25 CFR 161.603 - Can mediation be used in the event of a permit violation or dispute?

Science.gov (United States)

2010-04-01

... 25 Indians 1 2010-04-01 2010-04-01 false Can mediation be used in the event of a permit violation... AND WATER NAVAJO PARTITIONED LANDS GRAZING PERMITS Permit Violations § 161.603 Can mediation be used... to be resolved with the District Grazing Committee through mediation. (a) The District Grazing...

Insights into the molecular mechanism of RGL2-mediated inhibition of seed germination in Arabidopsis thaliana

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Stamm Petra

2012-10-01

Full Text Available Abstract Background Seed germination is of immense significance for agriculture and has been studied for centuries. Yet, our understanding of the molecular mechanisms underlying regulation of dormancy and germination is still in its infancy. Gibberellins are the key phytohormones that promote germination, and the DELLA protein RGL2 is the main signalling intermediate involved in this response. Germination is completely inhibited if functional RGL2 is overexpressed and/or stabilized; however, the molecular mechanisms of RGL2 function are still largely unknown. We therefore attempted to shed light onto some of the genetic events downstream of RGL2. Results Gene ontology of the transcriptome differentially regulated by RGL2, as well as extensive cross-comparison with other available microarray data indicates that RGL2-mediated inhibition of germination causes seeds to enter a state of dormancy. RGL2 also appears to differentially regulate a number of transcription factors, many of which are known to be involved in light- or phytohormone-mediated aspects of germination. A promoter analysis of differentially expressed genes identified an enrichment of several motifs that can be bound by specific transcription factors, for example GAMYB, ARF1, or Dof-type zinc fingers. We show that Dof-binding motifs indeed play a role in RGL2-mediated transcription. Using Chromatin Immunoprecipitation (ChIP, we show that RGL2 directly downregulates at least one cell wall modifying enzyme, which is predicted to constrain cell growth thereby leading to inhibition of seed germination. Conclusions Our results reveal that RGL2 controls various aspects of germination. Through the repression of cell wall modifying enzymes, cell growth is directly constrained to inhibit germination. Furthermore, RGL2 likely interacts with various types of proteins to regulate transcription, and differentially regulates several transcription factors. Collectively, our data indicate that

Perceiving a negative event as central to one's identity partially mediates age differences in posttraumatic stress disorder symptoms.

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Boals, Adriel; Hayslip, Bert; Knowles, Laura R; Banks, Jonathan B

2012-04-01

Older adults report fewer posttraumatic stress disorder (PTSD) symptoms than younger adults, but the reasons for this age difference are unclear. In the current study, the authors explored the extent to which they may be due to age differences in event centrality (the extent to which a person construes a stressful event as central to their identity). A sample of older and younger adults nominated their most stressful event and completed measures of PTSD symptoms and event centrality. The results revealed that older adults were less likely to construe a stressful event as central to identity, even after controlling for type of event, how long ago the event occurred, and gender. In addition, the results of a mediation analysis indicated that age-related differences in event centrality partially mediated age-related differences in PTSD symptoms. The results are consistent with the Socioemotional Selectivity Theory view that older adults tend to use cognitive strategies designed to protect emotional health.

Mediators of the relationship between life events and memory functioning in a community sample of adults

NARCIS (Netherlands)

Korten, N.C.M.; Sliwinski, M.J.; Comijs, H.C.; Smyth, J.M.

2014-01-01

The present study examines the association of frequency and severity of life events with memory functioning in a community sample of adults. We tested the hypothesis that stress-related cognitive interference mediated the effects of recent life events on cognition, in addition to examining the

Ultraviolet radiation-induced interleukin 6 release in HeLa cells is mediated via membrane events in a DNA damage-independent way.

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Kulms, D; Pöppelmann, B; Schwarz, T

2000-05-19

Evidence exists that ultraviolet radiation (UV) affects molecular targets in the nucleus or at the cell membrane. UV-induced apoptosis was found to be mediated via DNA damage and activation of death receptors, suggesting that nuclear and membrane effects are not mutually exclusive. To determine whether participation of nuclear and membrane components is also essential for other UV responses, we studied the induction of interleukin-6 (IL-6) by UV. Exposing HeLa cells to UV at 4 degrees C, which inhibits activation of surface receptors, almost completely prevented IL-6 release. Enhanced repair of UV-mediated DNA damage by addition of the DNA repair enzyme photolyase did not affect UV-induced IL-6 production, suggesting that in this case membrane events predominant over nuclear effects. UV-induced IL-6 release is mediated via NFkappaB since the NFkappaB inhibitor MG132 or transfection of cells with a super-repressor form of the NFkappaB inhibitor IkappaB reduced IL-6 release. Transfection with a dominant negative mutant of the signaling protein TRAF-2 reduced IL-6 release upon exposure to UV, indicating that UV-induced IL-6 release is mediated by activation of the tumor necrosis factor receptor-1. These data demonstrate that UV can exert biological effects mainly by affecting cell surface receptors and that this is independent of its ability to induce nuclear DNA damage.

