. Quorum Sensing Enhances the Stress Response in Vibrio cholerae▿

    OpenAIRE

    Joelsson, Adam; Kan, Biao; Zhu, Jun

    2007-01-01

    Vibrio cholerae lives in aquatic environments and causes cholera. Here, we show that quorum sensing enhances V. cholerae viability under certain stress conditions by upregulating the expression of RpoS, and this regulation acts through HapR, suggesting that a quorum-sensing-enhanced stress response plays a role in V. cholerae environmental survival.

  20. Differentiating anticipatory from reactive cortisol responses to psychosocial stress

    NARCIS (Netherlands)

    Engert, V.; Efanov, S.I.; Duchesne, A.; Vogel, S.; Corbo, V.; Pruessner, J.C.

    2013-01-01

    Most psychosocial stress studies assess the overall cortisol response without further identifying the temporal dynamics within hormone levels. It has been shown, however, that the amplitude of anticipatory cortisol stress levels has a unique predictive value for psychological health. So far, no "bes

  1. Traumatic Experience in Infancy: How Responses to Stress Affect Development

    Science.gov (United States)

    Witten, Molly Romer

    2010-01-01

    Responses to traumatic stress during the earliest years of life can change quickly and can be difficult to identify because of the young child's rapid rate of development. The symptoms of traumatic stress will depend on the child's developmental level and individual coping styles, as well as the quality and nature of the child's most important…

  2. 53BP1 nuclear bodies form around DNA lesions generated by mitotic transmission of chromosomes under replication stress

    DEFF Research Database (Denmark)

    Lukas, Claudia; Savic, Velibor; Bekker-Jensen, Simon

    2011-01-01

    Completion of genome duplication is challenged by structural and topological barriers that impede progression of replication forks. Although this can seriously undermine genome integrity, the fate of DNA with unresolved replication intermediates is not known. Here, we show that mild replication...... bodies shield chromosomal fragile sites sequestered in these compartments against erosion. Together, these data indicate that restoration of DNA or chromatin integrity at loci prone to replication problems requires mitotic transmission to the next cell generations....... increases after genetic ablation of BLM, a DNA helicase associated with dissolution of entangled DNA. Conversely, 53BP1 nuclear bodies are partially suppressed by knocking down SMC2, a condensin subunit required for mechanical stability of mitotic chromosomes. Finally, we provide evidence that 53BP1 nuclear...

  3. The Link Between Oxidative Stress Response and Tumor Necrosis ...

    African Journals Online (AJOL)

    The Link Between Oxidative Stress Response and Tumor Necrosis Factor-Alpha ... Also, to investigate how this can affect normal hepatic tissues. ... A complex relationship exists between the thyroid gland and the liver in health and disease.

  4. Growth and physiological responses to water and nutrient stress in ...

    African Journals Online (AJOL)

    Growth and physiological responses to water and nutrient stress in oil palm. ... conditions) and to two nutrient regimes (with or without fertilization) of oil ... Moreover, deficiency of both water and nutrients in combination had the greatest impact ...

  5. Physiological responses of food animals to road transportation stress

    African Journals Online (AJOL)

    Physiological responses of food animals to road transportation stress. ... The increasing demand in proteins to feed the ever-growing world population has ... This review, in a new approach examines the effects of individual or the combination ...

  6. Physiological responses of food animals to road transportation stress

    African Journals Online (AJOL)

    Physiological responses of food animals to road transportation stress. ... African Journal of Biotechnology ... streaked compliance by transporters, several studies still report severe welfare problems during road transportation of food animals.

  7. Physiological blockage in plants in response to postharvest stress ...

    African Journals Online (AJOL)

    Physiological blockage in plants in response to postharvest stress. ... African Journal of Biotechnology. Journal Home · ABOUT ... However, ornamental plants are used in floral arrangements in vases and have limited shelf-life. Thus, this study ...

  8. Plant volatiles in polluted atmospheres: stress responses and signal degradation

    National Research Council Canada - National Science Library

    BLANDE, JAMES D; HOLOPAINEN, JARMO K; NIINEMETS, ÜLO

    2014-01-01

    .... Volatiles induced by herbivore feeding are among the best studied plant responses to stress and may constitute an informative message to the surrounding community and further function in plant defence processes...

  9. Variability salt stress response analysis of Tunisian natural ...

    African Journals Online (AJOL)

    Variability salt stress response analysis of Tunisian natural populations of Medicago ... African Journal of Biotechnology ... from 11 Tunisian natural populations collected from areas that varied in soil composition, salinity and water availability.

  10. Stress induced by premature chromatin condensation triggers chromosome shattering and chromothripsis at DNA sites still replicating in micronuclei or multinucleate cells when primary nuclei enter mitosis.

    Science.gov (United States)

    Terzoudi, Georgia I; Karakosta, Maria; Pantelias, Antonio; Hatzi, Vasiliki I; Karachristou, Ioanna; Pantelias, Gabriel

    2015-11-01

    Combination of next-generation DNA sequencing, single nucleotide polymorphism array analyses and bioinformatics has revealed the striking phenomenon of chromothripsis, described as complex genomic rearrangements acquired in a single catastrophic event affecting one or a few chromosomes. Via an unproven mechanism, it is postulated that mechanical stress causes chromosome shattering into small lengths of DNA, which are then randomly reassembled by DNA repair machinery. Chromothripsis is currently examined as an alternative mechanism of oncogenesis, in contrast to the present paradigm that considers a stepwise development of cancer. While evidence for the mechanism(s) underlying chromosome shattering during cancer development remains elusive, a number of hypotheses have been proposed to explain chromothripsis, including ionizing radiation, DNA replication stress, breakage-fusion-bridge cycles, micronuclei formation and premature chromosome compaction. In the present work, we provide experimental evidence on the mechanistic basis of chromothripsis and on how chromosomes can get locally shattered in a single catastrophic event. Considering the dynamic nature of chromatin nucleoprotein complex, capable of rapid unfolding, disassembling, assembling and refolding, we first show that chromatin condensation at repairing or replicating DNA sites induces the mechanical stress needed for chromosome shattering to ensue. Premature chromosome condensation is then used to visualize the dynamic nature of interphase chromatin and demonstrate that such mechanical stress and chromosome shattering can also occur in chromosomes within micronuclei or asynchronous multinucleate cells when primary nuclei enter mitosis. Following an aberrant mitosis, chromosomes could find themselves in the wrong place at the wrong time so that they may undergo massive DNA breakage and rearrangement in a single catastrophic event. Specifically, our results support the hypothesis that premature chromosome

  11. Responses of the Housefly, Musca domestica, to the Hytrosavirus Replication: Impacts on Host's Vitellogenesis and Immunity.

    Science.gov (United States)

    Kariithi, Henry M; Yao, Xu; Yu, Fahong; Teal, Peter E; Verhoeven, Chelsea P; Boucias, Drion G

    2017-01-01

    Hytrosaviridae family members replicate in the salivary glands (SGs) of their adult dipteran hosts and are transmitted to uninfected hosts via saliva during feeding. Despite inducing similar gross symptoms (SG hypertrophy; SGH), hytrosaviruses (SGHVs) have distinct pathobiologies, including sex-ratio distortions in tsetse flies and refusal of infected housefly females to copulate. Via unknown mechanism(s), SGHV replication in other tissues results in reduced fecundity in tsetse flies and total shutdown of vitellogenesis and sterility in housefly females. We hypothesized that vitellogenesis shutdown was caused by virus-induced modulation of hormonal titers. Here, we used RNA-Seq to investigate virus-induced modulation of host genes/pathways in healthy and virus-infected houseflies, and we validated expression of modulated genes (n = 23) by RT-qPCR. We also evaluated the levels and activities of hemolymph AMPs, levels of endogenous sesquiterpenoids, and impacts of exogenous hormones on ovarian development in viremic females. Of the 973 housefly unigenes that were significantly modulated (padj ≤ 0.01, log2FC ≤ -2.0 or ≥ 2.0), 446 and 527 genes were downregulated and upregulated, respectively. While the most downregulated genes were related to reproduction (embryogenesis/oogenesis), the repertoire of upregulated genes was overrepresented by genes related to non-self recognition, ubiquitin-protease system, cytoskeletal traffic, cellular proliferation, development and movement, and snRNA processing. Overall, the virus, Musca domestica salivary gland hytrosavirus (MdSGHV), induced the upregulation of various components of the siRNA, innate antimicrobial immune, and autophagy pathways. We show that MdSGHV undergo limited morphogenesis in the corpora allata/corpora cardiaca (CA/CC) complex of M. domestica. MdSGHV replication in CA/CC potentially explains the significant reduction of hemolymph sesquiterpenoids levels, the refusal to mate, and the complete shutdown of

  12. Replication Restart in Bacteria.

    Science.gov (United States)

    Michel, Bénédicte; Sandler, Steven J

    2017-07-01

    In bacteria, replication forks assembled at a replication origin travel to the terminus, often a few megabases away. They may encounter obstacles that trigger replisome disassembly, rendering replication restart from abandoned forks crucial for cell viability. During the past 25 years, the genes that encode replication restart proteins have been identified and genetically characterized. In parallel, the enzymes were purified and analyzed in vitro, where they can catalyze replication initiation in a sequence-independent manner from fork-like DNA structures. This work also revealed a close link between replication and homologous recombination, as replication restart from recombination intermediates is an essential step of DNA double-strand break repair in bacteria and, conversely, arrested replication forks can be acted upon by recombination proteins and converted into various recombination substrates. In this review, we summarize this intense period of research that led to the characterization of the ubiquitous replication restart protein PriA and its partners, to the definition of several replication restart pathways in vivo, and to the description of tight links between replication and homologous recombination, responsible for the importance of replication restart in the maintenance of genome stability. Copyright © 2017 American Society for Microbiology.

  13. Context and strain-dependent behavioral response to stress

    Directory of Open Access Journals (Sweden)

    Baum Amber E

    2008-06-01

    Full Text Available Abstract Background This study posed the question whether strain differences in stress-reactivity lead to differential behavioral responses in two different tests of anxiety. Strain differences in anxiety-measures are known, but strain differences in the behavioral responses to acute prior stress are not well characterized. Methods We studied male Fisher 344 (F344 and Wistar Kyoto (WKY rats basally and immediately after one hour restraint stress. To distinguish between the effects of novelty and prior stress, we also investigated behavior after repeated exposure to the test chamber. Two behavioral tests were explored; the elevated plus maze (EPM and the open field (OFT, both of which are thought to measure activity, exploration and anxiety-like behaviors. Additionally, rearing, a voluntary behavior, and grooming, a relatively automatic, stress-responsive stereotyped behavior were measured in both tests. Results Prior exposure to the test environment increased anxiety-related measures regardless of prior stress, reflecting context-dependent learning process in both tests and strains. Activity decreased in response to repeated testing in both tests and both strains, but prior stress decreased activity only in the OFT which was reversed by repeated testing. Prior stress decreased anxiety-related measures in the EPM, only in F344s, while in the OFT, stress led to increased freezing mainly in WKYs. Conclusion Data suggest that differences in stressfulness of these tests predict the behavior of the two strains of animals according to their stress-reactivity and coping style, but that repeated testing can overcome some of these differences.

  14. Stability analysis of Reynolds stress response functional candidates

    Energy Technology Data Exchange (ETDEWEB)

    Dafinger, M.; Hallatschek, K. [Max-Planck-Institute for Plasma Physics, EURATOM-IPP Association, Garching (Germany); Itoh, K. [National Institute for Fusion Science, Toki 509-5292 (Japan)

    2013-04-15

    Complete information on the behavior of zonal flows in turbulence systems is coded in the turbulent stress response to the respective flow pattern. We show that turbulence stress response functionals containing only the linear first order wavenumber dependence on the flow pattern result in unstable structures up to the system size. A minimal augmentation to reproduce the flow patterns observed in turbulence simulations is discussed.

  15. Anger responses to psychosocial stress predict heart rate and cortisol stress responses in men but not women.

    Science.gov (United States)

    Lupis, Sarah B; Lerman, Michelle; Wolf, Jutta M

    2014-11-01

    While previous research has suggested that anger and fear responses to stress are linked to distinct sympathetic nervous system (SNS) stress responses, little is known about how these emotions predict hypothalamus-pituitary-adrenal (HPA) axis reactivity. Further, earlier research primarily relied on retrospective self-report of emotion. The current study aimed at addressing both issues in male and female individuals by assessing the role of anger and fear in predicting heart rate and cortisol stress responses using both self-report and facial coding analysis to assess emotion responses. We exposed 32 healthy students (18 female; 19.6±1.7 yr) to an acute psychosocial stress paradigm (TSST) and measured heart rate and salivary cortisol levels throughout the protocol. Anger and fear before and after stress exposure was assessed by self-report, and video recordings of the TSST were assessed by a certified facial coder to determine emotion expression (FACS). Self-reported emotions and emotion expressions did not correlate (all p>.23). Increases in self-reported fear predicted blunted cortisol responses in men (β=0.41, p=.04). Also for men, longer durations of anger expression predicted exaggerated cortisol responses (β=0.67 p=.004), and more anger incidences predicted exaggerated cortisol and heart rate responses (β=0.51, p=.033; β=0.46, p=.066, resp.). Anger and fear did not predict SNS or HPA activity for females (all p>.23). The current differential self-report and facial coding findings support the use of multiple modes of emotion assessment. Particularly, FACS but not self-report revealed a robust anger-stress association that could have important downstream health effects for men. For women, future research may clarify the role of other emotions, such as self-conscious expressions of shame, for physiological stress responses. A better understanding of the emotion-stress link may contribute to behavioral interventions targeting health-promoting ways of

  16. Isometric stress in cardiovascular magnetic resonance - a simple and easily replicable method of assessing cardiovascular differences not apparent at rest

    Energy Technology Data Exchange (ETDEWEB)

    Mortensen, Kristian H.; Jones, Alexander; Steeden, Jennifer A.; Taylor, Andrew M.; Muthurangu, Vivek [UCL Centre for Cardiovascular MR, UCL Institute of Cardiovascular Science, Level 6 Old Nurses Home, Cardiorespiratory Unit, Great Ormond Street Hospital for Children, London (United Kingdom)

    2016-04-15

    Isometric exercise may unmask cardiovascular disease not evident at rest, and cardiovascular magnetic resonance (CMR) imaging is proven for comprehensive resting assessment. This study devised a simple isometric exercise CMR methodology and assessed the hemodynamic response evoked by isometric exercise. A biceps isometric exercise technique was devised for CMR, and 75 healthy volunteers were assessed at rest, after 3-minute biceps exercise, and 5-minute of recovery using: (1) blood pressure (BP) and (2) CMR measured aortic flow and left ventricular function. Total peripheral resistance (SVR) and arterial compliance (TAC), cardiac output (CO), left ventricular volumes and function (ejection fraction, stroke volume, power output), blood pressure (BP), heart rate (HR), and rate pressure product were assessed at all time points. Image quality was preserved during stress. During exercise there were increases in CO (+14.9 %), HR (+17.0 %), SVR (+9.8 %), systolic BP (+22.4 %), diastolic BP (+25.4 %) and mean BP (+23.2 %). In addition, there were decreases in TAC (-22.0 %) and left ventricular ejection fraction (-6.3 %). Age and body mass index modified the evoked response, even when resting measures were similar. Isometric exercise technique evokes a significant cardiovascular response in CMR, unmasking physiological differences that are not apparent at rest. (orig.)

  17. [Autoregulation of stress response in microorganisms].

    Science.gov (United States)

    Nikolaev, Iu A; Muliukin, A L; Stepanenko, I Iu; El'-Registan, G I

    2006-01-01

    Examples are considered of the involvement of low-molecular-weight autoregulators in the development of resistance of proliferating microbial cultures to unfavorable environmental impacts of various intensity, including impacts programmed to occur in the developmental cycle ("new medium stress," starvation stress) and nonprogrammed impacts. It was shown that extracellular adaptation factors control the reversible adhesion of cells in submerged cultures and the processes of cell reactivation in the poststress period and are involved in the stabilization of cellular biopolymers (proteins and DNA) and subcellular structures (membranes); the adaptogens of the phenolic type also act as efficient scavengers of reactive oxygen species. The protective effect of the adaptogenic autoregulators is manifested in the increase of resistance of microbial cells to stressors of various nature and in the preservation of the cell proliferative capacity.

  18. Plant Responses to Salt Stress: Adaptive Mechanisms

    Directory of Open Access Journals (Sweden)

    Jose Ramón Acosta-Motos

    2017-02-01

    Full Text Available This review deals with the adaptive mechanisms that plants can implement to cope with the challenge of salt stress. Plants tolerant to NaCl implement a series of adaptations to acclimate to salinity, including morphological, physiological and biochemical changes. These changes include increases in the root/canopy ratio and in the chlorophyll content in addition to changes in the leaf anatomy that ultimately lead to preventing leaf ion toxicity, thus maintaining the water status in order to limit water loss and protect the photosynthesis process. Furthermore, we deal with the effect of salt stress on photosynthesis and chlorophyll fluorescence and some of the mechanisms thought to protect the photosynthetic machinery, including the xanthophyll cycle, photorespiration pathway, and water-water cycle. Finally, we also provide an updated discussion on salt-induced oxidative stress at the subcellular level and its effect on the antioxidant machinery in both salt-tolerant and salt-sensitive plants. The aim is to extend our understanding of how salinity may affect the physiological characteristics of plants.

  19. Tissue Culture as a Source of Replicates in Nonmodel Plants: Variation in Cold Response in Arabidopsis lyrata ssp. petraea.

    Science.gov (United States)

    Kenta, Tanaka; Edwards, Jessica E M; Butlin, Roger K; Burke, Terry; Quick, W Paul; Urwin, Peter; Davey, Matthew P

    2016-12-07

    While genotype-environment interaction is increasingly receiving attention by ecologists and evolutionary biologists, such studies need genetically homogeneous replicates-a challenging hurdle in outcrossing plants. This could be potentially overcome by using tissue culture techniques. However, plants regenerated from tissue culture may show aberrant phenotypes and "somaclonal" variation. Here, we examined somaclonal variation due to tissue culturing using the response to cold treatment of photosynthetic efficiency (chlorophyll fluorescence measurements for Fv/Fm, Fv'/Fm', and ΦPSII, representing maximum efficiency of photosynthesis for dark- and light-adapted leaves, and the actual electron transport operating efficiency, respectively, which are reliable indicators of photoinhibition and damage to the photosynthetic electron transport system). We compared this to variation among half-sibling seedlings from three different families of Arabidopsis lyrata ssp. petraea Somaclonal variation was limited, and we could detect within-family variation in change in chlorophyll fluorescence due to cold shock successfully with the help of tissue-culture derived replicates. Icelandic and Norwegian families exhibited higher chlorophyll fluorescence, suggesting higher performance after cold shock, than a Swedish family. Although the main effect of tissue culture on Fv/Fm, Fv'/Fm', and ΦPSII was small, there were significant interactions between tissue culture and family, suggesting that the effect of tissue culture is genotype-specific. Tissue-cultured plantlets were less affected by cold treatment than seedlings, but to a different extent in each family. These interactive effects, however, were comparable to, or much smaller than the single effect of family. These results suggest that tissue culture is a useful method for obtaining genetically homogenous replicates for studying genotype-environment interaction related to adaptively-relevant phenotypes, such as cold response, in

  20. Low-stress and high-stress singing have contrasting effects on glucocorticoid response

    Directory of Open Access Journals (Sweden)

    Daisy eFancourt

    2015-09-01

    Full Text Available Performing music in public is widely recognised as a potentially stress-inducing activity. However, despite the interest in music performance as an acute psychosocial stressor, there has been relatively little research on the effects of public performance on the endocrine system. This study examined the impact of singing in a low-stress performance situation and a high-stress live concert on levels of glucocorticoids (cortisol and cortisone in 15 professional singers. The results showed a significant decrease in both cortisol and cortisone across the low-stress condition, suggesting that singing in itself is a stress-reducing (and possibly health-promoting activity, but significant increases across the high-stress condition. This is the first study to demonstrate that singing affects glucocorticoid responses and that these responses are modulated by the conditions of performance.

  1. The Response of Rice Root to Time Course Water Deficit Stress-Two Dimensional Electrophoresis Approach

    Directory of Open Access Journals (Sweden)

    Mahmood Toorchi

    2015-11-01

    Full Text Available Rice (Oryza sativa L. is the staple food of more than half of the population worldwide. Water deficit stress is one of the harsh limiting factors for successful production of crops. Rice during its growing period comes a cross different environmental hazards like drought stress. Recent advance in molecular physiology are promising for more progress in increasing rice yield by identification of novel candidate proteins for drought tolerance. To investigate the effect of water deficit on rice root protein expression pattern, an experiment was conducted in completely randomize design with four replications. With holding water for 24, 36 and 48 hours along with control constituted the experimental treatments. The experiment was conducted in growth chamber under controlled condition and root samples, after stress imposition, were harvested for two-dimensional electrophorese (2-DE. Proteome analysis of root tissue by 2-DE indicated that out of 135 protein spots diagnosed by Coomassie blue staining, 14 spots showed significant expression change under water deficit condition, seven of them at 1% and the other seven at 5% probability levels. Differentially changed proteins were taken into account for search in data bank using isoelectric point and molecular weight to identify the most probable responsive proteins. Up- regulation of ferredoxin oxidoreductase at first 24 hour after applying stress indicates the main role of this protein in reducing water deficit stress effects. On the other hand ribosomal proteins, GAP-3 and ATP synthase were down regulated under water deficit stress. Fructose 1,6-bisphosphate aldolase, glucose- 6-phosphate dehydrogenase and chitinase down regulated up to 36 h of stress imposition but, were later up- regulated by prolonging stress up to 48 h. It could be inferred the plant tries to decrease the effect of oxidative stress.

  2. Thermodynamic Modeling and Analysis of Human Stress Response

    Science.gov (United States)

    Boregowda, S. C.; Tiwari, S. N.

    1999-01-01

    A novel approach based on the second law of thermodynamics is developed to investigate the psychophysiology and quantify human stress level. Two types of stresses (thermal and mental) are examined. A Unified Stress Response Theory (USRT) is developed under the new proposed field of study called Engineering Psychophysiology. The USRT is used to investigate both thermal and mental stresses from a holistic (human body as a whole) and thermodynamic viewpoint. The original concepts and definitions are established as postulates which form the basis for thermodynamic approach to quantify human stress level. An Objective Thermal Stress Index (OTSI) is developed by applying the second law of thermodynamics to the human thermal system to quantify thermal stress or dis- comfort in the human body. The human thermal model based on finite element method is implemented. It is utilized as a "Computational Environmental Chamber" to conduct series of simulations to examine the human thermal stress responses under different environmental conditions. An innovative hybrid technique is developed to analyze human thermal behavior based on series of human-environment interaction simulations. Continuous monitoring of thermal stress is demonstrated with the help of OTSI. It is well established that the human thermal system obeys the second law of thermodynamics. Further, the OTSI is validated against the experimental data. Regarding mental stress, an Objective Mental Stress Index (OMSI) is developed by applying the Maxwell relations of thermodynamics to the combined thermal and cardiovascular system in the human body. The OMSI is utilized to demonstrate the technique of monitoring mental stress continuously and is validated with the help of series of experimental studies. Although the OMSI indicates the level of mental stress, it provides a strong thermodynamic and mathematical relationship between activities of thermal and cardiovascular systems of the human body.

  3. Recent Molecular Advances on Downstream Plant Responses to Abiotic Stress

    Directory of Open Access Journals (Sweden)

    Cláudia Regina Batista de Souza

    2012-07-01

    Full Text Available Abiotic stresses such as extremes of temperature and pH, high salinity and drought, comprise some of the major factors causing extensive losses to crop production worldwide. Understanding how plants respond and adapt at cellular and molecular levels to continuous environmental changes is a pre-requisite for the generation of resistant or tolerant plants to abiotic stresses. In this review we aimed to present the recent advances on mechanisms of downstream plant responses to abiotic stresses and the use of stress-related genes in the development of genetically engineered crops.

  4. Research Progress in Tomato Responses to Abiotic Stress

    Institute of Scientific and Technical Information of China (English)

    Jianing XU; Gang LIU; Liyun ZHANG

    2016-01-01

    Tomato is a kind of vegetable with high economic benefits in protected farmland.Accounting for 30% of vegetable planting area in the entire protected farmland,tomato plays an essential role in cultivation of protected vegetable.Different abiotic stresses have different degrees of influence on growth and development,yield,and fruit quality of tomatoes.Therefore,finding out life activity rules of tomatoes under different abiotic stresses will be of great significance to breeding for stress tolerance and increasing tomato yield and income.This paper made an overview of research progress in tomato responses to abiotic stress in growth and development,physiology and biochemistry,and gene regulation.

  5. Regulation of Replication Recovery and Genome Integrity

    DEFF Research Database (Denmark)

    Colding, Camilla Skettrup

    Preserving genome integrity is essential for cell survival. To this end, mechanisms that supervise DNA replication and respond to replication perturbations have evolved. One such mechanism is the replication checkpoint, which responds to DNA replication stress and acts to ensure replication pausing...

  6. When does stress help or harm? The effects of stress controllability and subjective stress response on Stroop performance.

    Directory of Open Access Journals (Sweden)

    Roselinde Kaiser Henderson

    2012-06-01

    Full Text Available The ability to engage in goal-directed behavior despite exposure to stress is critical to resilience. Questions of how stress can impair or improve behavioral functioning are important in diverse settings, from athletic competitions to academic testing to clinical therapy. Previous research suggests that controllability is a key factor in the impact of stress on behavior: learning how to control stressors buffers people from the negative effects of stress on subsequent cognitively demanding tasks. In addition, research suggests that the impact of stress on cognitive functioning depends on an individual’s response to stressors: moderate responses to stress can lead to improved performance while extreme (high or low responses can lead to impaired performance. The present studies tested the hypothesis that 1 learning to behaviorally control stressors leads to improved performance on a test of general executive functioning, the color-word Stroop, and that 2 this improvement emerges specifically for people who report moderate (subjective responses to stress. Experiment 1: Stroop performance, measured before and after a stress manipulation, was compared across groups of undergraduate participants (n=109. People who learned to control a noise stressor and received accurate performance feedback demonstrated reduced Stroop interference compared with people exposed to uncontrollable noise stress and feedback indicating an exaggerated rate of failure. In the group who learned behavioral control, those who reported moderate levels of stress showed the greatest reduction in Stroop interference. In contrast, in the group exposed to uncontrollable events, self-reported stress failed to predict performance. Experiment 2: In a second sample (n=90, we specifically investigated the role of controllability by keeping the rate of failure feedback constant across groups. In the group who learned behavioral control, those who reported moderate levels of stress

  7. Heart rate variability response to mental arithmetic stress in patients with schizophrenia Autonomic response to stress in schizophrenia

    NARCIS (Netherlands)

    Castro, Mariana N.; Vigo, Daniel E.; Weidema, Hylke; Fahrer, Rodolfo D.; Chu, Elvina M.; De Achaval, Delfina; Nogues, Martin; Leiguarda, Ramon C.; Cardinali, Daniel P.; Guinjoan, Salvador N.

    2008-01-01

    Background: The vulnerability-stress hypothesis is an established model of schizophrenia symptom formation. We sought to characterise the pattern of the cardiac autonomic response to mental arithmetic stress in patients with stable schizophrenia. Methods: We performed heart rate variability (HRV) an

  8. Heart rate variability response to mental arithmetic stress in patients with schizophrenia Autonomic response to stress in schizophrenia

    NARCIS (Netherlands)

    Castro, Mariana N.; Vigo, Daniel E.; Weidema, Hylke; Fahrer, Rodolfo D.; Chu, Elvina M.; De Achaval, Delfina; Nogues, Martin; Leiguarda, Ramon C.; Cardinali, Daniel P.; Guinjoan, Salvador N.

    2008-01-01

    Background: The vulnerability-stress hypothesis is an established model of schizophrenia symptom formation. We sought to characterise the pattern of the cardiac autonomic response to mental arithmetic stress in patients with stable schizophrenia. Methods: We performed heart rate variability (HRV) an

  9. Modulation of immune responses in stress by Yoga

    Directory of Open Access Journals (Sweden)

    Arora Sarika

    2008-01-01

    Full Text Available Stress is a constant factor in today′s fastpaced life that can jeopardize our health if left unchecked. It is only in the last half century that the role of stress in every ailment from the common cold to AIDS has been emphasized, and the mechanisms involved in this process have been studied. Stress influences the immune response presumably through the activation of the hypothalamic-pituitary adrenal axis, hypothalamic pituitary-gonadal axis, and the sympathetic-adrenal-medullary system. Various neurotransmitters, neuropeptides, hormones, and cytokines mediate these complex bidirectional interactions between the central nervous system (CNS and the immune system. The effects of stress on the immune responses result in alterations in the number of immune cells and cytokine dysregulation. Various stress management strategies such as meditation, yoga, hypnosis, and muscle relaxation have been shown to reduce the psychological and physiological effects of stress in cancers and HIV infection. This review aims to discuss the effect of stress on the immune system and examine how relaxation techniques such as Yoga and meditation could regulate the cytokine levels and hence, the immune responses during stress.

  10. Regulation of abiotic and biotic stress responses by plant hormones

    DEFF Research Database (Denmark)

    Grosskinsky, Dominik Kilian; van der Graaff, Eric; Roitsch, Thomas Georg

    2016-01-01

    Plant hormones (phytohormones) are signal molecules produced within the plant, and occur in very low concentrations. In the present chapter, the current knowledge on the regulation of biotic and biotic stress responses by plant hormones is summarized with special focus on the novel insights into ...... through ubiquitination. The wide range of biotic and abiotic stresses that affect crop plants limits agricultural production.......Plant hormones (phytohormones) are signal molecules produced within the plant, and occur in very low concentrations. In the present chapter, the current knowledge on the regulation of biotic and biotic stress responses by plant hormones is summarized with special focus on the novel insights...