MAPKs are essential upstream signaling pathways in proteolytic cartilage degradation--divergence in pathways leading to aggrecanase and MMP-mediated articular cartilage degradation

DEFF Research Database (Denmark)

Sondergaard, B-C; Schultz, N; Madsen, S H

2010-01-01

Matrix metalloproteinases (MMPs) and aggrecanases are essential players in cartilage degradation. However, the signaling pathways that results in MMP and/or aggrecanase synthesis and activation are not well understood. We investigated the molecular events leading to MMP- and aggrecanase-mediated ......Matrix metalloproteinases (MMPs) and aggrecanases are essential players in cartilage degradation. However, the signaling pathways that results in MMP and/or aggrecanase synthesis and activation are not well understood. We investigated the molecular events leading to MMP- and aggrecanase......-mediated cartilage degradation....

Positive future orientation as a mediator between traumatic events and mental health among children affected by HIV/AIDS in rural China.

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Zhang, Jintao; Zhao, Guoxiang; Li, Xiaoming; Hong, Yan; Fang, Xiaoyi; Barnett, Douglas; Lin, Xiuyun; Zhao, Junfeng; Zhang, Liying

2009-12-01

The current study was designed to explore the effect of future orientation in mediating the relationship between traumatic events and mental health in children affected by HIV/AIDS in rural China. Cross-sectional data were collected from 1221 children affected by HIV/AIDS (755 AIDS orphans and 466 vulnerable children). Future orientation among children was measured using three indicators (future expectation, hopefulness toward the future, and perceived control over the future). Measures of mental health consisted of depression, loneliness, and self-esteem. Children's experience of any traumatic events was measured using a modified version of the Life Incidence of Traumatic Events-Student Form. Mediation analysis was conducted using structural equation modeling (SEM) methods. Among the children surveyed, most of the traumatic indicators were negatively associated with future expectation, hopefulness, perceived control, and self-esteem, and positively associated with depression and loneliness. The SEM of mediation analysis demonstrated an adequate fit. Future orientation fully mediated the relationship between traumatic events and mental health and accounted for 67.9% of the total effect of traumatic events on mental health. Results of this study support the positive effect of future expectation in mediating the relationship between traumatic events and mental health among children affected by HIV/AIDS in China. Future mental health promotion and intervention efforts targeting children affected by HIV/AIDS should include components that can mitigate the negative impact of traumatic events on their lives. These components may aim to develop children's positive future expectations, increase their hopefulness toward the future, and improve their perceived control over the future.

Molecular aspects in inflammatory events of temporomandibular joint: Microarray-based identification of mediators

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Naomi Ogura

2015-02-01

Full Text Available Synovial inflammation (synovitis frequently accompanies intracapsular pathologic conditions of the temporomandibular joint (TMJ such as internal derangement (ID and/or osteoarthritis (OA, and is suggested to be associated with symptom severity. To identify the putative factors associated with synovitis, we investigated interleukin (IL-1β- and/or tumor necrosis factor (TNF-α-responsive genes of fibroblast-like synoviocytes (FLS from patients with ID and/or OA of TMJ using microarray analysis. In this review, we first summarize the FLS of TMJ and the signaling pathways of IL-1β and TNF-α. Next, we show the up-regulated genes in FLS after stimulation with IL-1β or TNF-α, and summarize the gene functions based on recent studies. Among the top 10 up-regulated factors, molecules such as IL-6 and cycrooxygense-2 have been well characterized and investigated in the inflammatory responses and tissue destruction associated with joint diseases such as RA and OA, but the roles of some molecules remain unclear. The FLS reaction can lead to the synthesis and release of a wide variety of inflammatory mediators. Some of these mediators are detected in joint tissues and synovial fluids under intracapsular pathologic conditions, and may represent potential targets for therapeutic interventions in ID and/or OA of TMJ.

Caspase-dependant activation of chymotrypsin-like proteases mediates nuclear events during Jurkat T cell apoptosis

International Nuclear Information System (INIS)

O'Connell, A.R.; Lee, B.W.; Stenson-Cox, C.