  11. Genes Acting on Transcriptional Control during Abiotic Stress Responses

    Directory of Open Access Journals (Sweden)

    Glacy Jaqueline da Silva

    2014-01-01

    Full Text Available Abiotic stresses are the major cause of yield loss in crops around the world. Greater genetic gains are possible by combining the classical genetic improvement with advanced molecular biology techniques. The understanding of mechanisms triggered by plants to meet conditions of stress is of fundamental importance for the elucidation of these processes. Current genetically modified crops help to mitigate the effects of these stresses, increasing genetic gains in order to supply the agricultural market and the demand for better quality food throughout the world. To obtain safe genetic modified organisms for planting and consumption, a thorough grasp of the routes and genes that act in response to these stresses is necessary. This work was developed in order to collect important information about essential TF gene families for transcriptional control under abiotic stress responses.

  12. Dynamics of telomerase activity in response to acute psychological stress

    Science.gov (United States)

    Epel, Elissa S.; Lin, Jue; Dhabhar, Firdaus S.; Wolkowitz, Owen M.; Puterman, E; Karan, Lori; Blackburn, Elizabeth H.

    2010-01-01

    Telomerase activity plays an essential role in cel0l survival, by lengthening telomeres and promoting cell growth and longevity. It is now possible to quantify the low levels of telomerase activity in human leukocytes. Low basal telomerase activity has been related to chronic stress in people and to chronic glucocorticoid exposure in vitro. Here we test whether leukocyte telomerase activity changes under acute psychological stress. We exposed 44 elderly women, including 22 high stress dementia caregivers and 22 matched low stress controls, to a brief laboratory psychological stressor, while examining changes in telomerase activity of peripheral blood mononuclear cells (PBMC). At baseline, caregivers had lower telomerase activity levels than controls, but during stress telomerase activity increased similarly in both groups. Across the entire sample, subsequent telomerase activity increased by 18% one hour after the end of the stressor (p<0.01). The increase in telomerase activity was independent of changes in numbers or percentages of monocytes, lymphocytes, and specific T cell types, although we cannot fully rule out some potential contribution from immune cell redistribution in the change in telomerase activity. Telomerase activity increases were associated with greater cortisol increases in response to the stressor. Lastly, psychological response to the tasks (greater threat perception) was also related to greater telomerase activity increases in controls. These findings uncover novel relationships of dynamic telomerase activity with exposure to an acute stressor, and with two classic aspects of the stress response -- perceived psychological stress and neuroendocrine (cortisol) responses to the stressor. PMID:20018236

  13. Lipolysis Response to Endoplasmic Reticulum Stress in Adipose Cells*

    Science.gov (United States)

    Deng, Jingna; Liu, Shangxin; Zou, Liangqiang; Xu, Chong; Geng, Bin; Xu, Guoheng

    2012-01-01

    In obesity and diabetes, adipocytes show significant endoplasmic reticulum (ER) stress, which triggers a series of responses. This study aimed to investigate the lipolysis response to ER stress in rat adipocytes. Thapsigargin, tunicamycin, and brefeldin A, which induce ER stress through different pathways, efficiently activated a time-dependent lipolytic reaction. The lipolytic effect of ER stress occurred with elevated cAMP production and protein kinase A (PKA) activity. Inhibition of PKA reduced PKA phosphosubstrates and attenuated the lipolysis. Although both ERK1/2 and JNK are activated during ER stress, lipolysis is partially suppressed by inhibiting ERK1/2 but not JNK and p38 MAPK and PKC. Thus, ER stress induces lipolysis by activating cAMP/PKA and ERK1/2. In the downstream lipolytic cascade, phosphorylation of lipid droplet-associated protein perilipin was significantly promoted during ER stress but attenuated on PKA inhibition. Furthermore, ER stress stimuli did not alter the levels of hormone-sensitive lipase and adipose triglyceride lipase but caused Ser-563 and Ser-660 phosphorylation of hormone-sensitive lipase and moderately elevated its translocation from the cytosol to lipid droplets. Accompanying these changes, total activity of cellular lipases was promoted to confer the lipolysis. These findings suggest a novel pathway of the lipolysis response to ER stress in adipocytes. This lipolytic activation may be an adaptive response that regulates energy homeostasis but with sustained ER stress challenge could contribute to lipotoxicity, dyslipidemia, and insulin resistance because of persistently accelerated free fatty acid efflux from adipocytes to the bloodstream and other tissues. PMID:22223650

  14. Lipolysis response to endoplasmic reticulum stress in adipose cells.

    Science.gov (United States)

    Deng, Jingna; Liu, Shangxin; Zou, Liangqiang; Xu, Chong; Geng, Bin; Xu, Guoheng

    2012-02-24

    In obesity and diabetes, adipocytes show significant endoplasmic reticulum (ER) stress, which triggers a series of responses. This study aimed to investigate the lipolysis response to ER stress in rat adipocytes. Thapsigargin, tunicamycin, and brefeldin A, which induce ER stress through different pathways, efficiently activated a time-dependent lipolytic reaction. The lipolytic effect of ER stress occurred with elevated cAMP production and protein kinase A (PKA) activity. Inhibition of PKA reduced PKA phosphosubstrates and attenuated the lipolysis. Although both ERK1/2 and JNK are activated during ER stress, lipolysis is partially suppressed by inhibiting ERK1/2 but not JNK and p38 MAPK and PKC. Thus, ER stress induces lipolysis by activating cAMP/PKA and ERK1/2. In the downstream lipolytic cascade, phosphorylation of lipid droplet-associated protein perilipin was significantly promoted during ER stress but attenuated on PKA inhibition. Furthermore, ER stress stimuli did not alter the levels of hormone-sensitive lipase and adipose triglyceride lipase but caused Ser-563 and Ser-660 phosphorylation of hormone-sensitive lipase and moderately elevated its translocation from the cytosol to lipid droplets. Accompanying these changes, total activity of cellular lipases was promoted to confer the lipolysis. These findings suggest a novel pathway of the lipolysis response to ER stress in adipocytes. This lipolytic activation may be an adaptive response that regulates energy homeostasis but with sustained ER stress challenge could contribute to lipotoxicity, dyslipidemia, and insulin resistance because of persistently accelerated free fatty acid efflux from adipocytes to the bloodstream and other tissues.

  15. Crop and medicinal plants proteomics in response to salt stress

    Directory of Open Access Journals (Sweden)

    Keyvan eAghaei

    2013-01-01

    Full Text Available Increasing of world population marks a serious need to create new crop cultivars and medicinal plants with high growth and production at any environmental situations. Among the environmental unfavorable conditions, salinity is the most widespread in the world. Crop production and growth severely decreases under salt stress; however, some crop cultivars show significant tolerance against the negative effects of salinity. Among salt stress responses of crops, proteomic responses play a pivotal role in their ability to cope with it and have become the main center of notification. Many physiological responses are detectable in terms of protein increase and decrease even before physiological responses take place. Thus proteomic approach makes a short cut in the way of inferring how crops response to salt stress. Nowadays many salt-responsive proteins such as heat shock proteins, pathogen related proteins, protein kinases, ascorbate peroxidase, osmotin, ornithine decarboxylase and some transcription factors, have been detected in some major crops which are thought to give them the ability of withstanding against salt stress. Proteomic analysis of medicinal plants also revealed that alkaloid biosynthesis related proteins such as tryptophan synthase, codeinone reductase, strictosidine synthase and 12-oxophytodienoate reductase might have major role in production of secondary metabolites. In this review we are comparing some different or similar proteomic responses of several crops and medicinal plants to salt stress and discuss about the future prospects.

  16. Stressed out? Associations between perceived and physiological stress responses in adolescents : The TRAILS study

    NARCIS (Netherlands)

    Oldehinkel, Albertine J.; Ormel, Johan; Bosch, Nienke M.; Bouma, Esther M. C.; Van Roon, Arie M.; Rosmalen, Judith G. M.; Riese, Harriette

    2011-01-01

    Studies regarding the interrelation of perceived and physiological stress indices have shown diverging results. Using a population sample of adolescents (N=715, 50.9% girls, mean age 16.11 years, SD=0.59), we tested three hypotheses: (1) perceived responses during social stress covary with concurren

  17. Stressed out? Associations between perceived and physiological stress responses in adolescents : The TRAILS study

    NARCIS (Netherlands)

    Oldehinkel, Albertine J.; Ormel, Johan; Bosch, Nienke M.; Bouma, Esther M. C.; Van Roon, Arie M.; Rosmalen, Judith G. M.; Riese, Harriette

    2011-01-01

    Studies regarding the interrelation of perceived and physiological stress indices have shown diverging results. Using a population sample of adolescents (N=715, 50.9% girls, mean age 16.11 years, SD=0.59), we tested three hypotheses: (1) perceived responses during social stress covary with concurren

  18. the response of plants to drought stress

    Directory of Open Access Journals (Sweden)

    Rys Magdalena

    2015-08-01

    a wider spectrum of compounds scattering the radiation in the leaves tested, and their subsequent comparative analysis. The impact of drought on metabolism of soybean was clearly visible on spectra and confirmed using cluster analysis. The technical problem of the influence of leaf water content on measurements, which appeared in studies, will be discussed. To conclude, FT-Raman spectroscopy may be a good complement to other non-invasive methods, e.g., fluorescent methods, in assessing the stress-induced damage of crops.

  19. Transcript changes in Vibrio cholerae in response to salt stress.

    Science.gov (United States)

    Fu, Xiuping; Liang, Weili; Du, Pengcheng; Yan, Meiying; Kan, Biao

    2014-01-01

    Vibrio cholerae, which is a serious human intestinal pathogen, often resides and thrives in estuaries but requires major self-regulation to overcome intestinal hyperosmotic stress or high salt stress in water and food. In the present study, we selected multiple O1 and O139 group V. cholerae strains that were isolated from different regions and during different years to study their salt tolerance. Based on the mechanisms that other bacteria use to respond to high salt stress, we selected salt stress-response related genes to study the mechanisms which V. cholerae responds to high salt stress. V. cholerae strains showed salt-resistance characteristics that varied in salt concentrations from 4% to 6%. However, group O1 and group O139 showed no significant difference in the degree of salt tolerance. The primary responses of bacteria to salt stress, including Na(+) exclusion, K(+) uptake and glutamate biosynthesis, were observed in V. cholerae strains. In addition, some sigma factors were up-regulated in V. cholerae strains, suggesting that V. cholerae may recruit common sigma factors to achieve an active salt stress response. However, some changes in gene transcript levels in response to salt stress in V. cholerae were strain-specific. In particular, hierarchical clustering of differentially expressed genes indicated that transcript levels of these genes were correlated with the degree of salt tolerance. Therefore, elevated transcript levels of some genes, including sigma factors and genes involved in peptidoglycan biosynthesis, may be due to the salt tolerance of strains. In addition, high salt-tolerant strains may recruit common as well as additional sigma factors to activate the salt stress response.

  20. Plant transcriptomics and responses to environmental stress: an overview

    Indian Academy of Sciences (India)

    Sameen Ruqia Imadi; Alvina Gul Kazi; Mohammad Abass Ahanger; Salih Gucel; Parvaiz Ahmad

    2015-09-01

    Different stresses include nutrient deficiency, pathogen attack, exposure to toxic chemicals etc. Transcriptomic studies have been mainly applied to only a few plant species including the model plant, Arabidopsis thaliana. These studies have provided valuable insights into the genetic networks of plant stress responses. Transcriptomics applied to cash crops including barley, rice, sugarcane, wheat and maize have further helped in understanding physiological and molecular responses in terms of genome sequence, gene regulation, gene differentiation, posttranscriptional modifications and gene splicing. On the other hand, comparative transcriptomics has provided more information about plant’s response to diverse stresses. Thus, transcriptomics, together with other biotechnological approaches helps in development of stress tolerance in crops against the climate change.

  1. Contrasting urban and rural heat stress responses to climate change

    Science.gov (United States)

    Fischer, E. M.; Oleson, K. W.; Lawrence, D. M.

    2012-02-01

    Hot temperatures in combination with high humidity cause human discomfort and may increase morbidity and mortality. A global climate model with an embedded urban model is used to explore the urban-rural contrast in the wet-bulb globe temperature, a heat stress index accounting for temperature and humidity. Wet-bulb globe temperatures are calculated at each model time step to resolve the heat stress diurnal cycle. The model simulates substantially higher heat stress in urban areas compared to neighbouring rural areas. Urban humidity deficit only weakly offsets the enhanced heat stress due to the large night-time urban heat island. The urban-rural contrast in heat stress is most pronounced at night and over mid-latitudes and subtropics. During heatwaves, the urban heat stress amplification is particularly pronounced. Heat stress strongly increases with doubled CO2 concentrations over both urban and rural surfaces. The tropics experience the greatest increase in number of high-heat-stress nights, despite a relatively weak ˜2°C warming. Given the lack of a distinct annual cycle and high relative humidity, the modest tropical warming leads to exceedance of the present-day record levels during more than half of the year in tropical regions, where adaptive capacity is often low. While the absolute urban and rural heat stress response to 2 × CO2 is similar, the occurrence of nights with extremely high heat stress increases more in cities than surrounding rural areas.

  2. Multiple aspects of the stress response under social evaluative threat: an electrophysiological investigation.

    Science.gov (United States)

    Cavanagh, James F; Allen, John J B

    2008-01-01

    Affective traits and states may be important moderators of stress reactivity, providing insight into stress-related consequences on cognitive functioning. This study assessed cognitive control processes using response-related brain electrical activities-the error-related negativity (ERN) and error positivity (Pe)-that are sensitive to trait and state affect. To assess the role of cognitive control in affective and cortisol reactivity to social evaluative threat, 55 undergraduates first completed a standard task designed to elicit the ERN in order to index 'baseline' error monitoring. Participants then performed a difficult mathematical task designed to elicit the ERN under conditions of exposed failure and social evaluation. Baseline ERN amplitude predicted future cortisol reactivity to social evaluative threat in highly punishment-sensitive individuals (high self-reported Behavioral Inhibition System: Carver and White [1994. Behavioral inhibition, behavioral activation, and affective responses to impending reward and punishment: the BIS/BAS scales. J. Pers. Soc. Psych. 67, 319-333], although the presence of outliers suggest the need for replication. The math stress ERN amplitude was diminished in direct relationship to trait (punishment sensitivity) and state (fear and shame) negative affect. Individuals high in punishment sensitivity also showed specific deficits in task performance following error feedback under stress. High state affect related to a larger Pe amplitude. Results are interpreted as consequences of different motivational and affective reactivities under social evaluative threat.

  3. Necdin modulates proliferative cell survival of human cells in response to radiation-induced genotoxic stress

    Directory of Open Access Journals (Sweden)

    Lafontaine Julie

    2012-06-01

    Full Text Available Abstract Background The finite replicative lifespan of cells, termed cellular senescence, has been proposed as a protective mechanism against the proliferation of oncogenically damaged cells, that fuel cancer. This concept is further supported by the induction of premature senescence, a process which is activated when an oncogene is expressed in normal primary cells as well as following intense genotoxic stresses. Thus, deregulation of genes that control this process, like the tumor suppressor p53, may contribute to promoting cancer by allowing cells to bypass senescence. A better understanding of the genes that contribute to the establishment of senescence is therefore warranted. Necdin interacts with p53 and is also a p53 target gene, although the importance of Necdin in the p53 response is not clearly understood. Methods In this study, we first investigated Necdin protein expression during replicative senescence and premature senescence induced by gamma irradiation and by the overexpression of oncogenic RasV12. Gain and loss of function experiments were used to evaluate the contribution of Necdin during the senescence process. Results Necdin expression declined during replicative aging of IMR90 primary human fibroblasts or following induction of premature senescence. Decrease in Necdin expression seemed to be a consequence of the establishment of senescence since the depletion of Necdin in human cells did not induce a senescence-like growth arrest nor a flat morphology or SA-β-galactosidase activity normally associated with senescence. Similarly, overexpression of Necdin did not affect the life span of IMR90 cells. However, we demonstrate that in normal human cells, Necdin expression mimicked the effect of p53 inactivation by increasing radioresistance. Conclusion This result suggests that Necdin potentially attenuate p53 signaling in response to genotoxic stress in human cells and supports similar results describing an inhibitory function

  4. Childhood stress, grown-up brain networks: corticolimbic correlates of threat-related early life stress and adult stress response.

    Science.gov (United States)

    Kaiser, R H; Clegg, R; Goer, F; Pechtel, P; Beltzer, M; Vitaliano, G; Olson, D P; Teicher, M H; Pizzagalli, D A

    2017-09-25

    Exposure to threat-related early life stress (ELS) has been related to vulnerability for stress-related disorders in adulthood, putatively via disrupted corticolimbic circuits involved in stress response and regulation. However, previous research on ELS has not examined both the intrinsic strength and flexibility of corticolimbic circuits, which may be particularly important for adaptive stress responding, or associations between these dimensions of corticolimbic dysfunction and acute stress response in adulthood. Seventy unmedicated women varying in history of threat-related ELS completed a functional magnetic resonance imaging scan to evaluate voxelwise static (overall) and dynamic (variability over a series of sliding windows) resting-state functional connectivity (RSFC) of bilateral amygdala. In a separate session and subset of participants (n = 42), measures of salivary cortisol and affect were collected during a social-evaluative stress challenge. Higher severity of threat-related ELS was related to more strongly negative static RSFC between amygdala and left dorsolateral prefrontal cortex (DLPFC), and elevated dynamic RSFC between amygdala and rostral anterior cingulate cortex (rACC). Static amygdala-DLPFC antagonism mediated the relationship between higher severity of threat-related ELS and blunted cortisol response to stress, but increased dynamic amygdala-rACC connectivity weakened this mediated effect and was related to more positive post-stress mood. Threat-related ELS was associated with RSFC within lateral corticolimbic circuits, which in turn was related to blunted physiological response to acute stress. Notably, increased flexibility between the amygdala and rACC compensated for this static disruption, suggesting that more dynamic medial corticolimbic circuits might be key to restoring healthy stress response.

  5. A replicated climate change field experiment reveals rapid evolutionary response in an ecologically important soil invertebrate

    DEFF Research Database (Denmark)

    Bataillon, Thomas; Galtier, Nicolas; Bernard, Aurelien

    2016-01-01

    Whether species can respond evolutionarily to current climate change is crucial for the persistence of many species. Yet, very few studies have examined genetic responses to climate change in manipulated experiments carried out innatural field conditions. We examined the evolutionary response to ...

  6. Increased virus replication in mammalian cells by blocking intracellular innate defense responses

    NARCIS (Netherlands)

    Vries, W. de; Haasnoot, J.; Velden, J. van der; Montfort, T. van; Zorgdrager, F.; Paxton, W.; Cornelissen, M.; Kuppeveld, F.J.M. van; Haan, P. de; Berkhout, B.

    2008-01-01

    The mammalian innate immune system senses viral infection by recognizing viral signatures and activates potent antiviral responses. Besides the interferon (IFN) response, there is accumulating evidence that RNA silencing or RNA interference (RNAi) serves as an antiviral mechanism in mammalian cells.

  7. Ontogeny of the stress response in chinook salmon, Oncorhynchus tshawytscha

    Science.gov (United States)

    Feist, G.; Schreck, C.B.

    2001-01-01

    Whole body concentrations of cortisol were determined via radioimmunoassay in chinook salmon, Onchorynchus tshawytscha, during early development in both stressed and non-stressed fish to determine when the corticosteroidogenic stress response first appeared. Progeny from both pooled and individual females were examined to determine if differences existed in offspring from different females. Levels of cortisol were low in eyed eggs, increased at hatch, decreased 2 weeks later and then remained constant thereafter. Differences in cortisol between stressed and control fish were found 1 week after hatch and persisted for the remainder of the study. The magnitude of the stress response, or relative amount of cortisol produced, generally increased from the time when it was first detected, but a decrease in the ability to elicit cortisol was seen 4 weeks after hatching. Cortisol content of separate progeny from two individual females showed a similar pattern to that seen in pooled eggs. Our results indicate that chinook salmon are capable of producing cortisol following a stressful event approximately 1 week after the time of hatching. The decrease in endogenous cortisol content seen 2 weeks after hatching, and the decrease in the magnitude of the stress response seen 4 weeks after hatching may be comparable to developmental events documented in mammals where corticosteroid synthesis is inhibited to neutralize possible detrimental effects of these hormones during critical periods of development.

  8. Molecular and biochemical responses of Volvox carteri to oxidative stress

    Science.gov (United States)

    Lingappa, U.; Rankin-Gee, E. K.; Lera, M.; Bebour, B.; Marcu, O.

    2014-03-01

    Understanding the intracellular response to environmental stresses is a key aspect to understanding the limits of habitability for life as we know it. A wide range of relevant stressors, from heat shock to radiation, result in the intracellular production of reactive oxygen species (ROS). ROS are used physiologically as signaling molecules to cause changes in gene expression and metabolism. However, ROS, including superoxide (O2-) and peroxides, are also highly reactive molecules that cause oxidative damage to proteins, lipids and DNA. Here we studied stress response in the multicellular, eukaryotic green alga Volvox carteri, after exposure to heat shock conditions. We show that the ROS response to heat stress is paralleled by changes in photosynthetic metabolism, antioxidant enzyme activity and gene expression, and fluctuations in the elemental composition of cells. Metabolism, as measured by pulse amplitude modulated (PAM) fluorometry over two hours of heat stress, showed a linear decrease in the photosynthetic efficiency of Volvox. ROS quantification uncovered an increase in ROS in the culture medium, paralleled by a decrease in ROS within the Volvox colonies, suggesting an export mechanism is utilized to mitigate stress. Enzyme kinetics indicated an increase in superoxide dismutase (SOD) activity over the heat stress timecourse. Using X-ray fluorescence (XRF) at the Stanford Synchrotron Radiation Lightsource, we show that these changes coincide with cell-specific import/export and intracellular redistribution of transition elements and halides, suggesting that the cellular metallome is also engaged in mediating oxidative stress in Volvox.

  9. The auditory startle response in post-traumatic stress disorder

    NARCIS (Netherlands)

    Siegelaar, S. E.; Olff, M.; Bour, L. J.; Veelo, D.; Zwinderman, A. H.; van Bruggen, G.; de Vries, G. J.; Raabe, S.; Cupido, C.; Koelman, J. H. T. M.; Tijssen, M. A. J.

    2006-01-01

    Post-traumatic stress disorder (PTSD) patients are considered to have excessive EMG responses in the orbicularis oculi (OO) muscle and excessive autonomic responses to startling stimuli. The aim of the present study was to gain more insight into the pattern of the generalized auditory startle reflex

  10. The effect of music on the human stress response.

    Directory of Open Access Journals (Sweden)

    Myriam V Thoma

    Full Text Available BACKGROUND: Music listening has been suggested to beneficially impact health via stress-reducing effects. However, the existing literature presents itself with a limited number of investigations and with discrepancies in reported findings that may result from methodological shortcomings (e.g. small sample size, no valid stressor. It was the aim of the current study to address this gap in knowledge and overcome previous shortcomings by thoroughly examining music effects across endocrine, autonomic, cognitive, and emotional domains of the human stress response. METHODS: Sixty healthy female volunteers (mean age = 25 years were exposed to a standardized psychosocial stress test after having been randomly assigned to one of three different conditions prior to the stress test: 1 relaxing music ('Miserere', Allegri (RM, 2 sound of rippling water (SW, and 3 rest without acoustic stimulation (R. Salivary cortisol and salivary alpha-amylase (sAA, heart rate (HR, respiratory sinus arrhythmia (RSA, subjective stress perception and anxiety were repeatedly assessed in all subjects. We hypothesized that listening to RM prior to the stress test, compared to SW or R would result in a decreased stress response across all measured parameters. RESULTS: The three conditions significantly differed regarding cortisol response (p = 0.025 to the stressor, with highest concentrations in the RM and lowest in the SW condition. After the stressor, sAA (p=0.026 baseline values were reached considerably faster in the RM group than in the R group. HR and psychological measures did not significantly differ between groups. CONCLUSION: Our findings indicate that music listening impacted the psychobiological stress system. Listening to music prior to a standardized stressor predominantly affected the autonomic nervous system (in terms of a faster recovery, and to a lesser degree the endocrine and psychological stress response. These findings may help better understanding the

  11. The Effect of Music on the Human Stress Response

    Science.gov (United States)

    Thoma, Myriam V.; La Marca, Roberto; Brönnimann, Rebecca; Finkel, Linda; Ehlert, Ulrike; Nater, Urs M.

    2013-01-01

    Background Music listening has been suggested to beneficially impact health via stress-reducing effects. However, the existing literature presents itself with a limited number of investigations and with discrepancies in reported findings that may result from methodological shortcomings (e.g. small sample size, no valid stressor). It was the aim of the current study to address this gap in knowledge and overcome previous shortcomings by thoroughly examining music effects across endocrine, autonomic, cognitive, and emotional domains of the human stress response. Methods Sixty healthy female volunteers (mean age = 25 years) were exposed to a standardized psychosocial stress test after having been randomly assigned to one of three different conditions prior to the stress test: 1) relaxing music (‘Miserere’, Allegri) (RM), 2) sound of rippling water (SW), and 3) rest without acoustic stimulation (R). Salivary cortisol and salivary alpha-amylase (sAA), heart rate (HR), respiratory sinus arrhythmia (RSA), subjective stress perception and anxiety were repeatedly assessed in all subjects. We hypothesized that listening to RM prior to the stress test, compared to SW or R would result in a decreased stress response across all measured parameters. Results The three conditions significantly differed regarding cortisol response (p = 0.025) to the stressor, with highest concentrations in the RM and lowest in the SW condition. After the stressor, sAA (p=0.026) baseline values were reached considerably faster in the RM group than in the R group. HR and psychological measures did not significantly differ between groups. Conclusion Our findings indicate that music listening impacted the psychobiological stress system. Listening to music prior to a standardized stressor predominantly affected the autonomic nervous system (in terms of a faster recovery), and to a lesser degree the endocrine and psychological stress response. These findings may help better understanding the

  12. The effect of music on the human stress response.

    Science.gov (United States)

    Thoma, Myriam V; La Marca, Roberto; Brönnimann, Rebecca; Finkel, Linda; Ehlert, Ulrike; Nater, Urs M

    2013-01-01

    Music listening has been suggested to beneficially impact health via stress-reducing effects. However, the existing literature presents itself with a limited number of investigations and with discrepancies in reported findings that may result from methodological shortcomings (e.g. small sample size, no valid stressor). It was the aim of the current study to address this gap in knowledge and overcome previous shortcomings by thoroughly examining music effects across endocrine, autonomic, cognitive, and emotional domains of the human stress response. Sixty healthy female volunteers (mean age = 25 years) were exposed to a standardized psychosocial stress test after having been randomly assigned to one of three different conditions prior to the stress test: 1) relaxing music ('Miserere', Allegri) (RM), 2) sound of rippling water (SW), and 3) rest without acoustic stimulation (R). Salivary cortisol and salivary alpha-amylase (sAA), heart rate (HR), respiratory sinus arrhythmia (RSA), subjective stress perception and anxiety were repeatedly assessed in all subjects. We hypothesized that listening to RM prior to the stress test, compared to SW or R would result in a decreased stress response across all measured parameters. The three conditions significantly differed regarding cortisol response (p = 0.025) to the stressor, with highest concentrations in the RM and lowest in the SW condition. After the stressor, sAA (p=0.026) baseline values were reached considerably faster in the RM group than in the R group. HR and psychological measures did not significantly differ between groups. Our findings indicate that music listening impacted the psychobiological stress system. Listening to music prior to a standardized stressor predominantly affected the autonomic nervous system (in terms of a faster recovery), and to a lesser degree the endocrine and psychological stress response. These findings may help better understanding the beneficial effects of music on the human body.

  13. Responses of marine plankton to pollutant stress

    DEFF Research Database (Denmark)

    Hjorth, M.

    The thesis analyses effects of pollutants on natural plankton communities on the basis of three independent mesocosm experiments and a series of laboratory experiments performed in Denmark and Greenland. The work focus on integrating functional and structural measures of community responses to re...... with examples of work done on natural communities of phytoplankton and zooplankton. Abiotic conditions such as UV light and nutrient concentrations are shown to influence pollutant effects.......The thesis analyses effects of pollutants on natural plankton communities on the basis of three independent mesocosm experiments and a series of laboratory experiments performed in Denmark and Greenland. The work focus on integrating functional and structural measures of community responses...

  14. Gene Response to Salt Stress in Populus euphratica

    Institute of Scientific and Technical Information of China (English)

    Shen Xin; Thomas Teichmenn; Wang Yiqin; Bai Genben; Yu Guangjun; Wang Shasheng

    2003-01-01

    Through construction of a subtracted cDNA library and library screening, a number of salt-induced cDNA fragmentshave been cloned from Populus euphratica. Based on the results of DNA sequencing and Northern analysis, the gene response ofPopulus euphratica to salt stress is discussed. It is indicated that in response to salt treatment the transcription level for some genes ofPopulus euphratica increases by about 1.5 times and significant difference between the responses to osmotic stress and to ion stresshas been observed in gene activity.

  15. The STATs in cell stress-type responses

    Directory of Open Access Journals (Sweden)

    Best James

    2004-08-01

    Full Text Available Abstract In the early 1990's, a new cell signaling pathway was described. This new paradigm, now known as the JAK/STAT pathway, has been extensively investigated in immune-type cells in response to interferons and interleukins. However, recent evidence suggests that the JAK/STAT pathway also mediates diverse cellular responses to various forms of biological stress including hypoxia/reperfusion, endotoxin, ultraviolet light, and hyperosmolarity. The current literature describing the JAK/STAT pathway's role in cellular stress responses has been reviewed herein, but it is clear that our knowledge in this area is far from complete.