2006-01-01

Apoptosis involves a cascade of biochemical and morphological changes resulting in the systematic disintegration of the cell. Caspases are central mediators of this process. Supporting and primary roles for serine proteases as pro-apoptotic mediators have also been highlighted. Evidence for such roles comes largely from the use of pharmacological inhibitors; as a consequence information regarding their apoptotic function and biochemical properties has been limited. Here, we circumvented limitations associated with traditional serine protease inhibitors through use of a fluorescently labelled inhibitor of serine proteases (FLISP) that allowed for analysis of the specificity, regulation and positioning of apoptotic serine proteases within a classical apoptotic cascade. We demonstrate that staurosporine triggers a caspase-dependant induction of chymotrypsin-like activity in the nucleus of apoptotic Jurkat T cells. We show that serine protease activity is required for the generation of late stage nuclear events including condensation, fragmentation and DNA degradation. Furthermore, we reveal caspase-dependant activation of two chymotrypsin-like protein species that we hypothesize mediate cell death-associated nuclear events

Pathogenesis of pulmonary emphysema – cellular and molecular events

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Antonio Di Petta

2010-06-01

Full Text Available Pulmonary emphysema is a chronic obstructive disease, resulting fromimportant alterations in the whole distal structure of terminal bronchioles, either by enlargement of air spaces or by destruction of the alveolar wall, leading to loss of respiratory surface, decreased elastic recoil and lung hyperinflation. For many years, the hypothesis of protease-antiprotease unbalance prevailed as the central theme in the pathogenesis of pulmonary emphysema. According to this hypothesis, the release of active proteolytic enzymes, produced mainly by neutrophils and macrophages, degrades the extracellular matrix, affecting the integrity of its components, especially collagen and elastic fibers. However, new concepts involving cellular and molecular events were proposed, including oxidative stress, cell apoptosis, cellular senescence and failed lung tissue repair. The aim of this review paper was to evaluate the cellular and molecular mechanisms seen in the pathogenesis of pulmonary emphysema.

The mediating role of emotional intelligence between negative life events and psychological distress among nursing students: A cross-sectional study.

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Zhang, Pan; Li, Chang-Zai; Zhao, Ya-Ning; Xing, Feng-Mei; Chen, Chang-Xiang; Tian, Xi-Feng; Tang, Qi-Qun

2016-09-01

Previous studies have highlighted that negative life events and emotional intelligence are significant predictors of mental health. However, whether emotional intelligence mediates the relationship between negative life events and psychological distress among nursing students have not been given adequate attention. To explore the relationship among negative life events, emotional intelligence and psychological distress and to examine the mediating role of emotional intelligence in psychological distress among Chinese nursing students. A cross-sectional survey using convenience sampling. A total of 467 nursing students who were enrolled in a university in mainland of China. A structured questionnaire was administered from September-November in 2013 to participants who consented to participate in the study. Independent variables were personal variables, emotional intelligence and negative life events. Outcome variable was psychological health. The means and standard deviations were computed. Student's t-test and one-way analysis of variance (ANOVA) were performed, to test the differences among the demographic characteristics on the psychological distress scores. Pearson correlation analyses and hierarchical regression analyses were performed. Negative life events were positively associated with psychological distress. Emotional intelligence was negatively associated with psychological distress and negative life events. Emotional intelligence mediated the relationship between negative life events and psychological distress. The findings support the theory of Salovey and his colleagues, and provide evidence for emotional intelligence as a factor that buffers effects of negative life events on psychological distress. Copyright © 2016 Elsevier Ltd. All rights reserved.

NMD Classifier: A reliable and systematic classification tool for nonsense-mediated decay events.

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Min-Kung Hsu

Full Text Available Nonsense-mediated decay (NMD degrades mRNAs that include premature termination codons to avoid the translation and accumulation of truncated proteins. This mechanism has been found to participate in gene regulation and a wide spectrum of biological processes. However, the evolutionary and regulatory origins of NMD-targeted transcripts (NMDTs have been less studied, partly because of the complexity in analyzing NMD events. Here we report NMD Classifier, a tool for systematic classification of NMD events for either annotated or de novo assembled transcripts. This tool is based on the assumption of minimal evolution/regulation-an event that leads to the least change is the most likely to occur. Our simulation results indicate that NMD Classifier can correctly identify an average of 99.3% of the NMD-causing transcript structural changes, particularly exon inclusions/exclusions and exon boundary alterations. Researchers can apply NMD Classifier to evolutionary and regulatory studies by comparing NMD events of different biological conditions or in different organisms.

Endpoint visual detection of three genetically modified rice events by loop-mediated isothermal amplification.

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Chen, Xiaoyun; Wang, Xiaofu; Jin, Nuo; Zhou, Yu; Huang, Sainan; Miao, Qingmei; Zhu, Qing; Xu, Junfeng

2012-11-07

Genetically modified (GM) rice KMD1, TT51-1, and KF6 are three of the most well known transgenic Bt rice lines in China. A rapid and sensitive molecular assay for risk assessment of GM rice is needed. Polymerase chain reaction (PCR), currently the most common method for detecting genetically modified organisms, requires temperature cycling and relatively complex procedures. Here we developed a visual and rapid loop-mediated isothermal amplification (LAMP) method to amplify three GM rice event-specific junction sequences. Target DNA was amplified and visualized by two indicators (SYBR green or hydroxy naphthol blue [HNB]) within 60 min at an isothermal temperature of 63 °C. Different kinds of plants were selected to ensure the specificity of detection and the results of the non-target samples were negative, indicating that the primer sets for the three GM rice varieties had good levels of specificity. The sensitivity of LAMP, with detection limits at low concentration levels (0.01%−0.005% GM), was 10- to 100-fold greater than that of conventional PCR. Additionally, the LAMP assay coupled with an indicator (SYBR green or HNB) facilitated analysis. These findings revealed that the rapid detection method was suitable as a simple field-based test to determine the status of GM crops.

Endpoint Visual Detection of Three Genetically Modified Rice Events by Loop-Mediated Isothermal Amplification

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Qing Zhu

2012-11-01

Full Text Available Genetically modified (GM rice KMD1, TT51-1, and KF6 are three of the most well known transgenic Bt rice lines in China. A rapid and sensitive molecular assay for risk assessment of GM rice is needed. Polymerase chain reaction (PCR, currently the most common method for detecting genetically modified organisms, requires temperature cycling and relatively complex procedures. Here we developed a visual and rapid loop-mediated isothermal amplification (LAMP method to amplify three GM rice event-specific junction sequences. Target DNA was amplified and visualized by two indicators (SYBR green or hydroxy naphthol blue [HNB] within 60 min at an isothermal temperature of 63 °C. Different kinds of plants were selected to ensure the specificity of detection and the results of the non-target samples were negative, indicating that the primer sets for the three GM rice varieties had good levels of specificity. The sensitivity of LAMP, with detection limits at low concentration levels (0.01%–0.005% GM, was 10- to 100-fold greater than that of conventional PCR. Additionally, the LAMP assay coupled with an indicator (SYBR green or HNB facilitated analysis. These findings revealed that the rapid detection method was suitable as a simple field-based test to determine the status of GM crops.

Molecular events leading to HPV-induced high grade neoplasia

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Saskia M. Wilting

2016-12-01

Full Text Available Cervical cancer is initiated by high-risk types of the human papillomavirus (hrHPV and develops via precursor stages, called cervical intraepithelial neoplasia (CIN. High-grade CIN lesions are considered true precancerous lesions when the viral oncogenes E6 and E7 are aberrantly expressed in the dividing cells. This results in abolishment of normal cell cycle control via p53 and pRb degradation. However, it has become clear that these viral oncogenes possess additional oncogenic properties, including interference with the DNA methylation machinery and mitotic checkpoints. Identification of the resulting molecular events leading to high-grade neoplasia will 1 increase our understanding of cervical carcinogenesis, 2 yield biomarkers for early diagnosis, and 3 identify therapeutic targets for HPV-induced (pre cancerous lesions.This review will briefly summarise current advances in our understanding of the molecular alterations in the host cell genome that occur during HPV-induced carcinogenesis.

Action-Derived Molecular Dynamics in the Study of Rare Events

Energy Technology Data Exchange (ETDEWEB)

Passerone, Daniele; Parrinello, Michele

2001-09-03

We present a practical method to generate classical trajectories with fixed initial and final boundary conditions. Our method is based on the minimization of a suitably defined discretized action. The method finds its most natural application in the study of rare events. Its capabilities are illustrated by nontrivial examples. The algorithm lends itself to straightforward parallelization, and when combined with ab initio molecular dynamics it promises to offer a powerful tool for the study of chemical reactions.

Action-Derived Molecular Dynamics in the Study of Rare Events

International Nuclear Information System (INIS)

Passerone, Daniele; Parrinello, Michele

2001-01-01

We present a practical method to generate classical trajectories with fixed initial and final boundary conditions. Our method is based on the minimization of a suitably defined discretized action. The method finds its most natural application in the study of rare events. Its capabilities are illustrated by nontrivial examples. The algorithm lends itself to straightforward parallelization, and when combined with ab initio molecular dynamics it promises to offer a powerful tool for the study of chemical reactions

The Dutch queen’s day event : How subjective experience mediates the relationship between motivation and satisfaction

NARCIS (Netherlands)

de Geus, S.; Richards, G.W.; Toepoel, V.

2013-01-01

Purpose The purpose of this paper is to clarify the relationship between subjective experience of an event, motivational style for participating and satisfaction afterwards. It proposes that subjective experience of positive affect acts as a mediator between motivation and satisfaction.

Molecular Characterization of Transgenic Events Using Next Generation Sequencing Approach.