  16. Analysis of stress-induced duplex destabilization (SIDD properties of replication origins, genes and intergenes in the fission yeast, Schizosaccharomyces pombe

    Directory of Open Access Journals (Sweden)

    Yadav Mukesh P

    2012-11-01

    Full Text Available Abstract Background Replication and transcription, the two key functions of DNA, require unwinding of the DNA double helix. It has been shown that replication origins in the budding yeast, Saccharomyces cerevisiae contain an easily unwound stretch of DNA. We have used a recently developed method for determining the locations and degrees of stress-induced duplex destabilization (SIDD for all the reported replication origins in the genome of the fission yeast, Schizosaccharomyces pombe. Results We have found that the origins are more susceptible to SIDD as compared to the non-origin intergenic regions (NOIRs and genes. SIDD analysis of many known origins in other eukaryotes suggests that SIDD is a common property of replication origins. Interestingly, the previously shown deletion-dependent changes in the activities of the origins of the ura4 origin region on chromosome 3 are paralleled by changes in SIDD properties, suggesting SIDD’s role in origin activity. SIDD profiling following in silico deletions of some origins suggests that many of the closely spaced S. pombe origins could be clusters of two or three weak origins, similar to the ura4 origin region. Conclusion SIDD appears to be a highly conserved, functionally important property of replication origins in S. pombe and other organisms. The distinctly low SIDD scores of origins and the long range effects of genetic alterations on SIDD properties provide a unique predictive potential to the SIDD analysis. This could be used in exploring different aspects of structural and functional organization of origins including interactions between closely spaced origins.

  17. Towards establishment of a rice stress response interactome.

    Directory of Open Access Journals (Sweden)

    Young-Su Seo

    2011-04-01

    Full Text Available Rice (Oryza sativa is a staple food for more than half the world and a model for studies of monocotyledonous species, which include cereal crops and candidate bioenergy grasses. A major limitation of crop production is imposed by a suite of abiotic and biotic stresses resulting in 30%-60% yield losses globally each year. To elucidate stress response signaling networks, we constructed an interactome of 100 proteins by yeast two-hybrid (Y2H assays around key regulators of the rice biotic and abiotic stress responses. We validated the interactome using protein-protein interaction (PPI assays, co-expression of transcripts, and phenotypic analyses. Using this interactome-guided prediction and phenotype validation, we identified ten novel regulators of stress tolerance, including two from protein classes not previously known to function in stress responses. Several lines of evidence support cross-talk between biotic and abiotic stress responses. The combination of focused interactome and systems analyses described here represents significant progress toward elucidating the molecular basis of traits of agronomic importance.

  18. Oxidative stress impairs the heat stress response and delays unfolded protein recovery.

    Directory of Open Access Journals (Sweden)

    Masaaki Adachi

    Full Text Available BACKGROUND: Environmental changes, air pollution and ozone depletion are increasing oxidative stress, and global warming threatens health by heat stress. We now face a high risk of simultaneous exposure to heat and oxidative stress. However, there have been few studies investigating their combined adverse effects on cell viability. PRINCIPAL FINDINGS: Pretreatment of hydrogen peroxide (H(2O(2 specifically and highly sensitized cells to heat stress, and enhanced loss of mitochondrial membrane potential. H(2O(2 exposure impaired the HSP40/HSP70 induction as heat shock response (HSR and the unfolded protein recovery, and enhanced eIF2alpha phosphorylation and/or XBP1 splicing, land marks of ER stress. These H(2O(2-mediated effects mimicked enhanced heat sensitivity in HSF1 knockdown or knockout cells. Importantly, thermal preconditioning blocked H(2O(2-mediated inhibitory effects on refolding activity and rescued HSF1 +/+ MEFs, but neither blocked the effects nor rescued HSF1 -/- MEFs. These data strongly suggest that inhibition of HSR and refolding activity is crucial for H(2O(2-mediated enhanced heat sensitivity. CONCLUSIONS: H(2O(2 blocks HSR and refolding activity under heat stress, thereby leading to insufficient quality control and enhancing ER stress. These uncontrolled stress responses may enhance cell death. Our data thus highlight oxidative stress as a crucial factor affecting heat tolerance.

  19. Nonlinear feedback drives homeostatic plasticity in H2O2 stress response

    Science.gov (United States)

    Goulev, Youlian; Morlot, Sandrine; Matifas, Audrey; Huang, Bo; Molin, Mikael; Toledano, Michel B; Charvin, Gilles

    2017-01-01

    Homeostatic systems that rely on genetic regulatory networks are intrinsically limited by the transcriptional response time, which may restrict a cell’s ability to adapt to unanticipated environmental challenges. To bypass this limitation, cells have evolved mechanisms whereby exposure to mild stress increases their resistance to subsequent threats. However, the mechanisms responsible for such adaptive homeostasis remain largely unknown. Here, we used live-cell imaging and microfluidics to investigate the adaptive response of budding yeast to temporally controlled H2O2 stress patterns. We demonstrate that acquisition of tolerance is a systems-level property resulting from nonlinearity of H2O2 scavenging by peroxiredoxins and our study reveals that this regulatory scheme induces a striking hormetic effect of extracellular H2O2 stress on replicative longevity. Our study thus provides a novel quantitative framework bridging the molecular architecture of a cellular homeostatic system to the emergence of nonintuitive adaptive properties. DOI: http://dx.doi.org/10.7554/eLife.23971.001 PMID:28418333

  20. Highly nonlinear stress-relaxation response of articular cartilage in indentation: Importance of collagen nonlinearity.

    Science.gov (United States)

    Mäkelä, J T A; Korhonen, R K

    2016-06-14

    Modern fibril-reinforced computational models of articular cartilage can include inhomogeneous tissue composition and structure, and nonlinear mechanical behavior of collagen, proteoglycans and fluid. These models can capture well experimental single step creep and stress-relaxation tests or measurements under small strains in unconfined and confined compression. Yet, it is known that in indentation, especially at high strain velocities, cartilage can express highly nonlinear response. Different fibril reinforced poroelastic and poroviscoelastic models were used to assess measured highly nonlinear stress-relaxation response of rabbit articular cartilage in indentation. Experimentally measured depth-dependent volume fractions of different tissue constituents and their mechanical nonlinearities were taken into account in the models. In particular, the collagen fibril network was modeled using eight separate models that implemented five different constitutive equations to describe the nonlinearity. These consisted of linear elastic, nonlinear viscoelastic and multiple nonlinear elastic representations. The model incorporating the most nonlinearly increasing Young׳s modulus of collagen fibrils as a function of strain captured best the experimental data. Relative difference between the model and experiment was ~3%. Surprisingly, the difference in the peak forces between the experiment and the model with viscoelastic collagen fibrils was almost 20%. Implementation of the measured volume fractions did not improve the ability of the model to capture the measured mechanical data. These results suggest that a highly nonlinear formulation for collagen fibrils is needed to replicate multi-step stress-relaxation response of rabbit articular cartilage in indentation with high strain rates.

  1. Interdependence of tetrapyrrole metabolism, the generation of oxidative stress and the mitigative oxidative stress response.

    Science.gov (United States)

    Busch, Andrea W U; Montgomery, Beronda L

    2015-01-01

    Tetrapyrroles are involved in light harvesting and light perception, electron-transfer reactions, and as co-factors for key enzymes and sensory proteins. Under conditions in which cells exhibit stress-induced imbalances of photosynthetic reactions, or light absorption exceeds the ability of the cell to use photoexcitation energy in synthesis reactions, redox imbalance can occur in photosynthetic cells. Such conditions can lead to the generation of reactive oxygen species (ROS) associated with alterations in tetrapyrrole homeostasis. ROS accumulation can result in cellular damage and detrimental effects on organismal fitness, or ROS molecules can serve as signals to induce a protective or damage-mitigating oxidative stress signaling response in cells. Induced oxidative stress responses include tetrapyrrole-dependent and -independent mechanisms for mitigating ROS generation and/or accumulation. Thus, tetrapyrroles can be contributors to oxidative stress, but are also essential in the oxidative stress response to protect cells by contributing to detoxification of ROS. In this review, we highlight the interconnection and interdependence of tetrapyrrole metabolism with the occurrence of oxidative stress and protective oxidative stress signaling responses in photosynthetic organisms. Copyright © 2015 The Authprs. Published by Elsevier B.V. All rights reserved.

  2. Interdependence of tetrapyrrole metabolism, the generation of oxidative stress and the mitigative oxidative stress response

    Directory of Open Access Journals (Sweden)

    Andrea W.U. Busch

    2015-04-01

    Full Text Available Tetrapyrroles are involved in light harvesting and light perception, electron-transfer reactions, and as co-factors for key enzymes and sensory proteins. Under conditions in which cells exhibit stress-induced imbalances of photosynthetic reactions, or light absorption exceeds the ability of the cell to use photoexcitation energy in synthesis reactions, redox imbalance can occur in photosynthetic cells. Such conditions can lead to the generation of reactive oxygen species (ROS associated with alterations in tetrapyrrole homeostasis. ROS accumulation can result in cellular damage and detrimental effects on organismal fitness, or ROS molecules can serve as signals to induce a protective or damage-mitigating oxidative stress signaling response in cells. Induced oxidative stress responses include tetrapyrrole-dependent and -independent mechanisms for mitigating ROS generation and/or accumulation. Thus, tetrapyrroles can be contributors to oxidative stress, but are also essential in the oxidative stress response to protect cells by contributing to detoxification of ROS. In this review, we highlight the interconnection and interdependence of tetrapyrrole metabolism with the occurrence of oxidative stress and protective oxidative stress signaling responses in photosynthetic organisms.

  3. Replication of the Frank-Starling response in a mock circulation loop.

    Science.gov (United States)

    Gregory, Shaun D; Stevens, Michael; Timms, Daniel; Pearcy, Mark

    2011-01-01

    Mock circulation loops (MCLs) are used to evaluate cardiovascular devices prior to in-vivo trials; however they lack the vital autoregulatory responses that occur in humans. This study aimed to develop and implement a left and right ventricular Frank-Starling response in a MCL. A proportional controller based on ventricular end diastolic volume was used to control the driving pressure of the MCL's pneumatically operated ventricles. Ventricular pressure-volume loops and end systolic pressure-volume relationships were produced for a variety of healthy and pathological conditions and compared with human data to validate the simulated Frank-Starling response. The non-linear Frank-Starling response produced in this study successfully altered left and right ventricular contractility with changing preload and was validated with previously reported data. This improvement to an already detailed MCL has resulted in a test rig capable of further refining cardiovascular devices and reducing the number of in-vivo trials.

  4. Exercise-Induced Oxidative Stress Responses in the Pediatric Population

    Directory of Open Access Journals (Sweden)

    Alexandra Avloniti

    2017-01-01

    Full Text Available Adults demonstrate an upregulation of their pro- and anti-oxidant mechanisms in response to acute exercise while systematic exercise training enhances their antioxidant capacity, thereby leading to a reduced generation of free radicals both at rest and in response to exercise stress. However, less information exists regarding oxidative stress responses and the underlying mechanisms in the pediatric population. Evidence suggests that exercise-induced redox perturbations may be valuable in order to monitor exercise-induced inflammatory responses and as such training overload in children and adolescents as well as monitor optimal growth and development. The purpose of this review was to provide an update on oxidative stress responses to acute and chronic exercise in youth. It has been documented that acute exercise induces age-specific transient alterations in both oxidant and antioxidant markers in children and adolescents. However, these responses seem to be affected by factors such as training phase, training load, fitness level, mode of exercise etc. In relation to chronic adaptation, the role of training on oxidative stress adaptation has not been adequately investigated. The two studies performed so far indicate that children and adolescents exhibit positive adaptations of their antioxidant system, as adults do. More studies are needed in order to shed light on oxidative stress and antioxidant responses, following acute exercise and training adaptations in youth. Available evidence suggests that small amounts of oxidative stress may be necessary for growth whereas the transition to adolescence from childhood may promote maturation of pro- and anti-oxidant mechanisms. Available evidence also suggests that obesity may negatively affect basal and exercise-related antioxidant responses in the peripubertal period during pre- and early-puberty.

  5. Sorbitol treatment extends lifespan and induces the osmotic stress response in Caenorhabditis elegans

    Directory of Open Access Journals (Sweden)

    Devon eChandler-Brown

    2015-10-01

    Full Text Available The response to osmotic stress is a highly conserved process for adapting to changing environmental conditions. Prior studies have shown that hyperosmolarity by addition of sorbitol to the growth medium is sufficient to increase both chronological and replicative lifespan in the budding yeast, Saccharomyces cerevisiae. Here we report a similar phenomenon in the nematode Caenorhabditis elegans. Addition of sorbitol to the nematode growth medium induces an adaptive osmotic response and increases C. elegans lifespan by about 35%. Lifespan extension from 5% sorbitol behaves similarly to dietary restriction in a variety of genetic backgrounds, increasing lifespan additively with mutation of daf-2(e1370 and independently of daf-16(mu86, sir-2.1(ok434, aak-2(ok524, and hif-1(ia04. Dietary restriction by bacterial deprivation or mutation of eat-2(ad1113 fails to further extend lifespan in the presence of 5% sorbitol. Two mutants with constitutive activation of the osmotic response, osm-5(p813 and osm-7(n1515, were found to be long-lived, and lifespan extension from sorbitol required the glycerol biosynthetic enzymes GPDH-1 and GPDH-2. Taken together, these observations demonstrate that exposure to sorbitol at levels sufficient to induce an adaptive osmotic response extends lifespan in worms and define the osmotic stress response pathway as a longevity pathway conserved between yeast and nematodes.

  6. Sorbitol treatment extends lifespan and induces the osmotic stress response in Caenorhabditis elegans.

    Science.gov (United States)

    Chandler-Brown, Devon; Choi, Haeri; Park, Shirley; Ocampo, Billie R; Chen, Shiwen; Le, Anna; Sutphin, George L; Shamieh, Lara S; Smith, Erica D; Kaeberlein, Matt

    2015-01-01

    The response to osmotic stress is a highly conserved process for adapting to changing environmental conditions. Prior studies have shown that hyperosmolarity by addition of sorbitol to the growth medium is sufficient to increase both chronological and replicative lifespan in the budding yeast, Saccharomyces cerevisiae. Here we report a similar phenomenon in the nematode Caenorhabditis elegans. Addition of sorbitol to the nematode growth medium induces an adaptive osmotic response and increases C. elegans lifespan by about 35%. Lifespan extension from 5% sorbitol behaves similarly to dietary restriction in a variety of genetic backgrounds, increasing lifespan additively with mutation of daf-2(e1370) and independently of daf-16(mu86), sir-2.1(ok434), aak-2(ok524), and hif-1(ia04). Dietary restriction by bacterial deprivation or mutation of eat-2(ad1113) fails to further extend lifespan in the presence of 5% sorbitol. Two mutants with constitutive activation of the osmotic response, osm-5(p813) and osm-7(n1515), were found to be long-lived, and lifespan extension from sorbitol required the glycerol biosynthetic enzymes GPDH-1 and GPDH-2. Taken together, these observations demonstrate that exposure to sorbitol at levels sufficient to induce an adaptive osmotic response extends lifespan in worms and define the osmotic stress response pathway as a longevity pathway conserved between yeast and nematodes.

  7. Regulation of Viral Replication, Apoptosis and Pro-Inflammatory Responses by 17-AAG during Chikungunya Virus Infection in Macrophages

    Directory of Open Access Journals (Sweden)

    Tapas K. Nayak

    2017-01-01

    Full Text Available Chikungunya virus (CHIKV infection has re-emerged as a major public health concern due to its recent worldwide epidemics and lack of control measures. Although CHIKV is known to infect macrophages, regulation of CHIKV replication, apoptosis and immune responses towards macrophages are not well understood. Accordingly, the Raw264.7 cells, a mouse macrophage cell line, were infected with CHIKV and viral replication as well as new viral progeny release was assessed by flow cytometry and plaque assay, respectively. Moreover, host immune modulation and apoptosis were studied through flow cytometry, Western blot and ELISA. Our current findings suggest that expression of CHIKV proteins were maximum at 8 hpi and the release of new viral progenies were remarkably increased around 12 hpi. The induction of Annexin V binding, cleaved caspase-3, cleaved caspase-9 and cleaved caspase-8 in CHIKV infected macrophages suggests activation of apoptosis through both intrinsic and extrinsic pathways. The pro-inflammatory mediators (TNF and IL-6 MHC-I/II and B7.2 (CD86 were also up-regulated during infection over time. Further, 17-AAG, a potential HSP90 inhibitor, was found to regulate CHIKV infection, apoptosis and pro-inflammatory cytokine/chemokine productions of host macrophages significantly. Hence, the present findings might bring new insight into the therapeutic implication in CHIKV disease biology.

  8. Regulation of Viral Replication, Apoptosis and Pro-Inflammatory Responses by 17-AAG during Chikungunya Virus Infection in Macrophages

    Science.gov (United States)

    Nayak, Tapas K.; Mamidi, Prabhudutta; Kumar, Abhishek; Singh, Laishram Pradeep K.; Sahoo, Subhransu S.; Chattopadhyay, Soma; Chattopadhyay, Subhasis

    2017-01-01

    Chikungunya virus (CHIKV) infection has re-emerged as a major public health concern due to its recent worldwide epidemics and lack of control measures. Although CHIKV is known to infect macrophages, regulation of CHIKV replication, apoptosis and immune responses towards macrophages are not well understood. Accordingly, the Raw264.7 cells, a mouse macrophage cell line, were infected with CHIKV and viral replication as well as new viral progeny release was assessed by flow cytometry and plaque assay, respectively. Moreover, host immune modulation and apoptosis were studied through flow cytometry, Western blot and ELISA. Our current findings suggest that expression of CHIKV proteins were maximum at 8 hpi and the release of new viral progenies were remarkably increased around 12 hpi. The induction of Annexin V binding, cleaved caspase-3, cleaved caspase-9 and cleaved caspase-8 in CHIKV infected macrophages suggests activation of apoptosis through both intrinsic and extrinsic pathways. The pro-inflammatory mediators (TNF and IL-6) MHC-I/II and B7.2 (CD86) were also up-regulated during infection over time. Further, 17-AAG, a potential HSP90 inhibitor, was found to regulate CHIKV infection, apoptosis and pro-inflammatory cytokine/chemokine productions of host macrophages significantly. Hence, the present findings might bring new insight into the therapeutic implication in CHIKV disease biology. PMID:28067803

  9. (p)ppGpp modulates cell size and the initiation of DNA replication in Caulobacter crescentus in response to a block in lipid biosynthesis.

    Science.gov (United States)

    Stott, Kristina V; Wood, Shannon M; Blair, Jimmy A; Nguyen, Bao T; Herrera, Anabel; Mora, Yannet G Perez; Cuajungco, Math P; Murray, Sean R

    2015-03-01

    Stress conditions, such as a block in fatty acid synthesis, signal bacterial cells to exit the cell cycle. Caulobacter crescentus FabH is a cell-cycle-regulated β-ketoacyl-acyl carrier protein synthase that initiates lipid biosynthesis and is essential for growth in rich media. To explore how C. crescentus responds to a block in lipid biosynthesis, we created a FabH-depletion strain. We found that FabH depletion blocks lipid biosynthesis in rich media and causes a cell cycle arrest that requires the alarmone (p)ppGpp for adaptation. Notably, basal levels of (p)ppGpp coordinate both a reduction in cell volume and a block in the over-initiation of DNA replication in response to FabH depletion. The gene ctrA encodes a master transcription factor that directly regulates 95 cell-cycle-controlled genes while also functioning to inhibit the initiation of DNA replication. Here, we demonstrate that ctrA transcription is (p)ppGpp-dependent during fatty acid starvation. CtrA fails to accumulate when FabH is depleted in the absence of (p)ppGpp due to a substantial reduction in ctrA transcription. The (p)ppGpp-dependent maintenance of ctrA transcription during fatty acid starvation initiated from only one of the two ctrA promoters. In the absence of (p)ppGpp, the majority of FabH-depleted cells enter a viable but non-culturable state, with multiple chromosomes, and are unable to recover from the miscoordination of cell cycle events. Thus, basal levels of (p)ppGpp facilitate C. crescentus' re-entry into the cell cycle after termination of fatty acid starvation.

  10. Immune Responses and Viral Replication in Long-Term Inapparent Carrier Ponies Inoculated with Equine Infectious Anemia Virus

    Science.gov (United States)

    Hammond, Scott A.; Li, Feng; McKeon, Brian M.; Cook, Sheila J.; Issel, Charles J.; Montelaro, Ronald C.

    2000-01-01

    Persistent infection of equids by equine infectious anemia virus (EIAV) is typically characterized by a progression during the first year postinfection from chronic disease with recurring disease cycles to a long-term asymptomatic infection that is maintained indefinitely. The goal of the current study was to perform a comprehensive longitudinal analysis of the course of virus infection and development of host immunity in experimentally infected horses as they progressed from chronic disease to long-term inapparent carriage. We previously described the evolution of EIAV genomic quasispecies (C. Leroux, C. J. Issel, and R. C. Montelaro, J. Virol. 71:9627–9639, 1997) and host immune responses (S. A. Hammond, S. J. Cook, D. L. Lichtenstein, C. J. Issel, and R. C. Montelaro, J. Virol. 71:3840–3852, 1997) in four experimentally infected ponies during sequential disease episodes associated with chronic disease during the first 10 months postinfection. In the current study, we extended the studies of these experimentally infected ponies to 3 years postinfection to characterize the levels of virus replication and development of host immune responses associated with the progression from chronic disease to long-term inapparent infection. The results of these studies revealed over a 103-fold difference in the steady-state levels of plasma viral RNA detected during long-term inapparent infection that correlated with the severity of chronic disease, indicating different levels of control of virus replication during long-term inapparent infections. Detailed analyses of antibody and cellular immune responses in all four ponies over the 3-year course of infection revealed a similar evolution during the first year postinfection of robust humoral and cellular immunity that then remained relatively constant during long-term inapparent infection. These observations indicate that immune parameters that have previously been correlated with EIAV vaccine protection fail to provide

  11. Ultra Low-Dose Radiation: Stress Responses and Impacts Using Rice as a Grass Model

    Directory of Open Access Journals (Sweden)

    Junko Shibato

    2009-03-01

    Full Text Available We report molecular changes in leaves of rice plants (Oryza sativa L. - reference crop plant and grass model exposed to ultra low-dose ionizing radiation, first using contaminated soil from the exclusion zone around Chernobyl reactor site. Results revealed induction of stress-related marker genes (Northern blot and secondary metabolites (LC-MS/MS in irradiated leaf segments over appropriate control. Second, employing the same in vitro model system, we replicated results of the first experiment using in-house fabricated sources of ultra low-dose gamma (g rays and selected marker genes by RT-PCR. Results suggest the usefulness of the rice model in studying ultra low-dose radiation response/s.

  12. Physiological roles of plastid terminal oxidase in plant stress responses

    Indian Academy of Sciences (India)

    Xin Sun; Tao Wen

    2011-12-01

    The plastid terminal oxidase (PTOX) is a plastoquinol oxidase localized in the plastids of plants. It is able to transfer electrons from plastoquinone (PQ) to molecular oxygen with the formation of water. Recent studies have suggested that PTOX is beneficial for plants under environmental stresses, since it is involved in the synthesis of photoprotective carotenoids and chlororespiration, which could potentially protect the chloroplast electron transport chain (ETC) from over-reduction. The absence of PTOX in plants usually results in photo-bleached variegated leaves and impaired adaptation to environment alteration. Although PTOX level and activity has been found to increase under a wide range of stress conditions, the functions of plant PTOX in stress responses are still disputed now. In this paper, the possible physiological roles of PTOX in plant stress responses are discussed based on the recent progress.

  13. Proteomics analysis of alfalfa response to heat stress.

    Directory of Open Access Journals (Sweden)

    Weimin Li

    Full Text Available The proteome responses to heat stress have not been well understood. In this study, alfalfa (Medicago sativa L. cv. Huaiyin seedlings were exposed to 25 °C (control and 40 °C (heat stress in growth chambers, and leaves were collected at 24, 48 and 72 h after treatment, respectively. The morphological, physiological and proteomic processes were negatively affected under heat stress. Proteins were extracted and separated by two-dimensional polyacrylamide gel electrophoresis (2-DE, and differentially expressed protein spots were identified by mass spectrometry (MS. Totally, 81 differentially expressed proteins were identified successfully by MALDI-TOF/TOF. These proteins were categorized into nine classes: including metabolism, energy, protein synthesis, protein destination/storage, transporters, intracellular traffic, cell structure, signal transduction and disease/defence. Five proteins were further analyzed for mRNA levels. The results of the proteomics analyses provide a better understanding of the molecular basis of heat-stress responses in alfalfa.

  14. Dynamic modeling of cellular response to DNA damage based on p53 stress response networks

    Institute of Scientific and Technical Information of China (English)

    Jinpeng Qi; Yongsheng Ding; Shihuang Shao

    2009-01-01

    Under acute perturbations from the outside, cells can trigger self-defensive mechanisms to fight against genome stress. To investigate the cellular response to continuous ion radiation (IR), a dynamic model for p53 stress response networks at the cellular level is proposed. The model can successfully be used to simulate the dynamic processes of double-strand breaks (DSBs) generation and their repair, switch-like ataxia telangiectasia mutated (ATM) activation, oscillations occurring in the p53-MDM2 feedback loop, as well as toxins elimination triggered by p53 stress response networks. Especially, the model can predict the plausible outcomes of cellular response under different IR dose regimes.

  15. Stress and fear responses in the teleost pallium

    DEFF Research Database (Denmark)

    Silva, Patricia Isabel da Mota E.; Martins, C.I.M.; Khan, Uniza Wahid

    2015-01-01

    Evolution has resulted in behavioural responses to threat which show extensive similarities between different animal species. The reaction to predator cues is one example of such prevailing responses, and functional homologies to mammalian limbic regions involved in threat-sensitive behaviour hav...... to chemical alarm cues, but this effect did not reach the level of statistical significance. Hence, limbic responses to stress and fear, akin to those seen in extant mammals, are also present in the teleost lineage...

  16. Inactivation of p53 in Human Keratinocytes Leads to Squamous Differentiation and Shedding via Replication Stress and Mitotic Slippage.

    Science.gov (United States)

    Freije, Ana; Molinuevo, Rut; Ceballos, Laura; Cagigas, Marta; Alonso-Lecue, Pilar; Rodriguez, René; Menendez, Pablo; Aberdam, Daniel; De Diego, Ernesto; Gandarillas, Alberto

    2014-11-20

    Tumor suppressor p53 is a major cellular guardian of genome integrity, and its inactivation is the most frequent genetic alteration in cancer, rising up to 80% in squamous cell carcinoma (SCC). By adapting the small hairpin RNA (shRNA) technology, we inactivated endogenous p53 in primary epithelial cells from the epidermis of human skin. We show that either loss of endogenous p53 or overexpression of a temperature-sensitive dominant-negative conformation triggers a self-protective differentiation response, resulting in cell stratification and expulsion. These effects follow DNA damage and exit from mitosis without cell division. p53 preserves the proliferative potential of the stem cell compartment and limits the power of proto-oncogene MYC to drive cell cycle stress and differentiation. The results provide insight into the role of p53 in self-renewal homeostasis and help explain why p53 mutations do not initiate skin cancer but increase the likelihood that cancer cells will appear.

  17. Inactivation of p53 in Human Keratinocytes Leads to Squamous Differentiation and Shedding via Replication Stress and Mitotic Slippage

    Directory of Open Access Journals (Sweden)

    Ana Freije

    2014-11-01

    Full Text Available Tumor suppressor p53 is a major cellular guardian of genome integrity, and its inactivation is the most frequent genetic alteration in cancer, rising up to 80% in squamous cell carcinoma (SCC. By adapting the small hairpin RNA (shRNA technology, we inactivated endogenous p53 in primary epithelial cells from the epidermis of human skin. We show that either loss of endogenous p53 or overexpression of a temperature-sensitive dominant-negative conformation triggers a self-protective differentiation response, resulting in cell stratification and expulsion. These effects follow DNA damage and exit from mitosis without cell division. p53 preserves the proliferative potential of the stem cell compartment and limits the power of proto-oncogene MYC to drive cell cycle stress and differentiation. The results provide insight into the role of p53 in self-renewal homeostasis and help explain why p53 mutations do not initiate skin cancer but increase the likelihood that cancer cells will appear.

  18. Hemodynamic responses to mental stress during salt loading

    DEFF Research Database (Denmark)

    Goyal, Maria Gefke; Christensen, Niels Juel; Bech, Per

    2017-01-01

    PURPOSE: The purpose was to examine whether prolonged moderate stress associated with a student exam would increase the blood pressure response to a salt load in young healthy normotensive individuals. METHODS: Ten healthy young subjects were examined at two different occasions in random order (i...... in day-to-night systolic blood pressure during high-salt intake and moderate stress may indicate that stress affects blood pressure regulation.......PURPOSE: The purpose was to examine whether prolonged moderate stress associated with a student exam would increase the blood pressure response to a salt load in young healthy normotensive individuals. METHODS: Ten healthy young subjects were examined at two different occasions in random order (i......) during preparation for a medical exam (prolonged stress) and (ii) outside the exam period (low stress). All subjects consumed a controlled diet for 3 days with low- or high-salt content in randomized order. The subjective stress was measured by Spielberger's State-Trait Anxiety Inventory-Scale, SCL...

  19. The ethanol stress response and ethanol tolerance of Saccharomyces cerevisiae.

    Science.gov (United States)

    Stanley, D; Bandara, A; Fraser, S; Chambers, P J; Stanley, G A

    2010-07-01

    Saccharomyces cerevisiae is traditionally used for alcoholic beverage and bioethanol production; however, its performance during fermentation is compromised by the impact of ethanol accumulation on cell vitality. This article reviews studies into the molecular basis of the ethanol stress response and ethanol tolerance of S. cerevisiae; such knowledge can facilitate the development of genetic engineering strategies for improving cell performance during ethanol stress. Previous studies have used a variety of strains and conditions, which is problematic, because the impact of ethanol stress on gene expression is influenced by the environment. There is however some commonality in Gene Ontology categories affected by ethanol assault that suggests that the ethanol stress response of S. cerevisiae is compromised by constraints on energy production, leading to increased expression of genes associated with glycolysis and mitochondrial function, and decreased gene expression in energy-demanding growth-related processes. Studies using genome-wide screens suggest that the maintenance of vacuole function is important for ethanol tolerance, possibly because of the roles of this organelle in protein turnover and maintaining ion homoeostasis. Accumulation of Asr1 and Rat8 in the nucleus specifically during ethanol stress suggests S. cerevisiae has a specific response to ethanol stress although this supposition remains controversial. © 2010 The Authors. Journal compilation © 2010 The Society for Applied Microbiology.