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Guttikonda, Satish K; Marri, Pradeep; Mammadov, Jafar; Ye, Liang; Soe, Khaing; Richey, Kimberly; Cruse, James; Zhuang, Meibao; Gao, Zhifang; Evans, Clive; Rounsley, Steve; Kumpatla, Siva P

2016-01-01

Demand for the commercial use of genetically modified (GM) crops has been increasing in light of the projected growth of world population to nine billion by 2050. A prerequisite of paramount importance for regulatory submissions is the rigorous safety assessment of GM crops. One of the components of safety assessment is molecular characterization at DNA level which helps to determine the copy number, integrity and stability of a transgene; characterize the integration site within a host genome; and confirm the absence of vector DNA. Historically, molecular characterization has been carried out using Southern blot analysis coupled with Sanger sequencing. While this is a robust approach to characterize the transgenic crops, it is both time- and resource-consuming. The emergence of next-generation sequencing (NGS) technologies has provided highly sensitive and cost- and labor-effective alternative for molecular characterization compared to traditional Southern blot analysis. Herein, we have demonstrated the successful application of both whole genome sequencing and target capture sequencing approaches for the characterization of single and stacked transgenic events and compared the results and inferences with traditional method with respect to key criteria required for regulatory submissions.

Molecular Characterization of Transgenic Events Using Next Generation Sequencing Approach.

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Satish K Guttikonda

Full Text Available Demand for the commercial use of genetically modified (GM crops has been increasing in light of the projected growth of world population to nine billion by 2050. A prerequisite of paramount importance for regulatory submissions is the rigorous safety assessment of GM crops. One of the components of safety assessment is molecular characterization at DNA level which helps to determine the copy number, integrity and stability of a transgene; characterize the integration site within a host genome; and confirm the absence of vector DNA. Historically, molecular characterization has been carried out using Southern blot analysis coupled with Sanger sequencing. While this is a robust approach to characterize the transgenic crops, it is both time- and resource-consuming. The emergence of next-generation sequencing (NGS technologies has provided highly sensitive and cost- and labor-effective alternative for molecular characterization compared to traditional Southern blot analysis. Herein, we have demonstrated the successful application of both whole genome sequencing and target capture sequencing approaches for the characterization of single and stacked transgenic events and compared the results and inferences with traditional method with respect to key criteria required for regulatory submissions.

A DNAzyme-mediated logic gate for programming molecular capture and release on DNA origami.

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Li, Feiran; Chen, Haorong; Pan, Jing; Cha, Tae-Gon; Medintz, Igor L; Choi, Jong Hyun

2016-06-28

Here we design a DNA origami-based site-specific molecular capture and release platform operated by a DNAzyme-mediated logic gate process. We show the programmability and versatility of this platform with small molecules, proteins, and nanoparticles, which may also be controlled by external light signals.

Plasticity-mediated collapse and recrystallization in hollow copper nanowires: a molecular dynamics simulation

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Amlan Dutta

2016-02-01

Full Text Available We study the thermal stability of hollow copper nanowires using molecular dynamics simulation. We find that the plasticity-mediated structural evolution leads to transformation of the initial hollow structure to a solid wire. The process involves three distinct stages, namely, collapse, recrystallization and slow recovery. We calculate the time scales associated with different stages of the evolution process. Our findings suggest a plasticity-mediated mechanism of collapse and recrystallization. This contradicts the prevailing notion of diffusion driven transport of vacancies from the interior to outer surface being responsible for collapse, which would involve much longer time scales as compared to the plasticity-based mechanism.

Peptide aptamers as new tools to modulate clathrin-mediated internalisation--inhibition of MT1-MMP internalisation.

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Wickramasinghe, Rochana D; Ko Ferrigno, Paul; Roghi, Christian

2010-07-23

Peptide aptamers are combinatorial protein reagents that bind to targets with a high specificity and a strong affinity thus providing a molecular tool kit for modulating the function of their targets in vivo. Here we report the isolation of a peptide aptamer named swiggle that interacts with the very short (21 amino acid long) intracellular domain of membrane type 1-metalloproteinase (MT1-MMP), a key cell surface protease involved in numerous and crucial physiological and pathological cellular events. Expression of swiggle in mammalian cells was found to increase the cell surface expression of MT1-MMP by impairing its internalisation. Swiggle interacts with the LLY573 internalisation motif of MT1-MMP intracellular domain, thus disrupting the interaction with the mu2 subunit of the AP-2 internalisation complex required for endocytosis of the protease. Interestingly, swiggle-mediated inhibition of MT1-MMP clathrin-mediated internalisation was also found to promote MT1-MMP-mediated cell migration. Taken together, our results provide further evidence that peptide aptamers can be used to dissect molecular events mediated by individual protein domains, in contrast to the pleiotropic effects of RNA interference techniques.

Molecular Events in Primary and Metastatic Colorectal Carcinoma: A Review

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Rani Kanthan

2012-01-01

Full Text Available Colorectal cancer (CRC is a heterogeneous disease, developing through a multipathway sequence of events guided by clonal selections. Pathways included in the development of CRC may be broadly categorized into (a genomic instability, including chromosomal instability (CIN, microsatellite instability (MSI, and CpG island methylator phenotype (CIMP, (b genomic mutations including suppression of tumour suppressor genes and activation of tumour oncogenes, (c microRNA, and (d epigenetic changes. As cancer becomes more advanced, invasion and metastases are facilitated through the epithelial-mesenchymal transition (EMT, with additional genetic alterations. Despite ongoing identification of genetic and epigenetic markers and the understanding of alternative pathways involved in the development and progression of this disease, CRC remains the second highest cause of malignancy-related mortality in Canada. The molecular events that underlie the tumorigenesis of primary and metastatic colorectal carcinoma are detailed in this manuscript.