  20. N-Aroyl Indole Thiobarbituric Acids as Inhibitors of DNA Repair and Replication Stress Response Polymerases

    Science.gov (United States)

    Coggins, Grace E.; Maddukuri, Leena; Penthala, Narsima R.; Hartman, Jessica H.; Eddy, Sarah; Ketkar, Amit; Crooks, Peter A.; Eoff, Robert L.

    2013-01-01

    Using a robust and quantitative assay, we have identified a novel class of DNA polymerase inhibitors that exhibits some specificity against an enzyme involved in resistance to anti-cancer drugs, namely human DNA polymerase eta (hpol η). In our initial screen, we identified the indole thiobarbituric acid (ITBA) derivative 5-((1-(2-bromobenzoyl)-5-chloro-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (ITBA-12) as an inhibitor of the Y-family DNA member hpol η, an enzyme that has been associated with increased resistance to cisplatin and doxorubicin treatments. An additional seven DNA polymerases from different sub-families were tested for inhibition by ITBA-12. Hpol η was the most potently inhibited enzyme (30 ± 3 μM), with hpol β, hpol γ and hpol κ exhibiting comparable but higher IC50 values of 41 ± 24 μM, 49 ± 6 μM and 59 ± 11 μM, respectively. The other polymerases tested had IC50 values closer to 80 μM. Steady-state kinetic analysis was used to investigate the mechanism of polymerase inhibition by ITBA-12. Based on changes in the Michaelis constant, it was determined that ITBA-12 acts as an allosteric (or partial) competitive inhibitor of dNTP binding. The parent ITBA scaffold was modified to produce 20 derivatives and establish structure-activity relationships by testing for inhibition of hpol η. Two compounds with N-naphthoyl Ar-substituents, ITBA-16 and ITBA-19, were both found to have improved potency against hpol η with IC50 values of 16 ± 3 μM and 17 ± 3 μM, respectively. Moreover, the specificity of ITBA-16 was improved relative to ITBA-12. The presence of a chloro substituent at position 5 on the indole ring appears to be crucial for effective inhibition of hpol η, with the indole N-1-naphthoyl and N-2-naphthoyl analogs being the most potent inhibitors of hpol η. These results provide a framework from which second-generation ITBA derivatives may be developed against specialized polymerases that are involved in mechanisms of radio- and chemo-resistance. PMID:23679919

  1. A replicated climate change field experiment reveals rapid evolutionary response in an ecologically important soil invertebrate

    DEFF Research Database (Denmark)

    Bataillon, Thomas; Galtier, Nicolas; Bernard, Aurelien;

    2016-01-01

    associated to changes in soil temperature and soil moisture. This shows an evolutionaryresponse to realistic climate change happening over short-time scale, and calls for incorporating evolution into modelspredicting future response of species to climate change. It also shows that designed climate change...

  2. Response character styles in adolescents: a replication of convergent validity between the MMPI-A and the Rorschach.

    Science.gov (United States)

    Stokes, John M; Pogge, David L; Zaccario, Michele

    2013-01-01

    This study explored the extent to which similar or discordant response character styles (RCS) affected convergence between MMPI-A and Rorschach findings in a sample of 673 adolescents from a psychiatric inpatient setting. Meyer's (Meyer, 1997; Meyer, Riethmiller, Brooks, Benoit, & Handler, 2000) findings for adult samples were generally replicated in that adolescents showing similar RCS across both measures showed moderate to strong relationships between Rorschach and MMPI-A indicants of affective distress, psychosis, and interpersonal wariness, whereas those showing discordant RCS demonstrated negligible or negative correlations between these indicants. This pattern was evident for conceptually similar, but not conceptually unrelated variable pairs. Similarity and discordance of RCS was also found to have an impact on relationships with external criterion variables, including therapist ratings and discharge diagnoses. Moderated regression analysis supports the hypothesis that RCS moderates the strength of the relationship between Rorschach and MMPI-A. Implications for practice and future research are discussed.

  3. Proteomic responses of fruits to environmental stresses

    Directory of Open Access Journals (Sweden)

    Zhulong eChan

    2013-01-01

    Full Text Available Fruits and vegetables are extremely susceptible to decay and easily lose commercial value after harvest. Different strategies have been developed to control postharvest decay and prevent quality deterioration during postharvest storage, including cold storage, controlled atmosphere, and application of biotic and abiotic stimulus. In this review, mechanisms related to protein level responses of host side and pathogen side were characterized. Protein extraction protocols have been successfully developed for recalcitrant, low protein content fruit tissues. Comparative proteome profiling and functional analysis revealed that defense related proteins, energy metabolism and antioxidant pathway played important roles in fruits in response to storage conditions and exogenous elicitor treatments. Secretome of pathogenic fungi has been well investigated and the results indicated that hydrolytic enzymes were the key virulent factors for the pathogen infection. These protein level changes shed new light on interaction among fruits, pathogens and environmental conditions. Potential postharvest strategies to reduce risk of fruit decay were further proposed based on currently available proteomic data.

  4. Hormonal contraception use alters stress responses and emotional memory.

    Science.gov (United States)

    Nielsen, Shawn E; Segal, Sabrina K; Worden, Ian V; Yim, Ilona S; Cahill, Larry

    2013-02-01

    Emotionally arousing material is typically better remembered than neutral material. Since norepinephrine and cortisol interact to modulate emotional memory, sex-related influences on stress responses may be related to sex differences in emotional memory. Two groups of healthy women - one naturally cycling (NC women, n=42) and one using hormonal contraceptives (HC women, n=36) - viewed emotionally arousing and neutral images. Immediately after, they were assigned to Cold Pressor Stress (CPS) or a control procedure. One week later, participants received a surprise free recall test. Saliva samples were collected and later assayed for salivary alpha-amylase (biomarker for norepinephrine) and cortisol. Compared to NC women, HC women exhibited significantly blunted stress hormone responses to the images and CPS. Recall of emotional images differed between HC and NC women depending on noradrenergic and cortisol responses. These findings may have important implications for understanding the neurobiology of emotional memory disorders, especially those that disproportionately affect women.

  5. Orientational Polarizability and Stress Response of Biological Cells

    Science.gov (United States)

    Safran, S. A.; de, R.; Zemel, A.

    We present a theoretical treatment of the orientational response to external stress of active, contractile cells embedded in a gel-like elastic medium. The theory includes random forces as well as forces that arise from the deformation of the matrix and those due to the internal regulation of the stress fibers and focal adhesions of the cell. We calculate both the static and high frequency limits of the orientational response in terms of the cellular polarizability. For systems in which the forces due to regulation and activity dominate the mechanical forces, we show that there is a non-linear dynamical response which, in the high frequency limit, causes the cell to orient nearly perpendicular to the direction of the applied stress.

  6. Tissue Culture as a Source of Replicates in Nonmodel Plants: Variation in Cold Response in Arabidopsis lyrata ssp. petraea

    Directory of Open Access Journals (Sweden)

    Tanaka Kenta

    2016-12-01

    Full Text Available While genotype–environment interaction is increasingly receiving attention by ecologists and evolutionary biologists, such studies need genetically homogeneous replicates—a challenging hurdle in outcrossing plants. This could be potentially overcome by using tissue culture techniques. However, plants regenerated from tissue culture may show aberrant phenotypes and “somaclonal” variation. Here, we examined somaclonal variation due to tissue culturing using the response to cold treatment of photosynthetic efficiency (chlorophyll fluorescence measurements for Fv/Fm, Fv′/Fm′, and ΦPSII, representing maximum efficiency of photosynthesis for dark- and light-adapted leaves, and the actual electron transport operating efficiency, respectively, which are reliable indicators of photoinhibition and damage to the photosynthetic electron transport system. We compared this to variation among half-sibling seedlings from three different families of Arabidopsis lyrata ssp. petraea. Somaclonal variation was limited, and we could detect within-family variation in change in chlorophyll fluorescence due to cold shock successfully with the help of tissue-culture derived replicates. Icelandic and Norwegian families exhibited higher chlorophyll fluorescence, suggesting higher performance after cold shock, than a Swedish family. Although the main effect of tissue culture on Fv/Fm, Fv′/Fm′, and ΦPSII was small, there were significant interactions between tissue culture and family, suggesting that the effect of tissue culture is genotype-specific. Tissue-cultured plantlets were less affected by cold treatment than seedlings, but to a different extent in each family. These interactive effects, however, were comparable to, or much smaller than the single effect of family. These results suggest that tissue culture is a useful method for obtaining genetically homogenous replicates for studying genotype–environment interaction related to adaptively

  7. Transcriptional responses of Arabidopsis thaliana plants to As (V stress

    Directory of Open Access Journals (Sweden)

    Yuan Joshua S

    2008-08-01

    Full Text Available Abstract Background Arsenic is toxic to plants and a common environmental pollutant. There is a strong chemical similarity between arsenate [As (V] and phosphate (Pi. Whole genome oligonucleotide microarrays were employed to investigate the transcriptional responses of Arabidopsis thaliana plants to As (V stress. Results Antioxidant-related genes (i.e. coding for superoxide dismutases and peroxidases play prominent roles in response to arsenate. The microarray experiment revealed induction of chloroplast Cu/Zn superoxide dismutase (SOD (at2g28190, Cu/Zn SOD (at1g08830, as well as an SOD copper chaperone (at1g12520. On the other hand, Fe SODs were strongly repressed in response to As (V stress. Non-parametric rank product statistics were used to detect differentially expressed genes. Arsenate stress resulted in the repression of numerous genes known to be induced by phosphate starvation. These observations were confirmed with qRT-PCR and SOD activity assays. Conclusion Microarray data suggest that As (V induces genes involved in response to oxidative stress and represses transcription of genes induced by phosphate starvation. This study implicates As (V as a phosphate mimic in the cell by repressing genes normally induced when available phosphate is scarce. Most importantly, these data reveal that arsenate stress affects the expression of several genes with little or unknown biological functions, thereby providing new putative gene targets for future research.

  8. Formaldehyde stress responses in bacterial pathogens

    Directory of Open Access Journals (Sweden)

    Nathan Houqian Chen

    2016-03-01

    Full Text Available Formaldehyde is the simplest of all aldehydes and is highly cytotoxic. Its use and associated dangers from environmental exposure have been well documented. Detoxification systems for formaldehyde are found throughout the biological world and they are especially important in methylotrophic bacteria, which generate this compound as part of their metabolism of methanol. Formaldehyde metabolizing systems can be divided into those dependent upon pterin cofactors, sugar phosphates and those dependent upon glutathione. The more prevalent thiol-dependent formaldehyde detoxification system is found in many bacterial pathogens, almost all of which do not metabolize methane or methanol. This review describes the endogenous and exogenous sources of formaldehyde, its toxic effects and mechanisms of detoxification. The methods of formaldehyde sensing are also described with a focus on the formaldehyde responsive transcription factors HxlR, FrmR and NmlR. Finally, the physiological relevance of detoxification systems for formaldehyde in bacterial pathogens is discussed.

  9. Eccentric-exercise induced inflammation attenuates the vascular responses to mental stress

    NARCIS (Netherlands)

    Paine, N.J.; Ring, C.; Aldred, S.; Bosch, J.A.; Wadley, A.J.; Veldhuijzen van Zanten, J.J.C.S.

    2013-01-01

    Mental stress has been identified as a trigger of myocardial infarction (MI), with inflammation and vascular responses to mental stress independently implicated as contributing factors. This study examined whether inflammation moderates the vascular responses to mental stress. Eighteen healthy male

  10. Eccentric-exercise induced inflammation attenuates the vascular responses to mental stress

    NARCIS (Netherlands)

    Paine, N.J.; Ring, C.; Aldred, S.; Bosch, J.A.; Wadley, A.J.; Veldhuijzen van Zanten, J.J.C.S.

    2013-01-01

    Mental stress has been identified as a trigger of myocardial infarction (MI), with inflammation and vascular responses to mental stress independently implicated as contributing factors. This study examined whether inflammation moderates the vascular responses to mental stress. Eighteen healthy male

  11. Stress exposure and psychological stress responses are related to glucose concentrations during pregnancy.

    Science.gov (United States)

    Horsch, Antje; Kang, Ji Seon; Vial, Yvan; Ehlert, Ulrike; Borghini, Ayala; Marques-Vidal, Pedro; Jacobs, Ingo; Puder, Jardena J

    2016-09-01

    The role of stress in the development of gestational diabetes mellitus (GDM) has so far been neglected. We investigated the impact of stress exposure (pregnancy-related and pregnancy-unrelated major life events), psychological stress responses (perceived stress, subjective experience of stress, anxiety, depression, sleep), and physiological stress responses (salivary cortisol, plasma copeptin levels) on glucose concentrations during pregnancy. Cross-sectional study, including 203 pregnant women at the maternity department of a Swiss university hospital. All women underwent routine screening for GDM with a 75-g oral glucose-tolerance test at 24-30 weeks of gestation. Pregnancy-related and pregnancy-unrelated major life events, perceived stress, general psychological distress, anxiety, depression, and amount of sleep were assessed by validated self-report questionnaires. Cortisol was measured using fasting and bedtime saliva samples, and copeptin using fasting plasma. All data were collected before communication of the screening test results. Significant positive associations were found between the number of pregnancy-related major life events and fasting glucose, while there was no association with pregnancy-unrelated major life events. More anxiety and depressive symptoms, a higher general level of distress, and a shorter duration of sleep were related to fasting glucose, although the latter two were no longer significant when age and BMI were controlled for. However, physiological stress responses were not associated with glucose concentrations. When testing for unique associations with fasting glucose, more general distress and shorter duration of sleep independently accounted for higher fasting glucose levels. Finally, when comparing women with and without GDM, we found that women who subsequently received the diagnosis of GDM reported more pregnancy-related life events. Some indicators of stress exposure and psychological stress responses were associated with

  12. Transcriptional Regulation of Arabidopsis in Response to Salt Stress

    Institute of Scientific and Technical Information of China (English)

    Zhulong Chan

    2012-01-01

    Salt stress is a major factor limiting agricultural productivity worldwide.Adaptations to salt stress include avoidance by reduced sodium uptake,sequestration of toxic sodium ions away from the cytoplasm,or production of compatible solutes or osmoprotectants to reduce molecular disruption.Approaches to engineer salt stress resistance have included regulation of ion transport through introduction of Na+/H+ antiporter; synthesis of compatible solutes; or the introduction of transcription factors regulating expression of stress-responsive genes.On the other hand,naturally occurring variation among wild-type populations of plants also can be used to understand plant adaptive responses to their environments.In this study,we compared phenotypic and transcriptomic effects of constitutive expression of genes intended to confer salt stress tolerance by three different mechanisms:a transcription factor,CBF3/DREB1a; a metabolic gene,M6PR,for mannitol biosynthesis; and the Na+/H+ antiporter,SOS1.In the absence of salt,M6PR and SOS1 lines performed comparably with wild type; CBF3 lines exhibited dwarfing as reported previously.All three transgenes conferred fitness advantage when subjected to 100 mmol/L NaCI in the growth chamber.CBF3 and M6PR affected transcription of numerous abiotic stress-related genes as measured by Affymetrix microarray analysis.M6PR additionally modified expression of biotic stress and oxidative stress genes.Transcriptional effects of SOS1 were smaller and primarily limited to redox-related genes.In addition,we compared natural variations in salt tolerance between Ler and Sha ecotypes based on their responses to salt treatments and the results indicated that Ler was salt-sensitive,but Sha,which obtained a truncated RAS1 protein,was salt-tolerant.Transcriptome analysis revealed that many genes involved in secondary metabolism,photosynthesis,and protein synthesis were mainly down-regulated by salinity effects,while transposable element genes,microRNA and

  13. Oxidative stress response pathways: Fission yeast as archetype

    DEFF Research Database (Denmark)

    Papadakis, Manos A.; Workman, Christopher

    2015-01-01

    the transcriptional response of fission yeast cells to elevated levels of hydrogen peroxide. Particular attention is paid to the mechanisms that yeast cells employ to promote cell survival in conditions of intermediate and acute oxidative stress. The role of the Sty1/Spc1/Phh1 mitogen-activated protein kinase......Schizosaccharomyces pombe is a popular model eukaryotic organism to study diverse aspects of mammalian biology, including responses to cellular stress triggered by redox imbalances within its compartments. The review considers the current knowledge on the signaling pathways that govern...

  14. Oxidative stress response pathways: Fission yeast as archetype.

    Science.gov (United States)

    Papadakis, Manos A; Workman, Christopher T

    2015-01-01

    Schizosaccharomyces pombe is a popular model eukaryotic organism to study diverse aspects of mammalian biology, including responses to cellular stress triggered by redox imbalances within its compartments. The review considers the current knowledge on the signaling pathways that govern the transcriptional response of fission yeast cells to elevated levels of hydrogen peroxide. Particular attention is paid to the mechanisms that yeast cells employ to promote cell survival in conditions of intermediate and acute oxidative stress. The role of the Sty1/Spc1/Phh1 mitogen-activated protein kinase in regulating gene expression at multiple levels is discussed in detail.

  15. Stretching the stress boundary: Linking air pollution health effects to a neurohormonal stress response.

    Science.gov (United States)

    Kodavanti, Urmila P

    2016-12-01

    Inhaled pollutants produce effects in virtually all organ systems in our body and have been linked to chronic diseases including hypertension, atherosclerosis, Alzheimer's and diabetes. A neurohormonal stress response (referred to here as a systemic response produced by activation of the sympathetic nervous system and hypothalamus-pituitary-adrenal (HPA)-axis) has been implicated in a variety of psychological and physical stresses, which involves immune and metabolic homeostatic mechanisms affecting all organs in the body. In this review, we provide new evidence for the involvement of this well-characterized neurohormonal stress response in mediating systemic and pulmonary effects of a prototypic air pollutant - ozone. A plethora of systemic metabolic and immune effects are induced in animals exposed to inhaled pollutants, which could result from increased circulating stress hormones. The release of adrenal-derived stress hormones in response to ozone exposure not only mediates systemic immune and metabolic responses, but by doing so, also modulates pulmonary injury and inflammation. With recurring pollutant exposures, these effects can contribute to multi-organ chronic conditions associated with air pollution. This review will cover, 1) the potential mechanisms by which air pollutants can initiate the relay of signals from respiratory tract to brain through trigeminal and vagus nerves, and activate stress responsive regions including hypothalamus; and 2) the contribution of sympathetic and HPA-axis activation in mediating systemic homeostatic metabolic and immune effects of ozone in various organs. The potential contribution of chronic environmental stress in cardiovascular, neurological, reproductive and metabolic diseases, and the knowledge gaps are also discussed. This article is part of a Special Issue entitled Air Pollution, edited by Wenjun Ding, Andrew J. Ghio and Weidong Wu.

  16. The role of thyroid hormones in stress response of fish.

    Science.gov (United States)

    Peter, M C Subhash

    2011-06-01

    Thyroxine (T(4)) and triiodothyronine (T(3)), the principal thyroid hormones (THs) secreted from the hypothalamic-pituitary-thyroid (HPT) axis, produce a plethora of physiologic actions in fish. The diverse actions of THs in fishes are primarily due to the sensitivity of thyroid axis to many physical, chemical and biological factors of both intrinsic and extrinsic origins. The regulation of THs homeostasis becomes more complex due to extrathyroidal deiodination pathways by which the delivery of biologically active T(3) to target cells has been controlled. As primary stress hormones and the end products of hypothalamic-pituitary-interrenal (HPI) and brain-sympathetic-chromaffin (BSC) axes, cortisol and adrenaline exert its actions on its target tissues where it promote and integrate osmotic and metabolic competence. Despite possessing specific osmoregulatory and metabolic actions at cellular and whole-body levels, THs may fine-tune these processes in accordance with the actions of hormones like cortisol and adrenaline. Evidences are presented that THs can modify the pattern and magnitude of stress response in fishes as it modifies either its own actions or the actions of stress hormones. In addition, multiple lines of evidence indicate that hypothalamic and pituitary hormones of thyroid and interrenal axes can interact with each other which in turn may regulate THs/cortisol-mediated actions. Even though it is hard to define these interactions, the magnitude of stress response in fish has been shown to be modified by the changes in the status of THs, pointing to its functional relationship with endocrine stress axes particularly with the interrenal axis. The fine-tuned mechanism that operates in fish during stressor-challenge drives the THs to play both fundamental and modulator roles in stress response by controlling osmoregulation and metabolic regulation. A major role of THs in stress response is thus evident in fish. Copyright © 2011 Elsevier Inc. All rights

  17. Response to stress in Drosophila is mediated by gender, age and stress paradigm.

    Science.gov (United States)

    Neckameyer, Wendi S; Nieto-Romero, Andres R

    2015-01-01

    All living organisms must maintain equilibrium in response to internal and external challenges within their environment. Changes in neural plasticity (alterations in neuronal populations, dendritic remodeling, and synaptic turnover) are critical components of the homeostatic response to stress, which has been strongly implicated in the onset of affective disorders. However, stress is differentially perceived depending on the type of stress and its context, as well as genetic background, age and sex; therefore, an individual's maintenance of neuronal homeostasis must differ depending upon these variables. We established Drosophila as a model to analyze homeostatic responses to stress. Sexually immature and mature females and males from an isogenic wild-type strain raised under controlled environmental conditions were exposed to four reproducible and high-throughput translatable stressors to facilitate the analysis of a large number of animals for direct comparisons. These animals were assessed in an open-field arena, in a light-dark box, and in a forced swim test, as well as for sensitivity to the sedative effects of ethanol. These studies establish that immature and mature females and males represent behaviorally distinct populations under control conditions as well as after exposure to different stressors. Therefore, the neural substrates mediating the stress response must be differentially expressed depending upon the hormonal status of the brain. In addition, an adaptive response to a given stressor in one paradigm was not predictive for outcomes in other paradigms.

  18. Stress effects on mood, HPA axis, and autonomic response: comparison of three psychosocial stress paradigms.

    Science.gov (United States)

    Giles, Grace E; Mahoney, Caroline R; Brunyé, Tad T; Taylor, Holly A; Kanarek, Robin B

    2014-01-01

    Extensive experimental psychology research has attempted to parse the complex relationship between psychosocial stress, mood, cognitive performance, and physiological changes. To do so, it is necessary to have effective, validated methods to experimentally induce psychosocial stress. The Trier Social Stress Test (TSST) is the most commonly used method of experimentally inducing psychosocial stress, but it is resource intensive. Less resource intense psychosocial stress tasks include the Socially Evaluative Cold Pressor Task (SECPT) and a computerized mental arithmetic task (MAT). These tasks effectively produce a physiological and psychological stress response and have the benefits of requiring fewer experimenters and affording data collection from multiple participants simultaneously. The objective of this study was to compare the magnitude and duration of these three experimental psychosocial stress induction paradigms. On each of four separate days, participants completed either a control non-stressful task or one of the three experimental stressors: the TSST, SECPT, or MAT. We measured mood, working memory performance, salivary cortisol and alpha-amylase (AA), and heart rate. The TSST and SECPT exerted the most robust effects on mood and physiological measures. TSST effects were generally evident immediately post-stress as well as 10- and 20-minutes after stress cessation, whereas SECPT effects were generally limited to the duration of the stressor. The stress duration is a key determinant when planning a study that utilizes an experimental stressor, as researchers may be interested in collecting dependent measures prior to stress cessation. In this way, the TSST would allow the investigator a longer window to administer tasks of interest.

  19. Stress effects on mood, HPA axis, and autonomic response: comparison of three psychosocial stress paradigms.

    Directory of Open Access Journals (Sweden)

    Grace E Giles

    Full Text Available Extensive experimental psychology research has attempted to parse the complex relationship between psychosocial stress, mood, cognitive performance, and physiological changes. To do so, it is necessary to have effective, validated methods to experimentally induce psychosocial stress. The Trier Social Stress Test (TSST is the most commonly used method of experimentally inducing psychosocial stress, but it is resource intensive. Less resource intense psychosocial stress tasks include the Socially Evaluative Cold Pressor Task (SECPT and a computerized mental arithmetic task (MAT. These tasks effectively produce a physiological and psychological stress response and have the benefits of requiring fewer experimenters and affording data collection from multiple participants simultaneously. The objective of this study was to compare the magnitude and duration of these three experimental psychosocial stress induction paradigms. On each of four separate days, participants completed either a control non-stressful task or one of the three experimental stressors: the TSST, SECPT, or MAT. We measured mood, working memory performance, salivary cortisol and alpha-amylase (AA, and heart rate. The TSST and SECPT exerted the most robust effects on mood and physiological measures. TSST effects were generally evident immediately post-stress as well as 10- and 20-minutes after stress cessation, whereas SECPT effects were generally limited to the duration of the stressor. The stress duration is a key determinant when planning a study that utilizes an experimental stressor, as researchers may be interested in collecting dependent measures prior to stress cessation. In this way, the TSST would allow the investigator a longer window to administer tasks of interest.

  20. Response of Saccharomyces cerevisiae to cadmium stress

    Energy Technology Data Exchange (ETDEWEB)

    Moreira, Luciana Mara Costa; Ribeiro, Frederico Haddad; Neves, Maria Jose [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizonte, MG (Brazil). Lab. de Radiobiologia], e-mail: luamatu@uol.com.br; Porto, Barbara Abranches Araujo; Amaral, Angela M.; Menezes, Maria Angela B.C. [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Lab. de Ativacao Neutronica], e-mail: menezes@cdtn.br; Rosa, Carlos Augusto [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Dept. de Microbiologia], e-mail: carlrosa@icb.ufmg

    2009-07-01

    The intensification of industrial activity has been greatly contributing with the increase of heavy metals in the environment. Among these heavy metals, cadmium becomes a serious pervasive environmental pollutant. The cadmium is a heavy metal with no biological function, very toxic and carcinogenic at low concentrations. The toxicity of cadmium and several other metals can be mainly attributed to the multiplicity of coordination complexes and clusters that they can form. Some aspects of the cellular response to cadmium were extensively investigated in the yeast Saccharomyces cerevisiae. The primary site of interaction between many toxic metals and microbial cells is the plasma membrane. Plasma-membrane permeabilisation has been reported in a variety of microorganisms following cadmium exposure, and is considered one mechanism of cadmium toxicity in the yeast. In this work, using the yeast strain S. cerevisiae W303-WT, we have investigated the relationships between Cd uptake and release of cellular metal ions (K{sup +} and Na{sup +}) using neutron activation technique. The neutron activation was an easy, rapid and suitable technique for doing these metal determinations on yeast cells; was observed the change in morphology of the strains during the process of Cd accumulation, these alterations were observed by Transmission Electron Microscopy (TEM) and Scanning Electron Microscopy (SEM) during incorporation of cadmium. (author)

  1. Dysregulation of the stress response in asthmatic children.

    Science.gov (United States)

    Priftis, K N; Papadimitriou, A; Nicolaidou, P; Chrousos, G P

    2009-01-01

    The stress system co-ordinates the adaptive responses of the organism to stressors of any kind. Inappropriate responsiveness may account for increased susceptibility to a variety of disorders, including asthma. Accumulated evidence from animal models suggests that exogenously applied stress enhances airway reactivity and increases allergen-induced airway inflammation. This is in agreement with the clinical observation that stressful life events increase the risk of a new asthma attack. Activation of the hypothalamic-pituitary-adrenal (HPA) axis by specific cytokines increases the release of cortisol, which in turn feeds back and suppresses the immune reaction. Data from animal models suggest that inability to increase glucocorticoid production in response to stress is associated with increased airway inflammation with mechanical dysfunction of the lungs. Recently, a growing body of evidence shows that asthmatic subjects who are not treated with inhaled corticosteroids (ICS) are likely to have an attenuated activity and/or responsiveness of their HPA axis. In line with this concept, most asthmatic children demonstrate improved HPA axis responsiveness on conventional doses of ICS, as their airway inflammation subsides. Few patients may experience further deterioration of adrenal function, a phenomenon which may be genetically determined.

  2. Renal Function and Cardiovascular Response to Mental Stress

    Science.gov (United States)

    Seliger, Stephen L.; Katzel, Leslie I.; Fink, Jeffrey C.; Weir, Matthew R.; Waldstein, Shari R.

    2008-01-01

    Background/Aims Cardiovascular reactivity (CVR), defined as an exaggerated hemodynamic response to mental stress, is a putative vascular risk factor and may reflect sympathetic hyperactivity. Chronic kidney disease (CKD) is also associated with sympathetic hyperactivity and vascular risk, but its relationship with CVR is unknown. Methods CVR was assessed in 107 individuals without overt cardiovascular disease or diabetes. Blood pressure and heart rate responses were elicited by three experimental tasks designed to evoke mental stress. Glomerular filtration rate (eGFR) was estimated using the MDRD formula. General linear models estimated the association between renal function and CVR, adjusting for potential confounders. Results Mean age was 66 years and 11% had eGFR of <60 ml/min/1.73 m2. After multivariate adjustment, a low eGFR was associated with a greater stress response of systolic blood pressure, heart rate, and pulse pressure. Associations were only partially attenuated after adjustment for lipids and glucose tolerance. When considered as a continuous variable, lower eGFR was associated with a greater blood pressure response after adjustment for glycemia. Conclusion Although there were relatively few participants with CKD, these results suggest a relationship between CKD and greater CVR. Further investigation is warranted into factors that mediate this relationship and potential clinical consequences of this exaggerated response to stress in CKD. PMID:18025779

  3. Carbon cycling and phytoplankton responses within highly-replicated shipboard carbonate chemistry manipulation experiments conducted around Northwest European Shelf Seas

    Science.gov (United States)

    Richier, S.; Achterberg, E. P.; Dumousseaud, C.; Poulton, A. J.; Suggett, D. J.; Tyrrell, T.; Zubkov, M. V.; Moore, C. M.