Peptide aptamers as new tools to modulate clathrin-mediated internalisation — inhibition of MT1-MMP internalisation

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Ferrigno Paul

2010-07-01

Full Text Available Abstract Background Peptide aptamers are combinatorial protein reagents that bind to targets with a high specificity and a strong affinity thus providing a molecular tool kit for modulating the function of their targets in vivo. Results Here we report the isolation of a peptide aptamer named swiggle that interacts with the very short (21 amino acid long intracellular domain of membrane type 1-metalloproteinase (MT1-MMP, a key cell surface protease involved in numerous and crucial physiological and pathological cellular events. Expression of swiggle in mammalian cells was found to increase the cell surface expression of MT1-MMP by impairing its internalisation. Swiggle interacts with the LLY573 internalisation motif of MT1-MMP intracellular domain, thus disrupting the interaction with the μ2 subunit of the AP-2 internalisation complex required for endocytosis of the protease. Interestingly, swiggle-mediated inhibition of MT1-MMP clathrin-mediated internalisation was also found to promote MT1-MMP-mediated cell migration. Conclusions Taken together, our results provide further evidence that peptide aptamers can be used to dissect molecular events mediated by individual protein domains, in contrast to the pleiotropic effects of RNA interference techniques.

Negative life events vary by neighborhood and mediate the relation between neighborhood context and psychological well-being.

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Katherine King

Full Text Available Researchers have speculated that negative life events are more common in troubled neighborhoods, amplifying adverse effects on health. Using a clustered representative sample of Chicago residents (2001-03; n = 3,105 from the Chicago Community Adult Health Survey, we provide the first documentation that negative life events are highly geographically clustered compared to health outcomes. Associations between neighborhood context and negative life events were also found to vary by event type. We then demonstrate the power of a contextualized approach by testing path models in which life events mediate the relation between neighborhood characteristics and health outcomes, including self-rated health, anxiety, and depression. The indirect paths between neighborhood conditions and health through negative life event exposure are highly significant and large compared to the direct paths from neighborhood conditions to health. Our results indicate that neighborhood conditions can have acute as well as chronic effects on health, and that negative life events are a powerful mechanism by which context may influence health.

Negative life events vary by neighborhood and mediate the relation between neighborhood context and psychological well-being.

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King, Katherine; Ogle, Christin

2014-01-01

Researchers have speculated that negative life events are more common in troubled neighborhoods, amplifying adverse effects on health. Using a clustered representative sample of Chicago residents (2001-03; n = 3,105) from the Chicago Community Adult Health Survey, we provide the first documentation that negative life events are highly geographically clustered compared to health outcomes. Associations between neighborhood context and negative life events were also found to vary by event type. We then demonstrate the power of a contextualized approach by testing path models in which life events mediate the relation between neighborhood characteristics and health outcomes, including self-rated health, anxiety, and depression. The indirect paths between neighborhood conditions and health through negative life event exposure are highly significant and large compared to the direct paths from neighborhood conditions to health. Our results indicate that neighborhood conditions can have acute as well as chronic effects on health, and that negative life events are a powerful mechanism by which context may influence health.

Iterative Calibration: A Novel Approach for Calibrating the Molecular Clock Using Complex Geological Events.

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Loeza-Quintana, Tzitziki; Adamowicz, Sarah J

2018-02-01

During the past 50 years, the molecular clock has become one of the main tools for providing a time scale for the history of life. In the era of robust molecular evolutionary analysis, clock calibration is still one of the most basic steps needing attention. When fossil records are limited, well-dated geological events are the main resource for calibration. However, biogeographic calibrations have often been used in a simplistic manner, for example assuming simultaneous vicariant divergence of multiple sister lineages. Here, we propose a novel iterative calibration approach to define the most appropriate calibration date by seeking congruence between the dates assigned to multiple allopatric divergences and the geological history. Exploring patterns of molecular divergence in 16 trans-Bering sister clades of echinoderms, we demonstrate that the iterative calibration is predominantly advantageous when using complex geological or climatological events-such as the opening/reclosure of the Bering Strait-providing a powerful tool for clock dating that can be applied to other biogeographic calibration systems and further taxa. Using Bayesian analysis, we observed that evolutionary rate variability in the COI-5P gene is generally distributed in a clock-like fashion for Northern echinoderms. The results reveal a large range of genetic divergences, consistent with multiple pulses of trans-Bering migrations. A resulting rate of 2.8% pairwise Kimura-2-parameter sequence divergence per million years is suggested for the COI-5P gene in Northern echinoderms. Given that molecular rates may vary across latitudes and taxa, this study provides a new context for dating the evolutionary history of Arctic marine life.