    2014-03-01

    The ongoing oceanic uptake of anthropogenic carbon dioxide (CO2) is significantly altering the carbonate chemistry of seawater, a phenomenon referred to as ocean acidification. Experimental manipulations have been increasingly used to gauge how continued ocean acidification will potentially impact marine ecosystems and their associated biogeochemical cycles in the future; however, results amongst studies, particularly when performed on natural communities, are highly variable, which in part likely reflects inconsistencies in experimental approach. To investigate the potential for identification of more generic responses and greater experimentally reproducibility, we devised and implemented a series of highly replicated (n = 8), short term (2-4 days) multi-level (≥ 4 conditions) carbonate chemistry/nutrient manipulation experiments on a range of natural microbial communities sampled in Northwest European shelf seas. Carbonate chemistry manipulations and resulting biological responses were found to be highly reproducible within individual experiments and to a lesser extent between geographically different experiments. Statistically robust reproducible physiological responses of phytoplankton to increasing pCO2, characterized by a suppression of net growth for small sized cells (ocean.

  4. A Novel Mechanism Underlying the Innate Immune Response Induction upon Viral-Dependent Replication of Host Cell mRNA: A Mistake of +sRNA Viruses' Replicases

    Science.gov (United States)

    Delgui, Laura R.; Colombo, María I.

    2017-01-01

    Viruses are lifeless particles designed for setting virus-host interactome assuring a new generation of virions for dissemination. This interactome generates a pressure on host organisms evolving mechanisms to neutralize viral infection, which places the pressure back onto virus, a process known as virus-host cell co-evolution. Positive-single stranded RNA (+sRNA) viruses are an important group of viral agents illustrating this interesting phenomenon. During replication, their genomic +sRNA is employed as template for translation of viral proteins; among them the RNA-dependent RNA polymerase (RdRp) is responsible of viral genome replication originating double-strand RNA molecules (dsRNA) as intermediates, which accumulate representing a potent threat for cellular dsRNA receptors to initiate an antiviral response. A common feature shared by these viruses is their ability to rearrange cellular membranes to serve as platforms for genome replication and assembly of new virions, supporting replication efficiency increase by concentrating critical factors and protecting the viral genome from host anti-viral systems. This review summarizes current knowledge regarding cellular dsRNA receptors and describes prototype viruses developing replication niches inside rearranged membranes. However, for several viral agents it's been observed both, a complex rearrangement of cellular membranes and a strong innate immune antiviral response induction. So, we have included recent data explaining the mechanism by, even though viruses have evolved elegant hideouts, host cells are still able to develop dsRNA receptors-dependent antiviral response. PMID:28164038

  5. TRPV1 Regulates Stress Responses through HDAC2

    Directory of Open Access Journals (Sweden)

    Sung Eun Wang

    2017-04-01

    Full Text Available Stress causes changes in neurotransmission in the brain, thereby influencing stress-induced behaviors. However, it is unclear how neurotransmission systems orchestrate stress responses at the molecular and cellular levels. Transient receptor potential vanilloid 1 (TRPV1, a non-selective cation channel involved mainly in pain sensation, affects mood and neuroplasticity in the brain, where its role is poorly understood. Here, we show that Trpv1-deficient (Trpv1−/− mice are more stress resilient than control mice after chronic unpredictable stress. We also found that glucocorticoid receptor (GR-mediated histone deacetylase 2 (HDAC 2 expression and activity are reduced in the Trpv1−/− mice and that HDAC2-regulated, cell-cycle- and neuroplasticity-related molecules are altered. Hippocampal knockdown of TRPV1 had similar effects, and its behavioral effects were blocked by HDAC2 overexpression. Collectively, our findings indicate that HDAC2 is a molecular link between TRPV1 activity and stress responses.

  6. Physiological responses of genotypes soybean to simulated drought stress

    Directory of Open Access Journals (Sweden)

    Eleonóra Krivosudská

    2016-12-01

    Full Text Available The objective of this research was to investigate possible genetic variation in the sensitivity of soybean cultivars for nitrogen fixation rates in response to soil drying. The work confirmed that the selected physiological characteristics (RWC, osmotic potential, stress index and created nodules on roots are good evaluating parameters for the determination of water stress in plant. In the floricultural year 2014 an experiment with four genetic resources of soybean was launched. Sowing of Maverick (USA, Drina (HRV, Nigra (SVK and Polanka (CZK genotypes was carried out in the containers of 15 l capacity. This stress had a negative impact on the physiological parameters. By comparing the RWC values, the decrease was more significant at the end of dehydration, which was monitored in Maverick and Drina genotypes using the Nitrazon inoculants and water stress effect. Inoculated stressed Nigra and Polanka genotypes have kept higher water content till the end of dehydration period. Also the proline accumulation was monitored during the water stress, whilst higher content of free proline reached of Maverick. More remarkable decrease of osmotic potential was again registered in a foreign Drina and Maverick genotypes in the inoculated variations. Nigra and Polanka genotypes responses not so significant in the given conditions.

  7. Latent Growth Curve Models for Biomarkers of the Stress Response

    Directory of Open Access Journals (Sweden)

    John M. Felt

    2017-06-01

    Full Text Available Objective: The stress response is a dynamic process that can be characterized by predictable biochemical and psychological changes. Biomarkers of the stress response are typically measured over time and require statistical methods that can model change over time. One flexible method of evaluating change over time is the latent growth curve model (LGCM. However, stress researchers seldom use the LGCM when studying biomarkers, despite their benefits. Stress researchers may be unaware of how these methods can be useful. Therefore, the purpose of this paper is to provide an overview of LGCMs in the context of stress research. We specifically highlight the unique benefits of using these approaches.Methods: Hypothetical examples are used to describe four forms of the LGCM.Results: The following four specifications of the LGCM are described: basic LGCM, latent growth mixture model, piecewise LGCM, and LGCM for two parallel processes. The specifications of the LGCM are discussed in the context of the Trier Social Stress Test. Beyond the discussion of the four models, we present issues of modeling nonlinear patterns of change, assessing model fit, and linking specific research questions regarding biomarker research using different statistical models.Conclusions: The final sections of the paper discuss statistical software packages and more advanced modeling capabilities of LGCMs. The online Appendix contains example code with annotation from two statistical programs for the LCGM.

  8. Adult hippocampal neurogenesis buffers stress responses and depressive behaviour.

    Science.gov (United States)

    Snyder, Jason S; Soumier, Amélie; Brewer, Michelle; Pickel, James; Cameron, Heather A

    2011-08-03

    Glucocorticoids are released in response to stressful experiences and serve many beneficial homeostatic functions. However, dysregulation of glucocorticoids is associated with cognitive impairments and depressive illness. In the hippocampus, a brain region densely populated with receptors for stress hormones, stress and glucocorticoids strongly inhibit adult neurogenesis. Decreased neurogenesis has been implicated in the pathogenesis of anxiety and depression, but direct evidence for this role is lacking. Here we show that adult-born hippocampal neurons are required for normal expression of the endocrine and behavioural components of the stress response. Using either transgenic or radiation methods to inhibit adult neurogenesis specifically, we find that glucocorticoid levels are slower to recover after moderate stress and are less suppressed by dexamethasone in neurogenesis-deficient mice than intact mice, consistent with a role for the hippocampus in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Relative to controls, neurogenesis-deficient mice also showed increased food avoidance in a novel environment after acute stress, increased behavioural despair in the forced swim test, and decreased sucrose preference, a measure of anhedonia. These findings identify a small subset of neurons within the dentate gyrus that are critical for hippocampal negative control of the HPA axis and support a direct role for adult neurogenesis in depressive illness.

  9. Reactive oxygen species in response of plants to gravity stress

    Science.gov (United States)

    Jadko, Sergiy

    2016-07-01

    Reactive oxygen species (ROS) as second messengers can induce stress response of plants. Thioredoxins (Trx) and peroxiredoxins (Prx) can function as sensors and transmitters of the ROS in stress signaling and antioxidant response. 12-14 days old tissue culture of Arabidopsis thaliana have been investigated. Hypergravity stress was induced by centrifugation at 10 and 20 g during 30 and 90 min and than intensity of spontaneous chemiluminescence (SChL/ROS content), Trx and Prx activities were determined. All experiments were repeated from 3 to 5 times and the obtained data were statistically treated. In the tissue culture under development of the stress there were an increase in intensity of SChL and Trx and Prx activities. Thus, under hypergravity stress in the plant occurred early increase in the ROS level and the ROS induced the increase in the Trx and Prx activities. Prx and Trx can also participate in the formation of stress respons as acceptors and transducers of the redox signals. Increase in the activity of these enzymes primarily aimed at increasing of the total antioxidant activity in the cells to prevent of the plant to development of oxidative degradation by ROS.

  10. The response to inositol: regulation of glycerolipid metabolism and stress response signaling in yeast.

    Science.gov (United States)

    Henry, Susan A; Gaspar, Maria L; Jesch, Stephen A

    2014-05-01

    This article focuses on discoveries of the mechanisms governing the regulation of glycerolipid metabolism and stress response signaling in response to the phospholipid precursor, inositol. The regulation of glycerolipid lipid metabolism in yeast in response to inositol is highly complex, but increasingly well understood, and the roles of individual lipids in stress response are also increasingly well characterized. Discoveries that have emerged over several decades of genetic, molecular and biochemical analyses of metabolic, regulatory and signaling responses of yeast cells, both mutant and wild type, to the availability of the phospholipid precursor, inositol are discussed.

  11. Understanding Abiotic Stress Tolerance Mechanisms: Recent Studies on Stress Response in Rice

    Institute of Scientific and Technical Information of China (English)

    Ji-Ping Gao; Dai-Yin Chao; Hong-Xuan Lin

    2007-01-01

    Abiotic stress is the main factor negatively affecting crop growth and productivity worldwide. The advances in physiology, genetics, and molecular biology have greatly improved our understanding of plant responses to stresses. Rice plants are sensitive to various abiotic stresses. In this short review, we present recent progresses in adaptation of rice to salinity, water deficit and submergence. Many studies show that salt tolerance is tightly associated with the ability to maintain ion homeostasis under salinity. Na+ transporter SKC1 unloads NaMrom xylem, plasma membrane NaVHTantiporter SOS1 excludes sodium out of cytosol and tonoplast Na+/H+antiporter NHX1 sequesters Na+ into the vacuole. Silicon deposition in exodermis and endodermis of rice root reduces sodium transport through the apoplastic pathway. A number of transcription factors regulate stress-inducible gene expression that leads to initiating stress responses and establishing plant stress tolerance. Overexpression of some transcription factors, including DREB/CBF and MAC, enhances salt, drought, and cold tolerance in rice. A variant of one of ERF family genes, Sub1A-1, confers immersion tolerance to lowland rice. These findings and their exploitation will hold promise for engineering breeding to protect crop plants from certain abiotic stresses.

  12. Neural regulation of the stress response: glucocorticoid feedback mechanisms

    Directory of Open Access Journals (Sweden)

    J.P. Herman

    2012-04-01

    Full Text Available The mammalian stress response is an integrated physiological and psychological reaction to real or perceived adversity. Glucocorticoids are an important component of this response, acting to redistribute energy resources to both optimize survival in the face of challenge and to restore homeostasis after the immediate challenge has subsided. Release of glucocorticoids is mediated by the hypothalamo-pituitary-adrenal (HPA axis, driven by a neural signal originating in the paraventricular nucleus (PVN. Stress levels of glucocorticoids bind to glucocorticoid receptors in multiple body compartments, including the brain, and consequently have wide-reaching actions. For this reason, glucocorticoids serve a vital function in negative feedback inhibition of their own secretion. Negative feedback inhibition is mediated by a diverse collection of mechanisms, including fast, non-genomic feedback at the level of the PVN, stress-shut-off at the level of the limbic system, and attenuation of ascending excitatory input through destabilization of mRNAs encoding neuropeptide drivers of the HPA axis. In addition, there is evidence that glucocorticoids participate in stress activation via feed-forward mechanisms at the level of the amygdala. Feedback deficits are associated with numerous disease states, underscoring the necessity for adequate control of glucocorticoid homeostasis. Thus, rather than having a single, defined feedback ‘switch’, control of the stress response requires a wide-reaching feedback ‘network’ that coordinates HPA activity to suit the overall needs of multiple body systems.

  13. Proteomic Analysis of Tomato Seedlings Response to Salt Stress

    Institute of Scientific and Technical Information of China (English)

    Xue Zhao; Feng Han; Shihua Shen

    2012-01-01

    The two species (Solanum pimpinellifolium-PI and S.lycopersicum-MM) of tomato showed marked differences in their responses to NaCI stress.PI appeared to be more tolerant to salt than MM.Comparative two-dimensional electrophoresis revealed that 187 and 110 protein spots were differentially expressed in the roots of PI and MM,respectively,in response to salt stress.Out of these spots,a total of 96 and 61 proteins were identified by MALDI-TOF MS analysis.The proteins identified included many previously characterized stress-responsive proteins and others related to processes including scavenging for reactive species; metabolism of energy,signal transduction; protein synthesis,cell growth and differentiation et al.The role of some of the proteins involved in the antioxidant defense mechanism,ion transport and compartmentalization of ions,and cell signaling pathways were discussed.Collectively,this work suggest that PI has more efficient antioxidant and defense machinery than MM,and that this is important for adapting to salt stress and for withstanding the oxidative stress imposed by high salt levels.

  14. Silver nanoparticles induce endoplasmatic reticulum stress response in zebrafish

    Energy Technology Data Exchange (ETDEWEB)

    Christen, Verena [University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences, Gründenstrasse 40, CH-4132 Muttenz (Switzerland); Capelle, Martinus [Crucell, P.O. Box 2048, NL-2301 Leiden (Netherlands); Fent, Karl, E-mail: karl.fent@fhnw.ch [University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences, Gründenstrasse 40, CH-4132 Muttenz (Switzerland); Swiss Federal Institute of Technology Zürich, Department of Environmental Systems Science, CH-8092 Zürich (Switzerland)

    2013-10-15

    Silver nanoparticles (AgNPs) find increasing applications, and therefore humans and the environment are increasingly exposed to them. However, potential toxicological implications are not sufficiently known. Here we investigate effects of AgNPs (average size 120 nm) on zebrafish in vitro and in vivo, and compare them to human hepatoma cells (Huh7). AgNPs are incorporated in zebrafish liver cells (ZFL) and Huh7, and in zebrafish embryos. In ZFL cells AgNPs lead to induction of reactive oxygen species (ROS), endoplasmatic reticulum (ER) stress response, and TNF-α. Transcriptional alterations also occur in pro-apoptotic genes p53 and Bax. The transcriptional profile differed in ZFL and Huh7 cells. In ZFL cells, the ER stress marker BiP is induced, concomitant with the ER stress marker ATF-6 and spliced XBP-1 after 6 h and 24 h exposure to 0.5 g/L and 0.05 g/L AgNPs, respectively. This indicates the induction of different pathways of the ER stress response. Moreover, AgNPs induce TNF-α. In zebrafish embryos exposed to 0.01, 0.1, 1 and 5 mg/L AgNPs hatching was affected and morphological defects occurred at high concentrations. ER stress related gene transcripts BiP and Synv are significantly up-regulated after 24 h at 0.1 and 5 mg/L AgNPs. Furthermore, transcriptional alterations occurred in the pro-apoptotic genes Noxa and p21. The ER stress response was strong in ZFL cells and occurred in zebrafish embryos as well. Our data demonstrate for the first time that AgNPs lead to induction of ER stress in zebrafish. The induction of ER stress can have several consequences including the activation of apoptotic and inflammatory pathways. - Highlights: • Effects of silver nanoparticles (120 nm AgNPs) are investigated in zebrafish. • AgNPs induce all ER stress reponses in vitro in zebrafish liver cells. • AgNPs induce weak ER stress in zebrafish embryos. • AgNPs induce oxidative stress and transcripts of pro-apoptosis genes.

  15. Erythropoietin Action in Stress Response, Tissue Maintenance and Metabolism

    Directory of Open Access Journals (Sweden)

    Yuanyuan Zhang

    2014-06-01

    Full Text Available Erythropoietin (EPO regulation of red blood cell production and its induction at reduced oxygen tension provides for the important erythropoietic response to ischemic stress. The cloning and production of recombinant human EPO has led to its clinical use in patients with anemia for two and half decades and has facilitated studies of EPO action. Reports of animal and cell models of ischemic stress in vitro and injury suggest potential EPO benefit beyond red blood cell production including vascular endothelial response to increase nitric oxide production, which facilitates oxygen delivery to brain, heart and other non-hematopoietic tissues. This review discusses these and other reports of EPO action beyond red blood cell production, including EPO response affecting metabolism and obesity in animal models. Observations of EPO activity in cell and animal model systems, including mice with tissue specific deletion of EPO receptor (EpoR, suggest the potential for EPO response in metabolism and disease.

  16. Glucocorticoids and the Brain: Neural Mechanisms Regulating the Stress Response.

    Science.gov (United States)

    Shirazi, Shawn N; Friedman, Aaron R; Kaufer, Daniela; Sakhai, Samuel A

    2015-01-01

    In this chapter, we describe the central role of the brain in the glucocorticoid mediated stress response. We describe the mechanisms by which the brain gauges the severity of stress, mechanisms of hypothalamic-pituitary-adrenal axis (HPA) regulation, and how various sub-systems of the brain respond to glucocorticoid (GC) signaling to regulate stress behavior. In particular, we focus on the hippocampus, pre-frontal cortex, and amygdala, where GCs can induce a series of changes. Finally, we briefly discuss an apparent paradox in GC signaling: while exposure to glucocorticoids promotes the survival of an organism during acute stress, these same hormones in chronic excess can also cause damage and promote illness.

  17. Response and energy dissipation of rock under stochastic stress waves

    Institute of Scientific and Technical Information of China (English)

    DENG Jian; BIAN Li

    2007-01-01

    The response and energy dissipation of rock under stochastic stress waves were analyzed based on dynamic fracture criterion of brittle materials integrating with Fourier transform methods of spectral analysis When the stochastic stress waves transnut through rocks,the frequency and energy ratio of harmonic components were calculated by analytical and discrete analysis methods.The stress waves in shale, malmstone and liparite were taken as examples to illustrate the proposed analysis methods.The results show the harder the rock, the less absorption of energy,the more the useless elastic waves transmitting through rock, and the narrower the cutoff frequency to fracture rock.When the whole stress energy doubles either by doubling the duration time or byincreasing the amplitude of stress wave, ratio of the energy of elastic waves transmitting through rock to me whole stress energy (i.e.energy dissipation ratio)is decreased to 10%-15%. When doubling the duration time.the cutoff frequency to fracture rock remains constant.However, with the increase of the amplitude of stress wave. the cutoff frequency increases accordingly.

  18. REM SLEEP REBOUND AS AN ADAPTIVE RESPONSE TO STRESSFUL SITUATIONS

    Directory of Open Access Journals (Sweden)

    Deborah eSuchecki

    2012-04-01

    Full Text Available Stress and sleep are related to each other in a bidirectional way. If on one hand poor or inadequate sleep exacerbates emotional, behavioral and stress-related responses, on the other hand acute stress induces sleep rebound, most likely as a form to cope with the adverse stimuli. Chronic stress, conversely, has been claimed to be one of the triggering factors of emotional-related sleep disorders, such as insomnia, depressive- and anxiety-disorders. These outcomes are dependent on individual psychobiological characteristics, which confer more complexity to the stress-sleep relationship. Its neurobiology has only recently begun to be explored, through animal models, which are also valuable for the development of potential therapeutic agents and preventive actions. This review seeks to present data on the effects of stress on sleep and the different approaches used to study this relationship as well as possible neurobiological underpinnings and mechanisms involved. The results of numerous studies in humans and animals indicate that increased sleep, especially the REM phase, following a stressful situation is an important adaptive behavior for recovery. However, this endogenous advantage appears to be impaired in human beings and rodent strains that exhibit high levels of anxiety and anxiety-like behavior.

  19. Morphological and Physiological Responses of Strawberry Plants to Water Stress

    OpenAIRE

    Krzysztof Klamkowski; Waldemar Treder

    2006-01-01

    The most of previous studies have been focused on the effect of water stress on plant yielding. However, the conditions in which plants grow from the moment of planting might affect their morphology and physiological response. The aim of this study was to examine the effect of water deficiency on growth and plant physiological response of strawberry (Fragaria x ananassa Duch. cv. ‘Salut’) under greenhouse conditions. The plants were grown in plastic containers filled with peat substratum. Wat...

  20. Husbandry of zebrafish, Danio rerio, and the cortisol stress response.

    Science.gov (United States)

    Pavlidis, Michail; Digka, Nikoletta; Theodoridi, Antonia; Campo, Aurora; Barsakis, Konstantinos; Skouradakis, Gregoris; Samaras, Athanasios; Tsalafouta, Alexandra

    2013-12-01

    The effect of common husbandry conditions (crowding, social environment, water quality, handling, and background color) on the cortisol stress response in adult zebrafish, Danio rerio, was investigated to check the usefulness of zebrafish as a model organism in aquaculture research. In addition, a noninvasive methodology for assessing stress was evaluated. Zebrafish showed a fast cortisol response with high values at 30 min that returned to basal levels within 2 h of poststress. There was a significant positive correlation between trunk cortisol concentrations and the free water cortisol rate (r(2)=0.829-0.850, pzebrafish. It is concluded that adult laboratory zebrafish had a preference for a transparent or black background aquarium, at a number of 10 individuals per 2 L of available water volume, to express their normal behavior and avoid increased cortisol stress reaction.

  1. Enterovirus Control of Translation and RNA Granule Stress Responses

    Directory of Open Access Journals (Sweden)

    Richard E. Lloyd

    2016-03-01

    Full Text Available Enteroviruses such as poliovirus (PV and coxsackievirus B3 (CVB3 have evolved several parallel strategies to regulate cellular gene expression and stress responses to ensure efficient expression of the viral genome. Enteroviruses utilize their encoded proteinases to take over the cellular translation apparatus and direct ribosomes to viral mRNAs. In addition, viral proteinases are used to control and repress the two main types of cytoplasmic RNA granules, stress granules (SGs and processing bodies (P-bodies, PBs, which are stress-responsive dynamic structures involved in repression of gene expression. This review discusses these processes and the current understanding of the underlying mechanisms with respect to enterovirus infections. In addition, the review discusses accumulating data suggesting linkage exists between RNA granule formation and innate immune sensing and activation.

  2. Enterovirus Control of Translation and RNA Granule Stress Responses

    Science.gov (United States)

    Lloyd, Richard E.

    2016-01-01

    Enteroviruses such as poliovirus (PV) and coxsackievirus B3 (CVB3) have evolved several parallel strategies to regulate cellular gene expression and stress responses to ensure efficient expression of the viral genome. Enteroviruses utilize their encoded proteinases to take over the cellular translation apparatus and direct ribosomes to viral mRNAs. In addition, viral proteinases are used to control and repress the two main types of cytoplasmic RNA granules, stress granules (SGs) and processing bodies (P-bodies, PBs), which are stress-responsive dynamic structures involved in repression of gene expression. This review discusses these processes and the current understanding of the underlying mechanisms with respect to enterovirus infections. In addition, the review discusses accumulating data suggesting linkage exists between RNA granule formation and innate immune sensing and activation. PMID:27043612

  3. THE PHYSIOLOGICAL RESPONSE OF SOYBEAN CULTIVARS TO ABIOTIC STRESS

    Directory of Open Access Journals (Sweden)

    Marija Špoljarević

    2016-06-01

    Full Text Available Drought, temperature and salt stress are the most prominent among different types of abiotic stress in soybean production. This PhD dissertation aimed to investigate the physiological mechanisms of soybean response to the above mentioned stresses. The research was performed with 6 cultivars in the germination - emergence stage and two cultivars in the flowering stage. In the first experiment, soybean seed was germinated in paper towels soaked in water or the solution with given osmotic pressure. Two levels of drought (5% and 10% PEG solutions, salt (50 and 100 mM NaCl solutions and temperature stress (10°C and 30°C, as well as a control treatment (20°C, water were applied through a 7 day germination period. Seed germinability (% and morphological traits were analysed, as well as enzymatic and non-enzymatic parameters in hypocotyls. The most effective were higher level of drought stress and low temperature. High temperature stimulated seedling development and mild drought stress had a priming effect and increased germination rate. In the second experiment, two cultivars were grown in pots filled with soil and kept in the open until flowering, and afterwards exposed to different temperature degrees (30°C, 10°C and 20°C as control during 3 days in a climate chamber. The photosynthesis efficiency parameters and, like in first experiment, physiological indicators of plant stress response were determined in the leaf tissue. Highly significant treatment influence on the analysed parameters in the both growth stages, confirms that the applied treatments invoked the oxidative stress and defence reactions in soybean.

  4. The insect capa neuropeptides impact desiccation and cold stress responses

    Science.gov (United States)

    Background: Insects are so successful because of great resistance to environmental stress, yet little is known about how such responses may be mediated by the neuroendocrine system. Results: We provide evidence that the capability (capa) neuropeptide gene and peptide are critical mediators of desic...

  5. Phosphate-dependent root system architecture responses to salt stress

    NARCIS (Netherlands)

    Kawa, D.; Julkowska, M.M.; Montero Sommerfeld, H.; ter Horst, A.; Haring, M.A.; Testerink, C.

    2016-01-01

    Nutrient availability and salinity of the soil affect growth and development of plant roots. Here, we describe how phosphate availability affects root system architecture (RSA) of Arabidopsis and how phosphate levels modulate responses of the root to salt stress. Phosphate (Pi) starvation reduced ma

  6. Phospholipid signaling responses in salt-stressed rice leaves

    NARCIS (Netherlands)

    Darwish, E.; Testerink, C.; Khalil, M.; El-Shihy, O.; Munnik, T.

    2009-01-01

    Salinity is one of the major environmental factors limiting growth and productivity of rice plants. In this study, the effect of salt stress on phospholipid signaling responses in rice leaves was investigated. Leaf cuts were radiolabeled with 32 P-orthophosphate and the lipids extracted and analyzed

  7. Adaptive Patterns of Stress Responsivity: A Preliminary Investigation

    Science.gov (United States)

    Del Giudice, Marco; Hinnant, J. Benjamin; Ellis, Bruce J.; El-Sheikh, Mona

    2012-01-01

    The adaptive calibration model (ACM) is an evolutionary-developmental theory of individual differences in stress responsivity. In this article, we tested some key predictions of the ACM in a middle childhood sample (N = 256). Measures of autonomic nervous system activity across the sympathetic and parasympathetic branches validated the 4-pattern…

  8. Stress response signaling and virulence: insights from entomopathogenic fungi.

    Science.gov (United States)

    Ortiz-Urquiza, Almudena; Keyhani, Nemat O

    2015-08-01

    The Ascomycete fungal insect pathogens, Beauveria and Metarhizium spp. have emerged as model systems with which to probe diverse aspects of fungal growth, stress response, and pathogenesis. Due to the availability of genomic resources and the development of robust methods for genetic manipulation, the last 5 years have witnessed a rapid increase in the molecular characterization of genes and their pathways involved in stress response and signal transduction in these fungi. These studies have been performed mainly via characterization of gene deletion/knockout mutants and have included the targeting of general proteins involved in stress response and/or virulence, e.g. catalases, superoxide dismutases, and osmolyte balance maintenance enzymes, membrane proteins and signaling pathways including GPI anchored proteins and G-protein coupled membrane receptors, MAPK pathways, e.g. (i) the pheromone/nutrient sensing, Fus3/Kss1, (ii) the cell wall integrity, Mpk1, and (iii) the high osmolarity, Hog1, the PKA/adenyl cyclase pathway, and various downstream transcription factors, e.g. Msn2, CreA and Pac1. Here, we will discuss current research that strongly suggests extensive underlying contributions of these biochemical and signaling pathways to both abiotic stress response and virulence.

  9. Genetic mapping of abiotic stress responses in sorghum

    Science.gov (United States)

    Due to rich genetic diversity for tolerance to various abiotic stress conditions, sorghum is an ideal system for genetic mapping and elucidation of genome regions that confer such response among cereal crops. Coupled with the development of DNA marker technologies and most recently the sequencing o...

  10. Regulation of Replication Recovery and Genome Integrity

    DEFF Research Database (Denmark)

    Colding, Camilla Skettrup

    facilitate replication recovery after MMS-induced replication stress. Our data reveal that control of Mrc1 turnover through the interplay between posttranslational modifications and INQ localization adds another layer of regulation to the replication checkpoint. We also add replication recovery to the list...... is mediated by Mrc1, which ensures Mec1 presence at the stalled replication fork thus facilitating Rad53 phosphorylation. When replication can be resumed safely, the replication checkpoint is deactivated and replication forks restart. One mechanism for checkpoint deactivation is the ubiquitin......-targeted proteasomal degradation of Mrc1. In this study, we describe a novel nuclear structure, the intranuclear quality control compartment (INQ), which regulates protein turnover and is important for recovery after replication stress. We find that upon methyl methanesulfonate (MMS)-induced replication stress, INQ...

  11. Interaction between Nitrogen and Phosphate Stress Responses in Sinorhizobium meliloti

    Directory of Open Access Journals (Sweden)

    Kelly Lynn Hagberg

    2016-11-01

    Full Text Available Bacteria have developed various stress response pathways to improve their assimilation and allocation of limited nutrients, such as nitrogen and phosphate. While both the Nitrogen Stress Response (NSR and Phosphate Stress Response (PSR have been studied individually, there are few experiments reported that characterize effects of multiple stresses on one or more pathways in Sinorhizobium meliloti, a facultatively symbiotic, nitrogen-fixing bacteria. The PII proteins, GlnB and GlnK, regulate the NSR activity, but analysis of global transcription changes in a PII deficient mutant suggest that the S. meliloti PII proteins may also regulate the PSR. PII double deletion mutants grow very slowly and pseudoreversion of the slow growth phenotype is common. To understand this phenomenon better, transposon mutants were isolated that had a faster growing phenotype. One mutation was in phoB, the response regulator for a two component regulatory system that is important in the PSR. phoB::Tn5 mutants had different phenotypes in the wild type compared to a PII deficient background. This led to the hypothesis that phosphate stress affects the NSR and conversely, that nitrogen stress affects the PSR. Our results show that phosphate availability affects glutamine synthetase activity and expression, which are often used as indicators of NSR activity, but that nitrogen availability did not affect alkaline phosphatase activity and expression, which are indicators of PSR activity. We conclude that the NSR is co-regulated by nitrogen and phosphate, whereas the PSR does not appear to be co-regulated by nitrogen in addition to its known phosphate regulation.