Early molecular events involved in Pinus pinaster Ait. somatic embryo development under reduced water availability: transcriptomic and proteomic analyses.

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Morel, Alexandre; Teyssier, Caroline; Trontin, Jean-François; Eliášová, Kateřina; Pešek, Bedřich; Beaufour, Martine; Morabito, Domenico; Boizot, Nathalie; Le Metté, Claire; Belal-Bessai, Leila; Reymond, Isabelle; Harvengt, Luc; Cadene, Martine; Corbineau, Françoise; Vágner, Martin; Label, Philippe; Lelu-Walter, Marie-Anne

2014-09-01

Maritime pine somatic embryos (SEs) require a reduction in water availability (high gellan gum concentration in the maturation medium) to reach the cotyledonary stage. This key switch, reported specifically for pine species, is not yet well understood. To facilitate the use of somatic embryogenesis for mass propagation of conifers, we need a better understanding of embryo development. Comparison of both transcriptome (Illumina RNA sequencing) and proteome [two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis with mass spectrometry (MS) identification] of immature SEs, cultured on either high (9G) or low (4G) gellan gum concentration, was performed, together with analysis of water content, fresh and dry mass, endogenous abscisic acid (ABA; gas chromatography-MS), soluble sugars (high-pressure liquid chromatography), starch and confocal laser microscope observations. This multiscale, integrated analysis was used to unravel early molecular and physiological events involved in SE development. Under unfavorable conditions (4G), the glycolytic pathway was enhanced, possibly in relation to cell proliferation that may be antagonistic to SE development. Under favorable conditions (9G), SEs adapted to culture constraint by activating specific protective pathways, and ABA-mediated molecular and physiological responses promoting embryo development. Our results suggest that on 9G, germin-like protein and ubiquitin-protein ligase could be used as predictive markers of SE development, whereas protein phosphatase 2C could be a biomarker for culture adaptive responses. This is the first characterization of early molecular mechanisms involved in the development of pine SEs following an increase in gellan gum concentration in the maturation medium, and it is also the first report on somatic embryogenesis in conifers combining transcriptomic and proteomic datasets. © 2014 Scandinavian Plant Physiology Society.

The Role of Rumination and Stressful Life Events in the Relationship between the Qi Stagnation Constitution and Depression in Women: A Moderated Mediation Model

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Liu, Qiaosheng

2017-01-01

The qi stagnation constitution is associated with depression in traditional Chinese medicine. It is unclear how rumination and stressful life events affect the relationship between the qi stagnation constitution and depression. The Qi Stagnation Constitution Scale, Ruminative Response Scale, Center for Epidemiologic Studies Depression Scale, and Adolescent Self-Rating Life Events Checklist were used to assess this association in 1200 female college students. The results revealed that the qi stagnation constitution was positively associated with depression. Furthermore, rumination was a partial mediator of the relationship between the qi stagnation constitution and depression. In addition, stressful life events moderated the direct effect and mediating effect of the qi stagnation constitution on depression. These findings indicate that rumination and stressful life events may affect the relationship between the qi stagnation constitution and depression in women. PMID:28757889

A multiscale computational approach to dissect early events in the Erb family receptor mediated activation, differential signaling, and relevance to oncogenic transformations.

Science.gov (United States)

Liu, Yingting; Purvis, Jeremy; Shih, Andrew; Weinstein, Joshua; Agrawal, Neeraj; Radhakrishnan, Ravi

2007-06-01

We describe a hierarchical multiscale computational approach based on molecular dynamics simulations, free energy-based molecular docking simulations, deterministic network-based kinetic modeling, and hybrid discrete/continuum stochastic dynamics protocols to study the dimer-mediated receptor activation characteristics of the Erb family receptors, specifically the epidermal growth factor receptor (EGFR). Through these modeling approaches, we are able to extend the prior modeling of EGF-mediated signal transduction by considering specific EGFR tyrosine kinase (EGFRTK) docking interactions mediated by differential binding and phosphorylation of different C-terminal peptide tyrosines on the RTK tail. By modeling signal flows through branching pathways of the EGFRTK resolved on a molecular basis, we are able to transcribe the effects of molecular alterations in the receptor (e.g., mutant forms of the receptor) to differing kinetic behavior and downstream signaling response. Our molecular dynamics simulations show that the drug sensitizing mutation (L834R) of EGFR stabilizes the active conformation to make the system constitutively active. Docking simulations show preferential characteristics (for wildtype vs. mutant receptors) in inhibitor binding as well as preferential enhancement of phosphorylation of particular substrate tyrosines over others. We find that in comparison to the wildtype system, the L834R mutant RTK preferentially binds the inhibitor erlotinib, as well as preferentially phosphorylates the substrate tyrosine Y1068 but not Y1173. We predict that these molecular level changes result in preferential activation of the Akt signaling pathway in comparison to the Erk signaling pathway for cells with normal EGFR expression. For cells with EGFR over expression, the mutant over activates both Erk and Akt pathways, in comparison to wildtype. These results are consistent with qualitative experimental measurements reported in the literature. We discuss these

Energetic atomic and molecular ions of ionospheric origin observed in distant magnetotail flow-reversal events

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Christon, S. P.; Gloeckler, G.; Williams, D. J.; Mukai, T.; Mcentire, R. W.; Jacquey, C.; Angelopoulos, V.; Lui, A. T. Y.; Kokubun, S.; Fairfield, D. H.