  12. Interaction between Nitrogen and Phosphate Stress Responses in Sinorhizobium meliloti

    Science.gov (United States)

    Hagberg, Kelly L.; Yurgel, Svetlana N.; Mulder, Monika; Kahn, Michael L.

    2016-01-01

    Bacteria have developed various stress response pathways to improve their assimilation and allocation of limited nutrients, such as nitrogen and phosphate. While both the nitrogen stress response (NSR) and phosphate stress response (PSR) have been studied individually, there are few experiments reported that characterize effects of multiple stresses on one or more pathways in Sinorhizobium meliloti, a facultatively symbiotic, nitrogen-fixing bacteria. The PII proteins, GlnB and GlnK, regulate the NSR activity, but analysis of global transcription changes in a PII deficient mutant suggest that the S. meliloti PII proteins may also regulate the PSR. PII double deletion mutants grow very slowly and pseudoreversion of the slow growth phenotype is common. To understand this phenomenon better, transposon mutants were isolated that had a faster growing phenotype. One mutation was in phoB, the response regulator for a two component regulatory system that is important in the PSR. phoB::Tn5 mutants had different phenotypes in the wild type compared to a PII deficient background. This led to the hypothesis that phosphate stress affects the NSR and conversely, that nitrogen stress affects the PSR. Our results show that phosphate availability affects glutamine synthetase activity and expression, which are often used as indicators of NSR activity, but that nitrogen availability did not affect alkaline phosphatase activity and expression, which are indicators of PSR activity. We conclude that the NSR is co-regulated by nitrogen and phosphate, whereas the PSR does not appear to be co-regulated by nitrogen in addition to its known phosphate regulation. PMID:27965651

  13. Transactional Associations between Youths' Responses to Peer Stress and Depression: The Moderating Roles of Sex and Stress Exposure

    Science.gov (United States)

    Agoston, Anna M.; Rudolph, Karen D.

    2011-01-01

    This study examined transactional associations between responses to peer stress and depression in youth. Specifically, it tested the hypotheses that (a) depression would predict fewer effortful responses and more involuntary, dysregulated responses to peer stress over time; and (b) fewer adaptive and more maladaptive responses would predict…

  14. Response of restraint stress-selected lines of Japanese quail to heat stress and Escherichia coli challenge

    Science.gov (United States)

    Japanese quail selected for divergent corticosterone (Cort) response to restraint stress were evaluated for their susceptibility to heat stress and challenge with Escherichia coli. These quail lines are designated as the high stress (HS), low stress (LS), and the random-bred control (CS) lines. Hea...

  15. Understanding the Posttranscriptional Regulation of Plant Responses to Abiotic Stress

    KAUST Repository

    AlShareef, Sahar A.

    2017-06-01

    Constitutive and alternative splicing of pre-mRNAs from multiexonic genes controls the diversity of the proteome; these precisely regulated processes also fine-tune responses to cues related to growth, development, and biotic and abiotic stresses. Recent work showed that AS is pervasive across plant species, with more than 60% of intron-containing genes producing different isoforms. Mammalian cell-based assays have discovered various AS small-molecule inhibitors that perturb splicing and thereby provide invaluable tools for use as chemical probes to uncover the molecular underpinnings of splicing regulation and as potential anticancer compounds. Here, I show that the macrolide Pladienolide B (PB) and herboxidiene (GEX1A) inhibits both constitutive and alternative splicing, mimics an abiotic stress signal, and activates the abscisic acid (ABA) pathway in plants. Moreover, PB and GEX1A activate genome-wide transcriptional patterns involved in abiotic stress responses in plants. PB and GEX1A treatment triggered the ABA signaling pathway, activated ABA-inducible promoters, and led to stomatal closure. Interestingly, PB and GEX1A elicited similar cellular changes, including alterations in the patterns of transcription and splicing, suggesting that these compounds might target the same spliceosome complex in plant cells. This work establishes PB and GEX1A as potent splicing inhibitors in plants that can be used to probe the assembly, dynamics, and molecular functions of the spliceosome and to study the interplay between splicing stress and abiotic stresses, as well as having potential biotechnological applications.

  16. Transcriptional regulation of the stress response by mTOR.

    Science.gov (United States)

    Aramburu, Jose; Ortells, M Carmen; Tejedor, Sonia; Buxadé, Maria; López-Rodríguez, Cristina

    2014-07-01

    The kinase mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation that integrates inputs from growth factor receptors, nutrient availability, intracellular ATP (adenosine 5'-triphosphate), and a variety of stressors. Since early works in the mid-1990s uncovered the role of mTOR in stimulating protein translation, this kinase has emerged as a rather multifaceted regulator of numerous processes. Whereas mTOR is generally activated by growth- and proliferation-stimulating signals, its activity can be reduced and even suppressed when cells are exposed to a variety of stress conditions. However, cells can also adapt to stress while maintaining their growth capacity and mTOR function. Despite knowledge accumulated on how stress represses mTOR, less is known about mTOR influencing stress responses. In this review, we discuss the capability of mTOR, in particular mTOR complex 1 (mTORC1), to activate stress-responsive transcription factors, and we outline open questions for future investigation.

  17. Alternative Strategy for Alzheimer’s Disease: Stress Response Triggers

    Directory of Open Access Journals (Sweden)

    Joan Smith Sonneborn

    2012-01-01

    Full Text Available Stress resistance capacity is a hallmark of longevity protection and survival throughout the plant and animal kingdoms. Latent pathway activation of protective cascades, triggered by environmental challenges to tolerate heat, oxygen deprivation, reactive oxygen species (ROS, diet restriction, and exercise provides tolerance to these stresses. Age-related changes and disease vulnerability mark an increase in damage, like damage induced by environmental challenges. An alternative approach to immunotherapy intervention in Alzheimer’s Disease is the use of mimetics of stress to upregulate endogenous protective cascades to repair age damage, shift the balance of apoptosis to regeneration to promote delay of onset, and even progression of Alzheimer’s disease memory dysfunction. Mimetics of environmental stress, hormetic agents, and triggers, endogenous or engineered, can “trick” activation of expression patterns of repair and rejuvenation. Examples of known candidate triggers of heat response, endogenous antioxidants, DNA repair, exercise, hibernation, and telomeres are available for AD intervention trials. Telomeres and telomerase emerge as major regulators in crossroads of senescence, cancer, and rejuvenation responsive to mimetics of telomeres. Lessons emerge from transgenic rodent models, the long-lived mole rat, clinical studies, and conserved innate pathways of stress resistance. Cross-reaction of benefits of different triggers promises intervention into seemingly otherwise unrelated diseases.

  18. Ethanol-induced stress response of Staphylococcus aureus.

    Science.gov (United States)

    Pando, Jasmine M; Pfeltz, Richard F; Cuaron, Jesus A; Nagarajan, Vijayaraj; Mishra, Mukti N; Torres, Nathanial J; Elasri, Mohamed O; Wilkinson, Brian J; Gustafson, John E

    2017-09-01

    Transcriptional profiles of 2 unrelated clinical methicillin-resistant Staphylococcus aureus (MRSA) isolates were analyzed following 10% (v/v) ethanol challenge (15 min), which arrested growth but did not reduce viability. Ethanol-induced stress (EIS) resulted in differential gene expression of 1091 genes, 600 common to both strains, of which 291 were upregulated. With the exception of the downregulation of genes involved with osmotic stress functions, EIS resulted in the upregulation of genes that contribute to stress response networks, notably those altered by oxidative stress, protein quality control in general, and heat shock in particular. In addition, genes involved with transcription, translation, and nucleotide biosynthesis were downregulated. relP, which encodes a small alarmone synthetase (RelP), was highly upregulated in both MRSA strains following ethanol challenge, and relP inactivation experiments indicated that this gene contributed to EIS growth arrest. A number of persistence-associated genes were also upregulated during EIS, including those that encode toxin-antitoxin systems. Overall, transcriptional profiling indicated that the MRSA investigated responded to EIS by entering a state of dormancy and by altering the expression of elements from cross protective stress response systems in an effort to protect preexisting proteins.

  19. Assessing the Neuroendocrine Stress Response in the Functional Neuroimaging Context

    Science.gov (United States)

    King, Anthony P.; Liberzon, Israel

    2009-01-01

    Neural regulation of stress responses, and the feedback of stress hormones to the brain, reflect complex brain-body interactions that may underlie the effects of psychological stress on health. Elucidating the brain circuitry involved in the cortical control of limbic-hypothalamic-pituitary-adrenal axis, and the cortical “targets” of cortisol that in turn modulates brain function, requires careful assessment of glucocorticoid hormones, in the context of the neuroimaging paradigms. Here we discuss approaches for assessment of endocrine function in the context of neuroimaging, including methods of blood and saliva specimen collection, and methods for drug/hormone administration. We also briefly discuss important temporal considerations, including appropriate timing of sample collections for hormones with different time-courses of activation (e.g. ACTH vs. cortisol), the pharmacokinetics of both endogenous hormones and administered agents, and circadian considerations. These are crucial to experimental designs of rhythmic hormonal systems and multiple feedback loops. We briefly address psychological/behavioral ‘activation’ paradigms used for inducing endogenous LHPA axis responses within or in proximity to scanner, as well as strategies for administration of exogenous hormones or secretagogues. Finally, we discuss some of the analyses issues in terms of hormone responses (e.g. response and area under curve, diurnal variability) and strategies for linking measured levels of peripheral humoral factor to brain activity (e.g. hormone responses as between subject regressors of BOLD activations, hormone levels as within subject regressors in analyses of covariance of brain activity over time, etc.). PMID:19481160

  20. Cortisol response to social stress in parentally bereaved youth.

    Science.gov (United States)

    Dietz, Laura J; Stoyak, Samuel; Melhem, Nadine; Porta, Giovanna; Matthews, Karen A; Walker Payne, Monica; Brent, David A

    2013-02-15

    Parental bereavement is associated with increased risk for psychiatric illness and functional impairment in youth. Dysregulated hypothalamic-pituitary-adrenal (HPA) axis functioning may be one pathway through which bereaved children experience increased risk for poor outcomes. However, few studies have prospectively examined the association between parental bereavement and cortisol response while accounting for psychiatric disorders in both youth and their caregivers. One-hundred and eighty-one bereaved and nonbereaved offspring and their caregivers were assessed at multiple time points over a 5-year period after parental death. Offspring participated in an adaptation of the Trier Social Stress Task (TSST), and salivary cortisol samples were collected before and after exposure to social stressors. Mixed models for repeated measures were used to analyze the effects of bereavement status, psychiatric disorder in both offspring and caregiver, and demographic indices on trajectories of cortisol response. After controlling for demographic variables and offspring depression, bereaved offspring demonstrated significantly different trajectories of cortisol response compared with nonbereaved offspring, characterized by higher total cortisol output and an absence of cortisol reactivity to acute social stress. Within the bereaved group, offspring of parents who died by sudden natural death demonstrated significant cortisol reactivity to social stress compared with offspring whose parents died by suicide, who demonstrated more blunted trajectory of cortisol response. Parentally bereaved youth demonstrate higher cortisol output than nonbereaved youth but are less able to mount an acute response in the face of social stressors. Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  1. Gene Networks in Plant Ozone Stress Response and Tolerance

    Institute of Scientific and Technical Information of China (English)

    Agnieszka Ludwikow; Jan Sadowski

    2008-01-01

    For many plant species ozone stress has become much more severe in the last decade. The accumulating evidence for the significant effects of ozone pollutant on crop and forest yield situate ozone as one of the most important environmental stress factors that limits plant productivity woddwide. Today, transcdptomic approaches seem to give the best coverage of genome level responses. Therefore, microarray serves as an invaluable tool for global gene expression analyses, unravelling new information about gene pathways, in-species and crose-species gene expression comparison, and for the characterization of unknown relationships between genes. In this review we summadze the recent progress in the transcdptomics of ozone to demonstrate the benefits that can be harvested from the application of integrative and systematic analytical approaches to study ozone stress response. We focused our consideration on microarray analyses identifying gene networks responsible for response and tolerance to elevated ozone concentration. From these analyses it is now possible to notice how plant ozone defense responses depend on the interplay between many complex signaling pathways and metabolite signals.

  2. Transgenerational stress memory is not a general response in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Ales Pecinka

    Full Text Available Adverse conditions can trigger DNA damage as well as DNA repair responses in plants. A variety of stress factors are known to stimulate homologous recombination, the most accurate repair pathway, by increasing the concentration of necessary enzymatic components and the frequency of events. This effect has been reported to last into subsequent generations not exposed to the stress. To establish a basis for a genetic analysis of this transgenerational stress memory, a broad range of treatments was tested for quantitative effects on homologous recombination in the progeny. Several Arabidopsis lines, transgenic for well-established recombination traps, were exposed to 10 different physical and chemical stress treatments, and scored for the number of somatic homologous recombination (SHR events in the treated generation as well as in the two subsequent generations that were not treated. These numbers were related to the expression level of genes involved in homologous recombination and repair. SHR was enhanced after the majority of treatments, confirming previous data and adding new effective stress types, especially interference with chromatin. Compounds that directly modify DNA stimulated SHR to values exceeding previously described induction rates, concomitant with an induction of genes involved in SHR. In spite of the significant stimulation in the stressed generations, the two subsequent non-treated generations only showed a low and stochastic increase in SHR that did not correlate with the degree of stimulation in the parental plants. Transcripts coding for SHR enzymes generally returned to pre-treatment levels in the progeny. Thus, transgenerational effects on SHR frequency are not a general response to abiotic stress in Arabidopsis and may require special conditions.

  3. Hostility, sodium consumption, and cardiovascular response to interpersonal stress.

    Science.gov (United States)

    Miller, S B; Friese, M; Dolgoy, L; Sita, A; Lavoie, K; Campbell, T

    1998-01-01

    Previous studies have reported poorer health behaviors in high vs. low hostile subjects. The role of stress in these observed differences has not been explored although interpersonal stress does increase cardiovascular response in high hostiles. Given evidence that stress may induce increased salt-intake, this study examined the role of hostility and interpersonal stress in increasing sodium consumption in addition to cardiovascular reactivity. Sixty-nine male undergraduates were categorized into high (HiHo) and low hostile (LoHo) groups based on Buss-Durkee Hostility Inventory scores. Subjects engaged in either a math task with harassment, math task without harassment, or a control/rest condition. Sodium intake was assessed posttask by having subjects ingest a sodium-free soup that was presented with a saltshaker without any comments. Cardiovascular measures were also recorded. HiHo subjects consumed more salt than LoHo subjects irrespective of experimental condition. HiHo subjects who were harassed also exhibited greater cardiac output, systolic blood pressure, and forearm blood flow than did HiHo nonharassed, HiHo control, or LoHo subjects. HiHo subjects exhibited increased salt-intake, although evidence for stress-induced salt-intake was not obtained. Nonetheless, the combination of salt and stress may contribute to the cardiovascular hyperreactivity and risk for cardiovascular disease in hostile individuals.

  4. Responses of Yeast Biocontrol Agents to Environmental Stress

    Science.gov (United States)

    Sui, Yuan; Wisniewski, Michael; Droby, Samir

    2015-01-01

    Biological control of postharvest diseases, utilizing wild species and strains of antagonistic yeast species, is a research topic that has received considerable attention in the literature over the past 30 years. In principle, it represents a promising alternative to chemical fungicides for the management of postharvest decay of fruits, vegetables, and grains. A yeast-based biocontrol system is composed of a tritrophic interaction between a host (commodity), a pathogen, and a yeast species, all of which are affected by environmental factors such as temperature, pH, and UV light as well as osmotic and oxidative stresses. Additionally, during the production process, biocontrol agents encounter various severe abiotic stresses that also impact their viability. Therefore, understanding the ecological fitness of the potential yeast biocontrol agents and developing strategies to enhance their stress tolerance are essential to their efficacy and commercial application. The current review provides an overview of the responses of antagonistic yeast species to various environmental stresses, the methods that can be used to improve stress tolerance and efficacy, and the related mechanisms associated with improved stress tolerance. PMID:25710368

  5. Oxidative stress response of Deinococcus geothermalis via a cystine importer.

    Science.gov (United States)

    Kim, Minwook; Jeong, Sunwook; Lim, Sangyong; Sim, Jeonggu; Rhie, Ho-Gun; Lee, Sung-Jae

    2017-02-01

    A cystine-dependent anti-oxidative stress response is characterized in Deinococcus geothermalis for the first time. Nevertheless, the same transcriptional directed Δdgeo_1985F mutant strain was revealed to have an identical phenotype to the wild-type strain, while the reverse transcriptional directed Δdgeo_1985R mutant strain was more resistant to oxidative stress at a certain concentration of H2O2 than the wild-type strain. The wild-type and mutant strains expressed equal levels of superoxide dismutase and catalase under H2O2-induced stress. Although the expression levels of the general DNA-damage response-related genes recA, pprA, ddrA, and ddrB were up-regulated by more than five-fold in the wild-type strain relative to the Δdgeo_1985R mutant strain, the mutant strain had a higher survival rate than the wild-type under H2O2 stress. The Δdgeo_1985R mutant strain highly expressed a cystine-transporter gene (dgeo_1986), at levels 150-fold higher than the wild-type strain, leading to the conclusion that this cystine transporter might be involved in the defensive response to H2O2 stress. In this study, the cystine transporter was identified and characterized through membrane protein expression analysis, a cystine-binding assay, and assays of intracellular H2O2, cysteine, and thiol levels. The genedisrupted mutant strain of the cystine importer revealed high sensitivity to H2O2 and less absorbed cystine, resulting in low concentrations of total thiol. Thus, the absorbed cystine via this cystine-specific importer may be converted into cysteine, which acts as a primitive defense substrate that non-enzymatically scavenges oxidative stress agents in D. geothermalis.

  6. Molecular Responses of Groundnut (Arachis hypogea L. to Zinc Stress

    Directory of Open Access Journals (Sweden)

    A. John De Britto

    2013-08-01

    Full Text Available Heavy metals are important environmental pollutants and their toxicity is a problem of increasing significance for ecological, evolutionary and environmental reasons. The interference of germination related proteins by heavy metals has not been well documented at the proteomic and genomic level. In the current study, molecular responses of germinating groundnut seeds were investigated under Zinc stress. The SDS-PAGE showed the preliminary changes in the polypeptides patterns under Zinc stress. Restriction digestion banding pattern of EcoRI and Hind III enzymes showed distinct banding pattern in the treated plants.

  7. How are neuroticism and depression related to the psychophysiological stress response to acute stress in healthy older people?

    Science.gov (United States)

    Puig-Perez, Sara; Villada, Carolina; Pulopulos, Matias M; Hidalgo, Vanesa; Salvador, Alicia

    2016-03-15

    Neuroticism and depressive symptomatology have been related to a heightened and diminished physiological stress response, which may partly explain their negative relationship with health and wellbeing. Identifying factors that may increase disease vulnerability is especially relevant in older people, whose physiological systems decline. With this in mind, we investigated the influence of neuroticism and depression on the psychophysiological stress response in healthy older people (from 55 to 76years old). A total of 36 volunteers were exposed to a stressful task (Trier Social Stress Test, TSST), while 35 volunteers performed a control non-stressful task. The physiological stress response was assessed through measures of cortisol, alpha-amylase, heart rate (HR). Our results showed that, neuroticism was not related to physiological stress response. However, depression was related to higher cortisol response and lower HR reactivity in the stress condition. In summary, emotional states such as depressive mood seem to amplify the cortisol stress response and reduce the cardiovascular response, whereas more stable dispositions such as neuroticism did not affect stress response in older people. These findings confirm, in healthy older people, the adverse effects of depression, acting on different subsystems of the stress response.

  8. Differential activation of intra-S-phase checkpoint in response to tripchlorolide and its effects on DNA replication

    Institute of Scientific and Technical Information of China (English)

    Yan REN; Jia Rui WU

    2004-01-01

    DNA replication is tightly regulated during the S phase of the cell cycle, and the activation of the intra-S-phase checkpoint due to DNA damage usually results in arrest of DNA synthesis. However, the molecular details about the correlation between the checkpoint and regulation of DNA replication are still unclear. To investigate the connections between DNA replication and DNA damage checkpoint, a DNA-damage reagent, tripchlorolide, was applied to CHO (Chinese ovary hamster) cells at early- or middle-stages of the S phase. The early-S-phase treatment with TC significantly delayed the progression of the S phase and caused the phosphorylation of the Chk1 checkpoint protein, whereas the middle-S-phase treatment only slightly slowed down the progression of the S phase. Furthermore, the analysis of DNA replication patterns revealed that replication pattern Ⅱ was greatly prolonged in the cells treated with the drug during the early-S phase, whereas the late-replication patterns of these cells were hardly detected, suggesting that the activation of the intra-S-phase checkpoint inhibits the late-origin firing of DNA replication. We conclude that cells at different stages of the S phase are differentially sensitive to the DNA-damage reagent, and the activation of the intra-Sphase checkpoint blocks the DNA replication progression in the late stage of S phase.

  9. Human parvovirus B19 DNA replication induces a DNA damage response that is dispensable for cell cycle arrest at phase G2/M.

    Science.gov (United States)

    Lou, Sai; Luo, Yong; Cheng, Fang; Huang, Qinfeng; Shen, Weiran; Kleiboeker, Steve; Tisdale, John F; Liu, Zhengwen; Qiu, Jianming

    2012-10-01

    Human parvovirus B19 (B19V) infection is highly restricted to human erythroid progenitor cells, in which it induces a DNA damage response (DDR). The DDR signaling is mainly mediated by the ATR (ataxia telangiectasia-mutated and Rad3-related) pathway, which promotes replication of the viral genome; however, the exact mechanisms employed by B19V to take advantage of the DDR for virus replication remain unclear. In this study, we focused on the initiators of the DDR and the role of the DDR in cell cycle arrest during B19V infection. We examined the role of individual viral proteins, which were delivered by lentiviruses, in triggering a DDR in ex vivo-expanded primary human erythroid progenitor cells and the role of DNA replication of the B19V double-stranded DNA (dsDNA) genome in a human megakaryoblastoid cell line, UT7/Epo-S1 (S1). All the cells were cultured under hypoxic conditions. The results showed that none of the viral proteins induced phosphorylation of H2AX or replication protein A32 (RPA32), both hallmarks of a DDR. However, replication of the B19V dsDNA genome was capable of inducing the DDR. Moreover, the DDR per se did not arrest the cell cycle at the G(2)/M phase in cells with replicating B19V dsDNA genomes. Instead, the B19V nonstructural 1 (NS1) protein was the key factor in disrupting the cell cycle via a putative transactivation domain operating through a p53-independent pathway. Taken together, the results suggest that the replication of the B19V genome is largely responsible for triggering a DDR, which does not perturb cell cycle progression at G(2)/M significantly, during B19V infection.

  10. Ascending mechanisms of stress integration: Implications for brainstem regulation of neuroendocrine and behavioral stress responses.

    Science.gov (United States)

    Myers, Brent; Scheimann, Jessie R; Franco-Villanueva, Ana; Herman, James P

    2017-03-01

    In response to stress, defined as a real or perceived threat to homeostasis or well-being, brain systems initiate divergent physiological and behavioral processes that mobilize energy and promote adaptation. The brainstem contains multiple nuclei that engage in autonomic control and reflexive responses to systemic stressors. However, brainstem nuclei also play an important role in neuroendocrine responses to psychogenic stressors mediated by the hypothalamic-pituitary-adrenocortical axis. Further, these nuclei integrate neuroendocrine responses with stress-related behaviors, significantly impacting mood and anxiety. The current review focuses on the prominent brainstem monosynaptic inputs to the endocrine paraventricular hypothalamic nucleus (PVN), including the periaqueductal gray, raphe nuclei, parabrachial nuclei, locus coeruleus, and nucleus of the solitary tract (NTS). The NTS is a particularly intriguing area, as the region contains multiple cell groups that provide neurochemically-distinct inputs to the PVN. Furthermore, the NTS, under regulatory control by glucocorticoid-mediated feedback, integrates affective processes with physiological status to regulate stress responding. Collectively, these brainstem circuits represent an important avenue for delineating interactions between stress and health.

  11. RNAseq analysis reveals oxidative stress responses of Aspergillus flavus related to stress tolerance and aflatoxin production

    Science.gov (United States)

    Aflatoxin contamination by Aspergillus flavus is exacerbated by drought stress in the field. Given that reactive oxygen species (ROS) both accumulate in plant tissues during drought and can stimulate aflatoxin production in vitro, we examined the responses of toxigenic isolates of A. flavus to oxida...

  12. SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair

    DEFF Research Database (Denmark)

    Kanu, N.; Grönroos, E.; Martinez, P.

    2015-01-01

    Defining mechanisms that generate intratumour heterogeneity and branched evolution may inspire novel therapeutic approaches to limit tumour diversity and adaptation. SETD2 (Su(var), Enhancer of zeste, Trithorax-domain containing 2) trimethylates histone-3 lysine-36 (H3K36me3) at sites of active...... proteins minichromosome maintenance complex component (MCM7) and DNA polymerase δ hindering replication fork progression, and failure to load lens epithelium-derived growth factor and the Rad51 homologous recombination repair factor at DNA breaks. Consistent with these data, we observe chromosomal...... breakpoint locations are biased away from H3K36me3 sites in SETD2 wild-type ccRCCs relative to tumours with bi-allelic SETD2 aberrations and that H3K36me3-negative ccRCCs display elevated DNA damage in vivo. These data suggest a role for SETD2 in maintaining genome integrity through nucleosome stabilization...

  13. The role of stress mindset in shaping cognitive, emotional, and physiological responses to challenging and threatening stress.

    Science.gov (United States)

    Crum, Alia J; Akinola, Modupe; Martin, Ashley; Fath, Sean

    2017-07-01

    Prior research suggests that altering situation-specific evaluations of stress as challenging versus threatening can improve responses to stress. The aim of the current study was to explore whether cognitive, physiological and affective stress responses can be altered independent of situation-specific evaluations by changing individuals' mindsets about the nature of stress in general. Using a 2 × 2 design, we experimentally manipulated stress mindset using multi-media film clips orienting participants (N = 113) to either the enhancing or debilitating nature of stress. We also manipulated challenge and threat evaluations by providing positive or negative feedback to participants during a social stress test. Results revealed that under both threat and challenge stress evaluations, a stress-is-enhancing mindset produced sharper increases in anabolic ("growth") hormones relative to a stress-is-debilitating mindset. Furthermore, when the stress was evaluated as a challenge, a stress-is-enhancing mindset produced sharper increases in positive affect, heightened attentional bias towards positive stimuli, and greater cognitive flexibility, whereas a stress-is-debilitating mindset produced worse cognitive and affective outcomes. These findings advance stress management theory and practice by demonstrating that a short manipulation designed to generate a stress-is-enhancing mindset can improve responses to both challenging and threatening stress.

  14. Ethylene Response Factor Sl-ERF.B.3 Is Responsive to Abiotic Stresses and Mediates Salt and Cold Stress Response Regulation in Tomato

    Directory of Open Access Journals (Sweden)

    Imen Klay

    2014-01-01

    Full Text Available Sl-ERF.B.3 (Solanum lycopersicum ethylene response factor B.3 gene encodes for a tomato transcription factor of the ERF (ethylene responsive factor family. Our results of real-time RT-PCR showed that Sl-ERF.B.3 is an abiotic stress responsive gene, which is induced by cold, heat, and flooding, but downregulated by salinity and drought. To get more insight into the role of Sl-ERF.B.3 in plant response to separate salinity and cold, a comparative study between wild type and two Sl-ERF.B.3 antisense transgenic tomato lines was achieved. Compared with wild type, Sl-ERF.B.3 antisense transgenic plants exhibited a salt stress dependent growth inhibition. This inhibition was significantly enhanced in shoots but reduced in roots, leading to an increased root to shoot ratio. Furthermore, the cold stress essay clearly revealed that introducing antisense Sl-ERF.B.3 in transgenic tomato plants reduces their cell injury and enhances their tolerance against 14 d of cold stress. All these results suggest that Sl-ERF.B.3 gene is involved in plant response to abiotic stresses and may play a role in the layout of stress symptoms under cold stress and in growth regulation under salinity.

  15. Stress responses from the endoplasmic reticulum in cancer

    Directory of Open Access Journals (Sweden)

    Hironori eKato

    2015-04-01

    Full Text Available The endoplasmic reticulum (ER is a dynamic organelle that is essential for multiple cellular functions. During cellular stress conditions, including nutrient deprivation and dysregulation of protein synthesis, unfolded/misfolded proteins accumulate in the ER lumen, resulting in activation of the unfolded protein response (UPR. The UPR also contributes to the regulation of various intracellular signalling pathways such as calcium signalling and lipid signalling. More recently, the mitochondria-associated ER membrane (MAM, which is a site of close contact between the ER and mitochondria, has been shown to function as a platform for various intracellular stress responses including apoptotic signalling, inflammatory signalling, the autophagic response, and the UPR. Interestingly, in cancer, these signalling pathways from the ER are often dysregulated, contributing to cancer cell metabolism. Thus, the signalling pathway from the ER may be a novel therapeutic target for various cancers. In this review, we discuss recent research on the roles of stress responses from the ER, including the MAM.

  16. Ezrin Inhibition Up-regulates Stress Response Gene Expression*

    Science.gov (United States)

    Çelik, Haydar; Bulut, Gülay; Han, Jenny; Graham, Garrett T.; Minas, Tsion Z.; Conn, Erin J.; Hong, Sung-Hyeok; Pauly, Gary T.; Hayran, Mutlu; Li, Xin; Özdemirli, Metin; Ayhan, Ayşe; Rudek, Michelle A.; Toretsky, Jeffrey A.; Üren, Aykut

    2016-01-01

    Ezrin is a member of the ERM (ezrin/radixin/moesin) family of proteins that links cortical cytoskeleton to the plasma membrane. High expression of ezrin correlates with poor prognosis and metastasis in osteosarcoma. In this study, to uncover specific cellular responses evoked by ezrin inhibition that can be used as a specific pharmacodynamic marker(s), we profiled global gene expression in osteosarcoma cells after treatment with small molecule ezrin inhibitors, NSC305787 and NSC668394. We identified and validated several up-regulated integrated stress response genes including PTGS2, ATF3, DDIT3, DDIT4, TRIB3, and ATF4 as novel ezrin-regulated transcripts. Analysis of transcriptional response in skin and peripheral blood mononuclear cells from NSC305787-treated mice compared with a control group revealed that, among those genes, the stress gene DDIT4/REDD1 may be used as a surrogate pharmacodynamic marker of ezrin inhibitor compound activity. In addition, we validated the anti-metastatic effects of NSC305787 in reducing the incidence of lung metastasis in a genetically engineered mouse model of osteosarcoma and evaluated the pharmacokinetics of NSC305787 and NSC668394 in mice. In conclusion, our findings suggest that cytoplasmic ezrin, previously considered a dormant and inactive protein, has important functions in regulating gene expression that may result in down-regulation of stress response genes. PMID:27137931

  17. An epigenome-wide association meta-analysis of prenatal maternal stress in neonates: A model approach for replication

    NARCIS (Netherlands)

    J. Rijlaarsdam (Jolien); I. Pappa (Irene); E. Walton (Esther); M.J. Bakermans-Kranenburg (Marian); V. Mileva-Seitz; R.C.A. Rippe (Ralph C.A.); S.J. Roza (Sabine); V.W.V. Jaddoe (Vincent); F.C. Verhulst (Frank); J.F. Felix (Janine); C.A.M. Cecil (Charlotte A.M.); C.L. Relton (Caroline); T.R. Gaunt (Tom); W.L. McArdle (Wendy); J. Mill (Jonathan); E.D. Barker (Edward D.); H.W. Tiemeier (Henning); M.H. van IJzendoorn (Marinus)

    2016-01-01

    textabstractABSTRACT: Prenatal maternal stress exposure has been associated with neonatal differential DNA methylation. However, the available evidence in humans is largely based on candidate gene methylation studies, where only a few CpG sites were evaluated. The aim of this study was to examine th

  18. Characterization of the physiological stress response in lingcod

    Science.gov (United States)

    Milston, R.H.; Davis, M.W.; Parker, S.J.; Olla, B.L.; Clements, S.; Schreck, C.B.

    2006-01-01

    The goal of this study was to describe the duration and magnitude of the physiological stress response in lingcod Ophiodon elongatus after exposure to brief handling and sublethal air stressors. The response to these stressors was determined during a 24-h recovery period by measuring concentrations of plasma cortisol, lactate, glucose, sodium, and potassium. Lingcod were subjected to brief handling followed by either a 15-min or a 45-min air stressor in the laboratory. After the 15-min stressor, an increase in cortisol or glucose could not be detected until after 5 min of recovery. Peak concentrations were measured after 30 min for cortisol and after 60 min for glucose and lactate. Glucose and lactate had returned to basal levels after 12 h, whereas cortisol did not return to basal levels until after 24 h of recovery. Immediately following a 45-min air stressor, all measured parameters were significantly elevated over levels in prestressor control fish. Cortisol concentrations tended to increase and reached a measured peak after 8 h of recovery, whereas glucose and lactate reached a measured peak after 1 h of recovery. Cortisol and lactate returned to basal levels within 24 h. Glucose, however, remained elevated even after 24 h of recovery. Plasma ions initially increased during the first hour of recovery, and the concentrations then declined to a level below that measured in control fish for the remainder of the 24-h recovery period. In addition, we evaluated the effect of fish size on the stress response. There was no significant difference between the stress response of smaller (41-49-cm [total length] and larger (50-67-cm) lingcod after 45 min air exposure. In general, both the magnitude and duration of the primary and secondary stress responses in lingcod are comparable to those of salmonids. ?? Copyright by the American Fisheries Society 2006.

  19. Deciphering hepatocellular responses to metabolic and oncogenic stress

    Directory of Open Access Journals (Sweden)

    Kathrina L. Marcelo

    2015-08-01

    Full Text Available Each cell type responds uniquely to stress and fractionally contributes to global and tissue-specific stress responses. Hepatocytes, liver macrophages (MΦ, and sinusoidal endothelial cells (SEC play functionally important and interdependent roles in adaptive processes such as obesity and tumor growth. Although these cell types demonstrate significant phenotypic and functional heterogeneity, their distinctions enabling disease-specific responses remain understudied. We developed a strategy for the simultaneous isolation and quantification of these liver cell types based on antigenic cell surface marker expression. To demonstrate the utility and applicability of this technique, we quantified liver cell-specific responses to high-fat diet (HFD or diethylnitrosamine (DEN, a liver-specific carcinogen, and found that while there was only a marginal increase in hepatocyte number, MΦ and SEC populations were quantitatively increased. Global gene expression profiling of hepatocytes, MΦ and SEC identified characteristic gene signatures that define each cell type in their distinct physiological or pathological states. Integration of hepatic gene signatures with available human obesity and liver cancer microarray data provides further insight into the cell-specific responses to metabolic or oncogenic stress. Our data reveal unique gene expression patterns that serve as molecular “fingerprints” for the cell-centric responses to pathologic stimuli in the distinct microenvironment of the liver. The technical advance highlighted in this study provides an essential resource for assessing hepatic cell-specific contributions to metabolic and oncogenic stress, information that could unveil previously unappreciated molecular mechanisms for the cellular crosstalk that underlies the continuum from metabolic disruption to obesity and ultimately hepatic cancer.

  20. The plant response:stress in the daily environment

    Institute of Scientific and Technical Information of China (English)

    FERGUSON Ian B.

    2004-01-01

    @@STRESS IS NORMAL Like animals, plants have evolved to survive in almost every climatic and environmental niche available. They have, however, evolved more sophisticated and varied methods to enable them to survive environmental changes in light, temperature, atmosphere composition, water and nutrients and salinity. This, in part, is necessary because of the sessile nature of plants; they do not have the ability to move to more favourable environments. Stress conditions that plants encounter are not always as rare or unusual as we might at first think. The most common environmental variables, necessary for growth, can impose significant stresses on the plant. But should we think of these as unusual and extreme or just part of the normal diurnal responses experienced by the plant?

  1. The cellular response to curvature-induced stress

    Science.gov (United States)

    Biton, Y. Y.; Safran, S. A.

    2009-12-01

    We present a theoretical model to explain recent observations of the orientational response of cells to unidirectional curvature. Experiments show that some cell types when plated on a rigid cylindrical surface tend to reorient their shape and stress fibers along the axis of the cylinder, while others align their stress fibers perpendicular to that axis. Our model focuses on the competition of the shear stress—that results from cell adhesion and active contractility—and the anisotropic bending stiffness of the stress fibers. We predict the cell orientation angle that results from the balance of these two forces in a mechanical equilibrium. The conditions under which the different experimental observations can be obtained are discussed in terms of the theory.

  2. Quorum sensing regulates the osmotic stress response in Vibrio harveyi.

    Science.gov (United States)

    van Kessel, Julia C; Rutherford, Steven T; Cong, Jian-Ping; Quinodoz, Sofia; Healy, James; Bassler, Bonnie L

    2015-01-01

    Bacteria use a chemical communication process called quorum sensing to monitor cell density and to alter behavior in response to fluctuations in population numbers. Previous studies with Vibrio harveyi have shown that LuxR, the master quorum-sensing regulator, activates and represses >600 genes. These include six genes that encode homologs of the Escherichia coli Bet and ProU systems for synthesis and transport, respectively, of glycine betaine, an osmoprotectant used during osmotic stress. Here we show that LuxR activates expression of the glycine betaine operon betIBA-proXWV, which enhances growth recovery under osmotic stress conditions. BetI, an autorepressor of the V. harveyi betIBA-proXWV operon, activates the expression of genes encoding regulatory small RNAs that control quorum-sensing transitions. Connecting quorum-sensing and glycine betaine pathways presumably enables V. harveyi to tune its execution of collective behaviors to its tolerance to stress.

  3. Database Replication

    CERN Document Server

    Kemme, Bettina

    2010-01-01

    Database replication is widely used for fault-tolerance, scalability and performance. The failure of one database replica does not stop the system from working as available replicas can take over the tasks of the failed replica. Scalability can be achieved by distributing the load across all replicas, and adding new replicas should the load increase. Finally, database replication can provide fast local access, even if clients are geographically distributed clients, if data copies are located close to clients. Despite its advantages, replication is not a straightforward technique to apply, and

  4. Impacts of different expressions of PA-X protein on 2009 pandemic H1N1 virus replication, pathogenicity and host immune responses.

    Science.gov (United States)

    Lee, Jinhwa; Yu, Hai; Li, Yonghai; Ma, Jingjiao; Lang, Yuekun; Duff, Michael; Henningson, Jamie; Liu, Qinfang; Li, Yuhao; Nagy, Abdou; Bawa, Bhupinder; Li, Zejun; Tong, Guangzhi; Richt, Juergen A; Ma, Wenjun

    2017-04-01

    Although several studies have investigated the functions of influenza PA-X, the impact of different expressions of PA-X protein including full-length, truncated or PA-X deficient forms on virus replication, pathogenicity and host response remains unclear. Herein, we generated two mutated viruses expressing a full-length or deficient PA-X protein based on the A/California/04/2009 (H1N1) virus that expresses a truncated PA-X to understand three different expressions of PA-X protein on virus replication, pathogenicity and host immune responses. The results showed that expression of either full-length or truncated PA-X protein enhanced viral replication and pathogenicity as well as reduced host innate immune response in mice by host shutoff activity when compared to the virus expressing the deficient PA-X form. Furthermore, the full-length PA-X expression exhibited a greater effect on virus pathogenicity than the truncated PA-X form. Our results provide novel insights of PA-X on viral replication, pathogenicity and host immune responses.

  5. Brain 5-HT deficiency increases stress vulnerability and impairs antidepressant responses following psychosocial stress.

    Science.gov (United States)

    Sachs, Benjamin D; Ni, Jason R; Caron, Marc G

    2015-02-24

    Brain serotonin (5-HT) deficiency and exposure to psychosocial stress have both been implicated in the etiology of depression and anxiety disorders, but whether 5-HT deficiency influences susceptibility to depression- and anxiety-like phenotypes induced by psychosocial stress has not been formally established. Most clinically effective antidepressants increase the extracellular levels of 5-HT, and thus it has been hypothesized that antidepressant responses result from the reversal of endogenous 5-HT deficiency, but this hypothesis remains highly controversial. Here we evaluated the impact of brain 5-HT deficiency on stress susceptibility and antidepressant-like responses using tryptophan hydroxylase 2 knockin (Tph2KI) mice, which display 60-80% reductions in brain 5-HT. Our results demonstrate that 5-HT deficiency leads to increased susceptibility to social defeat stress (SDS), a model of psychosocial stress, and prevents the fluoxetine (FLX)-induced reversal of SDS-induced social avoidance, suggesting that 5-HT deficiency may impair antidepressant responses. In light of recent clinical and preclinical studies highlighting the potential of inhibiting the lateral habenula (LHb) to achieve antidepressant and antidepressant-like responses, we also examined whether LHb inhibition could achieve antidepressant-like responses in FLX-insensitive Tph2KI mice subjected to SDS. Our data reveal that using designer receptors exclusively activated by designer drugs (DREADDs) to inhibit LHb activity leads to reduced SDS-induced social avoidance behavior in both WT and Tph2KI mice. This observation provides additional preclinical evidence that inhibiting the LHb might represent a promising alternative therapeutic approach under conditions in which selective 5-HT reuptake inhibitors are ineffective.

  6. Cis-element of the rice PDIL2-3 promoter is responsible for inducing the endoplasmic reticulum stress response.

    Science.gov (United States)

    Takahashi, Hideyuki; Wang, Shuyi; Hayashi, Shimpei; Wakasa, Yuhya; Takaiwa, Fumio

    2014-05-01

    A protein disulfide isomerase (PDI) family oxidoreductase, PDIL2-3, is involved in endoplasmic reticulum (ER) stress responses in rice. We identified a critical cis-element required for induction of the ER stress response. The activation of PDIL2-3 in response to ER stress strongly depends on the IRE1-OsbZIP50 signaling pathway.

  7. Quantifying Responses of Winter Wheat Physiological Processes to Soil Water Stress for Use in Growth Simulation Modeling

    Institute of Scientific and Technical Information of China (English)

    HU Ji-Chao; CAO Wei-Xing; ZHANG Jia-Bao; JIANG Dong; FENG Jie

    2004-01-01

    A deep understanding of crop-water eco-physiological relations is the basis for quantifying plant physiological responses to soil water stress. Pot experiments were conducted to investigate the winter wheat crop-water relations under both drought and waterlogging conditions in two sequential growing seasons from 2000 to 2002, and then the data were used to develop and validate models simulating the responses of winter wheat growth to drought and waterlogging stress. The experiment consisted of four treatments, waterlogging (keep 1 to 2 cm water layer depth above soil surface), control (70%-80% field capacity), light drought (40%-50% field capacity) and severe drought (30%-40% field capacity) with six replicates at five stages in the 2000-2001 growth season. Three soil water content treatments (waterlogging, control and drought) with two replicates were designed in the 2001-2002 growth season. Waterlogging and control treatments are the same as in the 2000-2001 growth season. For the drought treatment, no water was supplied and the soil moisture decreased from field capacity to wilting point. Leaf net photosynthetic rate, transpiration rate, predawn leaf water potential, soil water potential, soil water content and dry matter weight of individual organs were measured. Based on crop-water eco-physiological relations, drought and waterlogging stress factors for winter wheat growth simulation model were put forward. Drought stress factors integrated soil water availability, the sensitivity of different development stages and the difference between physiological processes (such as photosynthesis, transpiration and partitioning). The quantification of waterlogging stress factor considered different crop species, soil water status, waterlogging days and sensitivity at different growth stages. Data sets from the pot experiments revealed favorable performance reliability for the simulation sub-models with the drought and waterlogging stress factors.

  8. N-substituted benzyl matrinic acid derivatives inhibit hepatitis C virus (HCV replication through down-regulating host heat-stress cognate 70 (Hsc70 expression.

    Directory of Open Access Journals (Sweden)

    Na-Na Du

    Full Text Available Heat-stress cognate 70 (Hsc70 is a host factor that helps hepatitis C virus (HCV to complete its life cycle in infected hepatocytes. Using Hsc70 as a target for HCV inhibition, a series of novel N-substituted benzyl matrinic/sophoridinic acid derivatives was synthesized and evaluated for their anti-HCV activity in vitro. Among these analogues, compound 7c possessing N-p-methylbenzyl afforded an appealing ability to inhibit HCV replication with SI value over 53. Furthermore, it showed a good oral pharmacokinetic profile with area-under-curve (AUC of 13.4 µM·h, and a considerably good safety in oral administration in mice (LD50>1000 mg/kg. As 7c suppresses HCV replication via an action mode distinctly different from that of the marketed anti-HCV drugs, it has been selected as a new mechanism anti-HCV candidate for further investigation, with an advantage of no or decreased chance to induce drug-resistant mutations.

  9. Stress induced hypertensive response: should it be evaluated more carefully?

    Directory of Open Access Journals (Sweden)

    Kucukler Nagehan

    2011-08-01

    Full Text Available Abstract Various diagnostic methods have been used to evaluate hypertensive patients under physical and pharmacological stress. Several studies have shown that exercise hypertension has an independent, adverse impact on outcome; however, other prognostic studies have shown that exercise hypertension is a favorable prognostic indicator and associated with good outcome. Exercise hypertension may be encountered as a warning signal of hypertension at rest and future hypertensive left ventricular hypertrophy. The results of diagnostic stress tests support that hypertensive response to exercise is frequently associated with high rate-pressure product in hypertensives. In addition to the observations on high rate-pressure product and enhanced ventricular contractility in patients with hypertension, evaluation of myocardial contractility by Doppler tissue imaging has shown hyperdynamic myocardial function under pharmacological stress. These recent quantitative data in hypertensives suggest that hyperdynamic myocardial function and high rate-pressure product response to stress may be related to exaggerated hypertension, which may have more importance than that it has been already given in clinical practice.

  10. Oxidative Stress Responses in the Human Fungal Pathogen, Candida albicans

    Directory of Open Access Journals (Sweden)

    Alessandra da Silva Dantas

    2015-02-01

    Full Text Available Candida albicans is a major fungal pathogen of humans, causing approximately 400,000 life-threatening systemic infections world-wide each year in severely immunocompromised patients. An important fungicidal mechanism employed by innate immune cells involves the generation of toxic reactive oxygen species (ROS, such as superoxide and hydrogen peroxide. Consequently, there is much interest in the strategies employed by C. albicans to evade the oxidative killing by macrophages and neutrophils. Our understanding of how C. albicans senses and responds to ROS has significantly increased in recent years. Key findings include the observations that hydrogen peroxide triggers the filamentation of this polymorphic fungus and that a superoxide dismutase enzyme with a novel mode of action is expressed at the cell surface of C. albicans. Furthermore, recent studies have indicated that combinations of the chemical stresses generated by phagocytes can actively prevent C. albicans oxidative stress responses through a mechanism termed the stress pathway interference. In this review, we present an up-date of our current understanding of the role and regulation of oxidative stress responses in this important human fungal pathogen.

  11. Roles of horseradish peroxidase in response to terbium stress.

    Science.gov (United States)

    Zhang, Xuanbo; Wang, Lihong; Zhou, Qing

    2014-10-01

    The pollution of the environment by rare earth elements (REEs) causes deleterious effects on plants. Peroxidase plays important roles in plant response to various environmental stresses. Here, to further understand the overall roles of peroxidase in response to REE stress, the effects of the REE terbium ion (Tb(3+)) on the peroxidase activity and H2O2 and lignin contents in the leaves and roots of horseradish during different growth stages were simultaneously investigated. The results showed that after 24 and 48 h of Tb(3+) treatment, the peroxidase activity in horseradish leaves decreased, while the H2O2 and lignin contents increased. After a long-term (8 and 16 days) treatment with Tb(3+), these effects were also observed in the roots. The analysis of the changes in peroxidase activity and H2O2 and lignin contents revealed that peroxidase plays important roles in not only reactive oxygen species scavenging but also cell wall lignification in horseradish under Tb(3+) stress. These roles were closely related to the dose of Tb(3+), duration of stress, and growth stages of horseradish.

  12. Peripheral vascular responses to heat stress after hindlimb suspension

    Science.gov (United States)

    Looft-Wilson, Robin C.; Gisolfi, Carl V.

    2002-01-01

    PURPOSE: The purpose of this study was to determine whether hindlimb suspension (which simulates the effects of microgravity) results in impaired hemodynamic responses to heat stress or alterations in mesenteric small artery sympathetic nerve innervation. METHODS: Over 28 d, 16 male Sprague-Dawley rats were hindlimb-suspended, and 13 control rats were housed in the same type of cage. After the treatment, mean arterial pressure (MAP), colonic temperature (Tcol), and superior mesenteric and iliac artery resistances (using Doppler flowmetry) were measured during heat stress [exposure to 42 degrees C until the endpoint of 80 mm Hg blood pressure was reached (75 +/- 9 min); endpoint Tcore = 43.6 +/- 0.2] while rats were anesthetized (sodium pentobarbital, 50 mg x kg(-1) BW). RESULTS: Hindlimb-suspended and control rats exhibited similar increases in Tcol, MAP, and superior mesenteric artery resistance, and similar decreases in iliac resistance during heat stress (endpoint was a fall in MAP below 80 mm Hg). Tyrosine hydroxylase immunostaining indicated similar sympathetic nerve innervation in small mesenteric arteries from both groups. CONCLUSION: Hindlimb suspension does not alter the hemodynamic or thermoregulatory responses to heat stress in the anesthetized rat or mesenteric sympathetic nerve innervation, suggesting that this sympathetic pathway is intact.

  13. Morphological and Physiological Responses of Strawberry Plants to Water Stress

    Directory of Open Access Journals (Sweden)

    Krzysztof Klamkowski

    2006-12-01

    Full Text Available The most of previous studies have been focused on the effect of water stress on plant yielding. However, the conditions in which plants grow from the moment of planting might affect their morphology and physiological response. The aim of this study was to examine the effect of water deficiency on growth and plant physiological response of strawberry (Fragaria x ananassa Duch. cv. ‘Salut’ under greenhouse conditions. The plants were grown in plastic containers filled with peat substratum. Water stress was imposed by reducing the irrigation according to substratum moisture readings. Water stressed plants had the lowest values of water potential and showed strong decrease in gas exchange rate. Also, biomass and leaf area were the lowest in this group of plants. No differences in the length of root system were observed between control and water stressed plants. The lack of water in growing medium resulted also in a decrease of density and reduction of dimensions of stomata on plant leaves. These changes contribute to optimizing the use of assimilates and water use efficiency in periods when water availability is decreased.

  14. Morphological and Physiological Responses of Strawberry Plants to Water Stress

    Directory of Open Access Journals (Sweden)

    Krzysztof Klamkowski

    2006-01-01

    Full Text Available The most of previous studies have been focused on the effect of water stress on plant yielding. However, the conditions in which plants grow from the moment of planting might affect their morphology and physiological response. The aim of this study was to examine the effect of water deficiency on growth and plant physiological response of strawberry (Fragaria x ananassa Duch. cv. ‘Salut’ under greenhouse conditions. The plants were grown in plastic containers filled with peat substratum. Water stress was imposed by reducing the irrigation according to substratum moisture readings. Water stressed plants had the lowest values of water potential and showed strong decrease in gas exchange rate. Also, biomass and leaf area were the lowest in this group of plants. No differences in the length of root system were observed between control and water stressed plants. The lack of water in growing medium resulted also in a decrease of density and reduction of dimensions of stomata on plant leaves.These changes contribute to optimizing the use of assimilates and water use efficiency in periods when water availability is decreased.

  15. Herboxidiene triggers splicing repression and abiotic stress responses in plants

    KAUST Repository

    Alshareef, Sahar

    2017-03-27

    Background Constitutive and alternative splicing of pre-mRNAs from multiexonic genes controls the diversity of the proteome; these precisely regulated processes also fine-tune responses to cues related to growth, development, and stresses. Small-molecule inhibitors that perturb splicing provide invaluable tools for use as chemical probes to uncover the molecular underpinnings of splicing regulation and as potential anticancer compounds. Results Here, we show that herboxidiene (GEX1A) inhibits both constitutive and alternative splicing. Moreover, GEX1A activates genome-wide transcriptional patterns involved in abiotic stress responses in plants. GEX1A treatment -activated ABA-inducible promoters, and led to stomatal closure. Interestingly, GEX1A and pladienolide B (PB) elicited similar cellular changes, including alterations in the patterns of transcription and splicing, suggesting that these compounds might target the same spliceosome complex in plant cells. Conclusions Our study establishes GEX1A as a potent splicing inhibitor in plants that can be used to probe the assembly, dynamics, and molecular functions of the spliceosome and to study the interplay between splicing stress and abiotic stresses, as well as having potential biotechnological applications.

  16. Selective impact of early parental responsivity on adolescent stress reactivity.

    Directory of Open Access Journals (Sweden)

    Daniel A Hackman

    Full Text Available Research in animals has shown that early life experience, particularly parenting behaviors, influences later-life stress reactivity. Despite the tremendous relevance of this finding to human development and brain function, it has not been tested prospectively in humans. In this study two aspects of parenting were measured at age 4 in a sample of healthy, low socioeconomic status, African American children, and stress reactivity was measured in the same children 11-14 years later using a modified version of the Trier Social Stress Test (n = 55. Salivary cortisol was measured before, during and after the stressor and data were analyzed using piecewise hierarchical linear modeling. Parental responsivity, independent of the use of physical discipline, was positively related to cortisol reactivity. Effects were independent of subjective appraisals of the stressor and were also independent of other environmental risk factors and current psychosocial functioning. Therefore this study demonstrates in a novel and precise fashion that early childhood parental responsivity prospectively and independently predicts stress reactivity in adolescence.

  17. Particle shape effects on the stress response of granular packings.

    Science.gov (United States)

    Athanassiadis, Athanasios G; Miskin, Marc Z; Kaplan, Paul; Rodenberg, Nicholas; Lee, Seung Hwan; Merritt, Jason; Brown, Eric; Amend, John; Lipson, Hod; Jaeger, Heinrich M

    2014-01-01

    We present measurements of the stress response of packings formed from a wide range of particle shapes. Besides spheres these include convex shapes such as the Platonic solids, truncated tetrahedra, and triangular bipyramids, as well as more complex, non-convex geometries such as hexapods with various arm lengths, dolos, and tetrahedral frames. All particles were 3D-printed in hard resin. Well-defined initial packing states were established through preconditioning by cyclic loading under given confinement pressure. Starting from such initial states, stress-strain relationships for axial compression were obtained at four different confining pressures for each particle type. While confining pressure has the largest overall effect on the mechanical response, we find that particle shape controls the details of the stress-strain curves and can be used to tune packing stiffness and yielding. By correlating the experimentally measured values for the effective Young's modulus under compression, yield stress and energy loss during cyclic loading, we identify trends among the various shapes that allow for designing a packing's aggregate behavior.

  18. Osmotic stress response in the wine yeast Dekkera bruxellensis.

    Science.gov (United States)

    Galafassi, Silvia; Toscano, Marco; Vigentini, Ileana; Piškur, Jure; Compagno, Concetta

    2013-12-01

    Dekkera bruxellensis is mainly associated with lambic beer fermentation and wine production and may contribute in a positive or negative manner to the flavor development. This yeast is able to produce phenolic compounds, such as 4-ethylguaiacol and 4-ethylphenol which could spoil the wine, depending on their concentration. In this work we have investigated how this yeast responds when exposed to conditions causing osmotic stress, as high sorbitol or salt concentrations. We observed that osmotic stress determined the production and accumulation of intracellular glycerol, and the expression of NADH-dependent glycerol-3-phosphate dehydrogenase (GPD) activity was elevated. The involvement of the HOG MAPK pathway in response to this stress condition was also investigated. We show that in D. bruxellensis Hog1 protein is activated by phosphorylation under hyperosmotic conditions, highlighting the conserved role of HOG MAP kinase signaling pathway in the osmotic stress response. Gene Accession numbers in GenBank: DbHOG1: JX65361, DbSTL1: JX965362. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Transcriptome Analysis of Enterococcus faecalis in Response to Alkaline Stress

    Directory of Open Access Journals (Sweden)

    Ran eshujun

    2015-08-01

    Full Text Available E. faecalis is the most commonly isolated species from endodontic failure root canals; its persistence in treated root canals has been attributed to its ability to resist high pH stress. The goal of this study was to characterize the E. faecalis transcriptome and to identify candidate genes for response and resistance to alkaline stress using Illumina HiSeq 2000 sequencing.We found that E. faecalis could survive and form biofilms in a pH 10 environment and that alkaline stress had a great impact on the transcription of many genes in the E. faecalis genome. The transcriptome sequencing results revealed that 613 genes were differentially expressed (DEGs for E. faecalis grown in pH 10 medium; 211 genes were found to be differentially up-regulated and 402 genes differentially down-regulated. Many of the down-regulated genes found are involved in cell energy production and metabolism and carbohydrate and amino acid metabolism, and the up-regulated genes are mostly related to nucleotide transport and metabolism. The results presented here reveal that cultivation of E. faecalis in alkaline stress has a profound impact on its transcriptome. The observed regulation of genes and pathways revealed that E. faecalis reduced its carbohydrate and amino acid metabolism and increased nucleotide synthesis to adapt and grow in alkaline stress. A number of the regulated genes may be useful candidates for the development of new therapeutic approaches for the treatment of E. faecalis infections.

  20. Magnitude-dependent response of osteoblasts regulated by compressive stress

    Science.gov (United States)

    Shen, Xiao-qing; Geng, Yuan-ming; Liu, Ping; Huang, Xiang-yu; Li, Shu-yi; Liu, Chun-dong; Zhou, Zheng; Xu, Ping-ping

    2017-01-01

    The present study aimed to investigate the role of magnitude in adaptive response of osteoblasts exposed to compressive stress. Murine primary osteoblasts and MC3T3-E1 cells were exposed to compressive stress (0, 1, 2, 3, 4, and 5 g/cm2) in 3D culture. Cell viability was evaluated, and expression levels of Runx2, Alp, Ocn, Rankl, and Opg were examined. ALP activity in osteoblasts and TRAP activity in RAW264.7 cells co-cultured with MC3T3-E1 cells were assayed. Results showed that compressive stress within 5.0 g/cm2 did not influence cell viability. Both osteoblastic and osteoblast-regulated osteoclastic differentiation were enhanced at 2 g/cm2. An increase in stress above 2 g/cm2 did not enhance osteoblastic differentiation further but significantly inhibited osteoblast-regualted osteoclastic differentiation. This study suggested that compressive stress regulates osteoblastic and osteoclastic differentiation through osteoblasts in a magnitude-dependent manner. PMID:28317941

  1. Proteomic Study for Responses to Cadmium Stress in Rice Seedlings

    Institute of Scientific and Technical Information of China (English)

    GE Cai-lin; WANG Ze-gang; WAN Ding-zhen; DING Yan; WANG Yu-long; SHANG Qi; LUO Shi-shi

    2009-01-01

    A proteomic approach including two-dimensional electrophoresis and mass spectrometric (MALDI-TOF MS) analyses was used to investigate the responses to cadmium (Cd) stress in seedlings of rice (Oryza sativa L.) varieties Shanyou 63 and Aizaizhan. Cd stress significantly inhibited root and shoot growth, and affected the global proteome in rice roots and leaves, which induced or upregulated the expression of corresponding proteins in rice roots and leaves when rice seedlings were exposed to 0.1 or 1.0 mmol/L Cd. The Cd-induced proteins are involved in chelation and compartmentation of Cd, elimination of active oxygen free radicals, detoxification of toxic substances, degradation of denatured proteins or inactivated enzymes, regulation of physiologic metabolism and induction of pathogenesis-related proteins. Comparing the Cd-induced proteins between the two varieties, the β-glucosidase and pathogenesis-related protein family 10 proteins were more drastically induced by Cd stress in roots and leaves of Aizaizhan, and the UDP-glucose protein transglucosylase and translational elongation factor Tu were induced by 0.1 mmol/L Cd stress in roots of Shanyou 63. This may be one of the important mechanisms for higher tolerance to Cd stress in Shanyou 63 than in Aizaizhan.

  2. Sex and stress: Men and women show different cortisol responses to psychological stress induced by the Trier social stress test and the Iowa singing social stress test.

    Science.gov (United States)

    Reschke-Hernández, Alaine E; Okerstrom, Katrina L; Bowles Edwards, Angela; Tranel, Daniel

    2017-01-02

    Acute psychological stress affects each of us in our daily lives and is increasingly a topic of discussion for its role in mental illness, aging, cognition, and overall health. A better understanding of how such stress affects the body and mind could contribute to the development of more effective clinical interventions and prevention practices. Over the past 3 decades, the Trier Social Stress Test (TSST) has been widely used to induce acute stress in a laboratory setting based on the principles of social evaluative threat, namely, a judged speech-making task. A comparable alternative task may expand options for examining acute stress in a controlled laboratory setting. This study uses a within-subjects design to examine healthy adult participants' (n = 20 men, n = 20 women) subjective stress and salivary cortisol responses to the standard TSST (involving public speaking and math) and the newly created Iowa Singing Social Stress Test (I-SSST). The I-SSST is similar to the TSST but with a new twist: public singing. Results indicated that men and women reported similarly high levels of subjective stress in response to both tasks. However, men and women demonstrated different cortisol responses; men showed a robust response to both tasks, and women displayed a lesser response. These findings are in line with previous literature and further underscore the importance of examining possible sex differences throughout various phases of research, including design, analysis, and interpretation of results. Furthermore, this nascent examination of the I-SSST suggests a possible alternative for inducing stress in the laboratory. © 2016 Wiley Periodicals, Inc.

  3. Sources of synchronized induced Gamma-Band responses during a simple object recognition task: a replication study in human MEG.

    Science.gov (United States)

    Gruber, T; Maess, B; Trujillo-Barreto, N J; Müller, M M

    2008-02-27

    Natural stimuli are compiled of numerous features, which are cortically represented in dispersed structures. Synchronized oscillations in the Gamma-Band (>30 Hz; induced Gamma-Band Responses, iGBRs), are regarded as a plausible mechanism to re-integrate these regions into a meaningful cortical object representation. Using electroencephalography (EEG) it was demonstrated that the generators of iGBRs can be localized to temporal, parietal, posterior, and frontal areas. The present magnetoencephalogram (MEG) study intended to replicate these findings in order contribute to the ongoing debate regarding the possible functional difference of high-frequency signals as measured by both techniques. During a standard object recognition task we found an augmentation of the iGBR after the presentation of meaningful as opposed to meaningless stimuli at approximately 160-440 ms after stimulus onset. This peak was localized to inferior temporal gyri, superior parietal lobules and the right middle frontal gyrus. Importantly, most of these brain structures were significantly phase-locked to each other. The implications of these results are twofold: (1) they present further evidence for the view that iGBRs signify neuronal activity in a broadly distributed network during object recognition. (2) MEG is well suited to detect induced high-frequency oscillations with a very similar morphology as revealed by EEG recordings, thereby eliminating known problems with electroencephalographical methods (e.g. reference confounds). In contrast to the iGBR, the localization of event-related fields (ERFs) and evoked Gamma-Band Response (eGBRs) revealed generators in focal visual areas, and thus, seem to mirror early sensory processing.

  4. Corneal replication is an interferon response-independent bottleneck for virulence of herpes simplex virus 1 in the absence of virion host shutoff.

    Science.gov (United States)

    Pasieka, Tracy Jo; Menachery, Vineet D; Rosato, Pamela C; Leib, David A

    2012-07-01

    Herpes simplex viruses lacking the virion host shutoff function (Δvhs) are avirulent and hypersensitive to type I and type II interferon (IFN). In this study, we demonstrate that even in the absence of IFN responses in AG129 (IFN-αβγR(-/-)) mice, Δvhs remains highly attenuated via corneal infection but is fully virulent via intracranial infection. The data demonstrate that the interferon-independent inherent replication defect of Δvhs has a significant impact upon peripheral replication and neuroinvasion.

  5. Cardiolipin at the heart of stress response across kingdoms.

    Science.gov (United States)

    de Paepe, Rosine; Lemaire, Stéphane D; Danon, Antoine

    2014-05-20

    Cardiolipin is a key phospholipid most specifically found in the membrane of mitochondria in yeasts, plants, and animals. Cardiolipins are essential for the maintenance, the integrity, and the dynamics of mitochondria. In most eukaryotes mitochondria play a central role in the response and adaptation to stress conditions especially through their importance in the control of programmed cell death. To assess the impact of the absence of cardiolipin, knock-down of the expression of cardiolipin synthase, the last enzyme of cardiolipin synthesis pathway in eukaryotes has been performed in yeasts, animals, and plants. These studies showed that cardiolipin is not only important for mitochondrial ultrastructure and for the stability of respiratory complexes, but it is also a key player in the response to stress, the formation of reactive oxygen species, and the execution of programmed cell death.

  6. Behaviour and stress responses in horses with gastric ulceration

    DEFF Research Database (Denmark)

    Malmkvist, Jens; Poulsen, Janne Møller; Luthersson, Nanna

    2012-01-01

    Only little is known about behaviour and stress responses in horses with gastric ulceration, despite the high prevalence of this condition. Our objectives in the present study was to (i) describe the severity of gastric ulceration in horses, housed under relatively standardised conditions, and (ii......) to investigate whether horses with severe glandular gastric ulceration have increased baseline and response concentration of stress hormones and behave differently than control horses. We investigated stomachs of 96 horses at one stud, and compared an ulcer group (n = 30; with severe lesions in the glandular.......2% and non-glandular lesions in 40.6% of the horses. The amount of starch in the feed (P = 0.006) and paternal stallion (P = 0.031) influenced ulceration in the non-glandular region only; it should be noted that our study does not allow for separating hereditary from environmental influences, as offspring...

  7. Stress-responsive hydroxycinnamate glycosyltransferase modulates phenylpropanoid metabolism in Populus

    OpenAIRE

    2014-01-01

    The diversity of phenylpropanoids offers a rich inventory of bioactive chemicals that can be exploited for plant improvement and human health. Recent evidence suggests that glycosylation may play a role in the partitioning of phenylpropanoid precursors for a variety of downstream uses. This work reports the functional characterization of a stress-responsive glycosyltransferase, GT1-316 in Populus. GT1-316 belongs to the UGT84A subfamily of plant glycosyltransferase family 1 and is designated ...

  8. MOF maintains transcriptional programs regulating cellular stress response.

    Science.gov (United States)

    Sheikh, B N; Bechtel-Walz, W; Lucci, J; Karpiuk, O; Hild, I; Hartleben, B; Vornweg, J; Helmstädter, M; Sahyoun, A H; Bhardwaj, V; Stehle, T; Diehl, S; Kretz, O; Voss, A K; Thomas, T; Manke, T; Huber, T B; Akhtar, A

    2016-05-01

    MOF (MYST1, KAT8) is the major H4K16 lysine acetyltransferase (KAT) in Drosophila and mammals and is essential for embryonic development. However, little is known regarding the role of MOF in specific cell lineages. Here we analyze the differential role of MOF in proliferating and terminally differentiated tissues at steady state and under stress conditions. In proliferating cells, MOF directly binds and maintains the expression of genes required for cell cycle progression. In contrast, MOF is dispensable for terminally differentiated, postmitotic glomerular podocytes under physiological conditions. However, in response to injury, MOF is absolutely critical for podocyte maintenance in vivo. Consistently, we detect defective nuclear, endoplasmic reticulum and Golgi structures, as well as presence of multivesicular bodies in vivo in podocytes lacking Mof following injury. Undertaking genome-wide expression analysis of podocytes, we uncover several MOF-regulated pathways required for stress response. We find that MOF, along with the members of the non-specific lethal but not the male-specific lethal complex, directly binds to genes encoding the lysosome, endocytosis and vacuole pathways, which are known regulators of podocyte maintenance. Thus, our work identifies MOF as a key regulator of cellular stress response in glomerular podocytes.

  9. Stress Response of Offshore Structures by Equivalent Polynomial Expansion Techniques

    DEFF Research Database (Denmark)

    Sigurdsson, Gudfinnur; Nielsen, Søren R.K.

    This paper concerns an investigation of the effects of nonlinearity of drag loading on offshore structures excited by 2D wave fields, where the nonlinear term in the Morison equation is replaced by an equivalent cubic expansion. The equivalent cubic expansion coefficients for the equivalent drag...... model are obtained using the least mean square procedure. Numerical results are given. The displacement response and stress response processes obtained using the above loading model are compared with simulation results and those obtained from equivalent linearization of the drag term....

  10. Repeated forced swim stress differentially affects formalin-evoked nociceptive behaviour and the endocannabinoid system in stress normo-responsive and stress hyper-responsive rat strains.

    Science.gov (United States)

    Jennings, Elaine M; Okine, Bright N; Olango, Weredeselam M; Roche, Michelle; Finn, David P

    2016-01-01

    Repeated exposure to a homotypic stressor such as forced swimming enhances nociceptive responding in rats. However, the influence of genetic background on this stress-induced hyperalgesia is poorly understood. The aim of the present study was to compare the effects of repeated forced swim stress on nociceptive responding in Sprague-Dawley (SD) rats versus the Wistar Kyoto (WKY) rat strain, a genetic background that is susceptible to stress, negative affect and hyperalgesia. Given the well-documented role of the endocannabinoid system in stress and pain, we investigated associated alterations in endocannabinoid signalling in the dorsal horn of the spinal cord and amygdala. In SD rats, repeated forced swim stress for 10 days was associated with enhanced late phase formalin-evoked nociceptive behaviour, compared with naive, non-stressed SD controls. In contrast, WKY rats exposed to 10 days of swim stress displayed reduced late phase formalin-evoked nociceptive behaviour. Swim stress increased levels of monoacylglycerol lipase (MAGL) mRNA in the ipsilateral side of the dorsal spinal cord of SD rats, an effect not observed in WKY rats. In the amygdala, swim stress reduced anandamide (AEA) levels in the contralateral amygdala of SD rats, but not WKY rats. Additional within-strain differences in levels of CB1 receptor and fatty acid amide hydrolase (FAAH) mRNA and levels of 2-arachidonylglycerol (2-AG) were observed between the ipsilateral and contralateral sides of the dorsal horn and/or amygdala. These data indicate that the effects of repeated stress on inflammatory pain-related behaviour are different in two rat strains that differ with respect to stress responsivity and affective state and implicate the endocannabinoid system in the spinal cord and amygdala in these differences.

  11. The Slx4-Dpb11 scaffold complex: coordinating the response to replication fork stalling in S-phase and the subsequent mitosis.

    Science.gov (United States)

    Princz, Lissa N; Gritenaite, Dalia; Pfander, Boris

    2015-01-01

    Replication fork stalling at DNA lesions is a common problem during the process of DNA replication. One way to allow the bypass of these lesions is via specific recombination-based mechanisms that involve switching of the replication template to the sister chromatid. Inherent to these mechanisms is the formation of DNA joint molecules (JMs) between sister chromatids. Such JMs need to be disentangled before chromatid separation in mitosis and the activity of JM resolution enzymes, which is under stringent cell cycle control, is therefore up-regulated in mitosis. An additional layer of control is facilitated by scaffold proteins. In budding yeast, specifically during mitosis, Slx4 and Dpb11 form a cell cycle kinase-dependent complex with the Mus81-Mms4 structure-selective endonuclease, which allows efficient JM resolution by Mus81. Furthermore, Slx4 and Dpb11 interact even prior to joining Mus81 and respond to replication fork stalling in S-phase. This S-phase complex is involved in the regulation of the DNA damage checkpoint as well as in early steps of template switch recombination. Similar interactions and regulatory principles are found in human cells suggesting that Slx4 and Dpb11 may have an evolutionary conserved role organizing the cellular response to replication fork stalling.

  12. Antiviral Innate Immune Response Interferes with the Formation of Replication-Associated Membrane Structures Induced by a Positive-Strand RNA Virus

    Directory of Open Access Journals (Sweden)

    Diede Oudshoorn

    2016-12-01

    Full Text Available Infection with nidoviruses like corona- and arteriviruses induces a reticulovesicular network of interconnected endoplasmic reticulum (ER-derived double-membrane vesicles (DMVs and other membrane structures. This network is thought to accommodate the viral replication machinery and protect it from innate immune detection. We hypothesized that the innate immune response has tools to counteract the formation of these virus-induced replication organelles in order to inhibit virus replication. Here we have investigated the effect of type I interferon (IFN treatment on the formation of arterivirus-induced membrane structures. Our approach involved ectopic expression of arterivirus nonstructural proteins nsp2 and nsp3, which induce DMV formation in the absence of other viral triggers of the interferon response, such as replicating viral RNA. Thus, this setup can be used to identify immune effectors that specifically target the (formation of virus-induced membrane structures. Using large-scale electron microscopy mosaic maps, we found that IFN-β treatment significantly reduced the formation of the membrane structures. Strikingly, we also observed abundant stretches of double-membrane sheets (a proposed intermediate of DMV formation in IFN-β-treated samples, suggesting the disruption of DMV biogenesis. Three interferon-stimulated gene products, two of which have been reported to target the hepatitis C virus replication structures, were tested for their possible involvement, but none of them affected membrane structure formation. Our study reveals the existence of a previously unknown innate immune mechanism that antagonizes the viral hijacking of host membranes. It also provides a solid basis for further research into the poorly understood interactions between the innate immune system and virus-induced replication structures.

  13. Differential oxidative stress responses in castor semilooper, Achaea janata.

    Science.gov (United States)

    Pavani, Ayinampudi; Chaitanya, R K; Chauhan, Vinod K; Dasgupta, Anwesha; Dutta-Gupta, Aparna

    2015-11-01

    Balance between reactive oxygen species (ROS) and the antioxidant (AO) defense mechanisms is vital for organism survival. Insects serve as an ideal model to elucidate oxidative stress responses as they are prone to different kinds of stress during their life cycle. The present study demonstrates the modulation of AO enzyme gene expression in the insect pest, Achaea janata (castor semilooper), when subjected to different oxidative stress stimuli. Antioxidant enzymes' (catalase (Cat), superoxide dismutase (Sod), glutathione-S-transferase (GST) and glutathione peroxidase (Gpx)) partial coding sequences were cloned and characterized from larval whole body. Tissue expression studies reveal a unique pattern of AO genes in the larval tissues with maximum expression in the gut and fat body. Ontogeny profile depicts differential expression pattern through the larval developmental stages for each AO gene studied. Using quantitative RT-PCR, the expression pattern of these genes was monitored during sugar-induced (d-galactose feeding), infection-induced (Gram positive, Gram negative and non-pathogenic bacteria) and pesticide-induced oxidative stress (Bt Cry toxin). d-Galactose feeding differentially modulates the expression of AO genes in the larval gut and fat body. Immune challenge with Escherichia coli induces robust upregulation of AO genes when compared to Bacillus coagulans and Bacillus cereus in the larval fat body and gut. Cry toxin feeding predominantly induced GST upregulation in the gut. The current study suggests that though there are multiple ways of generation of oxidative stress in the insect, the organism tailors its response by insult- and tissue-specific recruitment of the antioxidant players and their differential regulation for each inducer.

  14. Viral replication rate regulates clinical outcome and CD8 T cell responses during highly pathogenic H5N1 influenza virus infection in mice.

    Directory of Open Access Journals (Sweden)

    Yasuko Hatta

    2010-10-01

    Full Text Available Since the first recorded infection of humans with H5N1 viruses of avian origin in 1997, sporadic human infections continue to occur with a staggering mortality rate of >60%. Although sustained human-to-human transmission has not occurred yet, there is a growing concern that these H5N1 viruses might acquire this trait and raise the specter of a pandemic. Despite progress in deciphering viral determinants of pathogenicity, we still lack crucial information on virus/immune system interactions pertaining to severe disease and high mortality associated with human H5N1 influenza virus infections. Using two human isolates of H5N1 viruses that differ in their pathogenicity in mice, we have defined mechanistic links among the rate of viral replication, mortality, CD8 T cell responses, and immunopathology. The extreme pathogenicity of H5N1 viruses was directly linked to the ability of the virus to replicate rapidly, and swiftly attain high steady-state titers in the lungs within 48 hours after infection. The remarkably high replication rate of the highly pathogenic H5N1 virus did not prevent the induction of IFN-β or activation of CD8 T cells, but the CD8 T cell response was ineffective in controlling viral replication in the lungs and CD8 T cell deficiency did not affect viral titers or mortality. Additionally, BIM deficiency ameliorated lung pathology and inhibited T cell apoptosis without affecting survival of mice. Therefore, rapidly replicating, highly lethal H5N1 viruses could simply outpace and overwhelm the adaptive immune responses, and kill the host by direct cytopathic effects. However, therapeutic suppression of early viral replication and the associated enhancement of CD8 T cell responses improved the survival of mice following a lethal H5N1 infection. These findings suggest that suppression of early H5N1 virus replication is key to the programming of an effective host response, which has implications in treatment of this infection in humans.

  15. Viral replication rate regulates clinical outcome and CD8 T cell responses during highly pathogenic H5N1 influenza virus infection in mice.

    Science.gov (United States)

    Hatta, Yasuko; Hershberger, Karen; Shinya, Kyoko; Proll, Sean C; Dubielzig, Richard R; Hatta, Masato; Katze, Michael G; Kawaoka, Yoshihiro; Suresh, M

    2010-10-07

    Since the first recorded infection of humans with H5N1 viruses of avian origin in 1997, sporadic human infections continue to occur with a staggering mortality rate of >60%. Although sustained human-to-human transmission has not occurred yet, there is a growing concern that these H5N1 viruses might acquire this trait and raise the specter of a pandemic. Despite progress in deciphering viral determinants of pathogenicity, we still lack crucial information on virus/immune system interactions pertaining to severe disease and high mortality associated with human H5N1 influenza virus infections. Using two human isolates of H5N1 viruses that differ in their pathogenicity in mice, we have defined mechanistic links among the rate of viral replication, mortality, CD8 T cell responses, and immunopathology. The extreme pathogenicity of H5N1 viruses was directly linked to the ability of the virus to replicate rapidly, and swiftly attain high steady-state titers in the lungs within 48 hours after infection. The remarkably high replication rate of the highly pathogenic H5N1 virus did not prevent the induction of IFN-β or activation of CD8 T cells, but the CD8 T cell response was ineffective in controlling viral replication in the lungs and CD8 T cell deficiency did not affect viral titers or mortality. Additionally, BIM deficiency ameliorated lung pathology and inhibited T cell apoptosis without affecting survival of mice. Therefore, rapidly replicating, highly lethal H5N1 viruses could simply outpace and overwhelm the adaptive immune responses, and kill the host by direct cytopathic effects. However, therapeutic suppression of early viral replication and the associated enhancement of CD8 T cell responses improved the survival of mice following a lethal H5N1 infection. These findings suggest that suppression of early H5N1 virus replication is key to the programming of an effective host response, which has implications in treatment of this infection in humans.

  16. Cell identity regulators link development and stress responses in the Arabidopsis root.

    Science.gov (United States)

    Iyer-Pascuzzi, Anjali S; Jackson, Terry; Cui, Hongchang; Petricka, Jalean J; Busch, Wolfgang; Tsukagoshi, Hironaka; Benfey, Philip N

    2011-10-18

    Stress responses in plants are tightly coordinated with developmental processes, but interaction of these pathways is poorly understood. We used genome-wide assays at high spatiotemporal resolution to understand the processes that link development and stress in the Arabidopsis root. Our meta-analysis finds little evidence for a universal stress response. However, common stress responses appear to exist with many showing cell type specificity. Common stress responses may be mediated by cell identity regulators because mutations in these genes resulted in altered responses to stress. Evidence for a direct role for cell identity regulators came from genome-wide binding profiling of the key regulator SCARECROW, which showed binding to regulatory regions of stress-responsive genes. Coexpression in response to stress was used to identify genes involved in specific developmental processes. These results reveal surprising linkages between stress and development at cellular resolution, and show the power of multiple genome-wide data sets to elucidate biological processes.

  17. A replication study for genome-wide gene expression levels in two layer lines elucidates differentially expressed genes of pathways involved in bone remodeling and immune responsiveness.

    Directory of Open Access Journals (Sweden)

    Christin Habig

    Full Text Available The current replication study confirmed significant differences in gene expression profiles of the cerebrum among the two commercial layer lines Lohmann Selected Leghorn (LSL and Lohmann Brown (LB. Microarray analyses were performed for 30 LSL and another 30 LB laying hens kept in the small group housing system Eurovent German. A total of 14,103 microarray probe sets using customized Affymetrix ChiGene-1_0-st Arrays with 20,399 probe sets were differentially expressed among the two layer lines LSL and LB (FDR adjusted P-value <0.05. An at least 2-fold change in expression levels could be observed for 388 of these probe sets. In LSL, 214 of the 388 probe sets were down- and 174 were up-regulated and vice versa for the LB layer line. Among the 174 up-regulated probe sets in LSL, we identified 51 significantly enriched Gene ontology (GO terms of the biological process category. A total of 63 enriched GO-terms could be identified for the 214 down-regulated probe sets of the layer line LSL. We identified nine genes significantly differentially expressed between the two layer lines in both microarray experiments. These genes play a crucial role in protection of neuronal cells from oxidative stress, bone mineral density and immune response among the two layer lines LSL and LB. Thus, the different regulation of these genes may significantly contribute to phenotypic trait differences among these layer lines. In conclusion, these novel findings provide a basis for further research to improve animal welfare in laying hens and these layer lines may be of general interest as an animal model.

  18. Caregiving and Developmental Factors Differentiating Young At-Risk Urban Children Showing Resilient Versus Stress-Affected Outcomes: A Replication and Extension.

    Science.gov (United States)

    Wyman, Peter A.; And Others

    1999-01-01

    Tested hypotheses from an organizational-developmental model for childhood resilience among 7- to 9-year olds. Found that caregiving factors and early development differentiated children with resilient and stress-affected adaptations. Variables reflecting emotionally responsive, competent parenting were direct, proximal predictors of resilience…

  19. Long Term Salinity Stress Reveals Variety Specific Differences in Root Oxidative Stress Response

    Institute of Scientific and Technical Information of China (English)

    Prasad SENADHEERA; Shamala TIRIMANNE; Frans J M MAATHUIS

    2012-01-01

    Salinity stress induces oxidative stress caused by reactive oxygen species (ROS):superoxide radicals,hydrogen peroxide (H2O2) and hydroxyl radicals.Activities of both enzymatic and non-enzymatic components of the antioxidant system and related growth parameters were studied in the roots of the salt tolerant rice variety FL478 and the sensitive variety IR29 in response to long term stress (12 d) induced by 50 mmol/L NaCl.The comparative study showed that FL478maintained higher relative growth rate and lower Na+/K+ in the roots than IR29 due to a higher membrane stability index that effectively exclude Na+.Lower TBARS (thiobarbituric acid reactive substance) content in FL478 roots indicated that its membrane was relatively unaffected by ROS despite high H2O2 content recorded under the salinity stress.Relatively higher superoxide dismutase activity along with a parallel increase in transcript level of superoxide dismutase (Os07946990) in FL478 indicated that this protein might make a vital contribution to salt stress tolerance.Although the content of ascorbic acid remained unchanged in FL478,the activity of ascorbic peroxidases (APOXs) was reduced comparably in the both varieties.Transcriptomic data showed that a larger number of peroxidase genes were upregulated in FL478 compared to IR29 and several of which might provide engineering targets to improve rice salt tolerance.

  20. Reconstructing a Network of Stress-Response Regulators via Dynamic System Modeling of Gene Regulation

    Directory of Open Access Journals (Sweden)

    Wei-Sheng Wu

    2008-01-01

    Full Text Available Unicellular organisms such as yeasts have evolved mechanisms to respond to environmental stresses by rapidly reorganizing the gene expression program. Although many stress-response genes in yeast have been discovered by DNA microarrays, the stress-response transcription factors (TFs that regulate these stress-response genes remain to be investigated. In this study, we use a dynamic system model of gene regulation to describe the mechanism of how TFs may control a gene’s expression. Then, based on the dynamic system model, we develop the Stress Regulator Identification Algorithm (SRIA to identify stress-response TFs for six kinds of stresses. We identified some general stress-response TFs that respond to various stresses and some specific stress-response TFs that respond to one specifi c stress. The biological significance of our findings is validated by the literature. We found that a small number of TFs is probably suffi cient to control a wide variety of expression patterns in yeast under different stresses. Two implications can be inferred from this observation. First, the response mechanisms to different stresses may have a bow-tie structure. Second, there may be regulatory cross-talks among different stress responses. In conclusion, this study proposes a network of stress-response regulators and the details of their actions.

  1. Reconstructing a network of stress-response regulators via dynamic system modeling of gene regulation.

    Science.gov (United States)

    Wu, Wei-Sheng; Li, Wen-Hsiung; Chen, Bor-Sen

    2008-02-10

    Unicellular organisms such as yeasts have evolved mechanisms to respond to environmental stresses by rapidly reorganizing the gene expression program. Although many stress-response genes in yeast have been discovered by DNA microarrays, the stress-response transcription factors (TFs) that regulate these stress-response genes remain to be investigated. In this study, we use a dynamic system model of gene regulation to describe the mechanism of how TFs may control a gene's expression. Then, based on the dynamic system model, we develop the Stress Regulator Identification Algorithm (SRIA) to identify stress-response TFs for six kinds of stresses. We identified some general stress-response TFs that respond to various stresses and some specific stress-response TFs that respond to one specific stress. The biological significance of our findings is validated by the literature. We found that a small number of TFs is probably sufficient to control a wide variety of expression patterns in yeast under different stresses. Two implications can be inferred from this observation. First, the response mechanisms to different stresses may have a bow-tie structure. Second, there may be regulatory cross-talks among different stress responses. In conclusion, this study proposes a network of stress-response regulators and the details of their actions.

  2. Plasmid DNA initiates replication of yellow fever vaccine in vitro and elicits virus-specific immune response in mice

    Energy Technology Data Exchange (ETDEWEB)

    Tretyakova, Irina; Nickols, Brian; Hidajat, Rachmat [Medigen, Inc., 8420 Gas House Pike, Suite S, Frederick, MD 21701 (United States); Jokinen, Jenny; Lukashevich, Igor S. [Department of Pharmacology and Toxicology, School of Medicine, Center for Predictive Medicine and Emerging Infectious Diseases, University of Louisville, Louisville, KY (United States); Pushko, Peter, E-mail: ppushko@medigen-usa.com [Medigen, Inc., 8420 Gas House Pike, Suite S, Frederick, MD 21701 (United States)

    2014-11-15

    Yellow fever (YF) causes an acute hemorrhagic fever disease in tropical Africa and Latin America. To develop a novel experimental YF vaccine, we applied iDNA infectious clone technology. The iDNA represents plasmid that encodes the full-length RNA genome of 17D vaccine downstream from a cytomegalovirus (CMV) promoter. The vaccine was designed to transcribe the full-length viral RNA and to launch 17D vaccine virus in vitro and in vivo. Transfection with 10 ng of iDNA plasmid was sufficient to start replication of vaccine virus in vitro. Safety of the parental 17D and iDNA-derived 17D viruses was confirmed in AG129 mice deficient in receptors for IFN-α/β/γ. Finally, direct vaccination of BALB/c mice with a single 20 μg dose of iDNA plasmid resulted in seroconversion and elicitation of virus-specific neutralizing antibodies in animals. We conclude that iDNA immunization approach combines characteristics of DNA and attenuated vaccines and represents a promising vaccination strategy for YF. - Highlights: • The iDNA{sup ®} platform combines advantages of DNA and live attenuated vaccines. • Yellow fever (YF) 17D vaccine was launched from iDNA plasmid in vitro and in vivo. • Safety of iDNA-generated 17D virus was confirmed in AG129 mice. • BALB/c mice seroconverted after a single-dose vaccination with iDNA. • YF virus-neutralizing response was elicited in iDNA-vaccinated mice.

  3. Anthropometric dependence of the response of a thorax FE model under high speed loading: validation and real world accident replication.

    Science.gov (United States)

    Roth, Sébastien; Torres, Fabien; Feuerstein, Philippe; Thoral-Pierre, Karine

    2013-05-01

    Finite element analysis is frequently used in several fields such as automotive simulations or biomechanics. It helps researchers and engineers to understand the mechanical behaviour of complex structures. The development of computer science brought the possibility to develop realistic computational models which can behave like physical ones, avoiding the difficulties and costs of experimental tests. In the framework of biomechanics, lots of FE models have been developed in the last few decades, enabling the investigation of the behaviour of the human body submitted to heavy damage such as in road traffic accidents or in ballistic impact. In both cases, the thorax/abdomen/pelvis system is frequently injured. The understanding of the behaviour of this complex system is of extreme importance. In order to explore the dynamic response of this system to impact loading, a finite element model of the human thorax/abdomen/pelvis system has, therefore, been developed including the main organs: heart, lungs, kidneys, liver, spleen, the skeleton (with vertebrae, intervertebral discs, ribs), stomach, intestines, muscles, and skin. The FE model is based on a 3D reconstruction, which has been made from medical records of anonymous patients, who have had medical scans with no relation to the present study. Several scans have been analyzed, and specific attention has been paid to the anthropometry of the reconstructed model, which can be considered as a 50th percentile male model. The biometric parameters and laws have been implemented in the dynamic FE code (Radioss, Altair Hyperworks 11©) used for dynamic simulations. Then the 50th percentile model was validated against experimental data available in the literature, i