1994-01-01

Energetic atomic (O(+1) and N(+1)) and molecular (O2(+1), NO(+1), and N2(+1)) ions of ionospheric origin were observed in Earth's magnetotail at X approximately -146 R(sub E) during two plasma sheet sunward/tailward flow-reversal events measured by instruments on the GEOTAIL spacecraft. These events were associated with concurrent ground-measured geomagnetic disturbance intensification at auroral-and mid-latitudes (Kp = 7(-)). Energetic ions in the sunward-component and tailward flows were from both the solar wind and ionosphere. Plasma and energetic ions participated in the flows. During tailward flow, ionospheric origin ion abundance ratios at approximately 200-900 km/s in the rest frame were N(+1)/O(+1) = approximately 25-30% and ((O2(+1), NO(+1), and N2(+1))/O(+1) = approximately 1-2%. We argue that tailward flow most likely initiated approximately 80-100 R(sub E) tailward of Earth and molecular ions were in the plasma sheet prior to geomagnetic intensification onset.

Molecular events in matrix protein metabolism in the aging kidney

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Sataranatarajan, Kavithalakshmi; Feliers, Denis; Mariappan, Meenalakshmi M.; Lee, Hak Joo; Lee, Myung Ja; Day, Robert T.; Yalamanchili, Hima Bindu; Choudhury, Goutam G.; Barnes, Jeffrey L.; Van Remmen, Holly; Richardson, Arlan; Kasinath, Balakuntalam S.

2018-01-01

Summary We explored molecular events associated with aging-induced matrix changes in the kidney. C57BL6 mice were studied in youth, middle age, and old age. Albuminuria and serum cystatin C level (an index of glomerular filtration) increased with aging. Renal hypertrophy was evident in middle-aged and old mice and was associated with glomerulomegaly and increase in mesangial fraction occupied by extracellular matrix. Content of collagen types I and III and fibronectin was increased with aging; increment in their mRNA varied with the phase of aging. The content of ZEB1 and ZEB2, collagen type I transcription inhibitors, and their binding to the collagen type Iα2 promoter by ChIP assay also showed age-phase-specific changes. Lack of increase in mRNA and data from polysome assay suggested decreased degradation as a potential mechanism for kidney collagen type I accumulation in the middle-aged mice. These changes occurred with increment in TGFβ mRNA and protein and activation of its SMAD3 pathway; SMAD3 binding to the collagen type Iα2 promoter was also increased. TGFβ-regulated microRNAs (miRs) exhibited selective regulation. The renal cortical content of miR-21 and miR-200c, but not miR-192, miR-200a, or miR-200b, was increased with aging. Increased miR-21 and miR-200c contents were associated with reduced expression of their targets, Sprouty-1 and ZEB2, respectively. These data show that aging is associated with complex molecular events in the kidney that are already evident in the middle age and progress to old age. Agephase-specific regulation of matrix protein synthesis occurs and involves matrix protein-specific transcriptional and post-transcriptional mechanisms. PMID:23020145

Facilitating adverse drug event detection in pharmacovigilance databases using molecular structure similarity: application to rhabdomyolysis

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Vilar, Santiago; Harpaz, Rave; Chase, Herbert S; Costanzi, Stefano; Rabadan, Raul

2011-01-01

Background Adverse drug events (ADE) cause considerable harm to patients, and consequently their detection is critical for patient safety. The US Food and Drug Administration maintains an adverse event reporting system (AERS) to facilitate the detection of ADE in drugs. Various data mining approaches have been developed that use AERS to detect signals identifying associations between drugs and ADE. The signals must then be monitored further by domain experts, which is a time-consuming task. Objective To develop a new methodology that combines existing data mining algorithms with chemical information by analysis of molecular fingerprints to enhance initial ADE signals generated from AERS, and to provide a decision support mechanism to facilitate the identification of novel adverse events. Results The method achieved a significant improvement in precision in identifying known ADE, and a more than twofold signal enhancement when applied to the ADE rhabdomyolysis. The simplicity of the method assists in highlighting the etiology of the ADE by identifying structurally similar drugs. A set of drugs with strong evidence from both AERS and molecular fingerprint-based modeling is constructed for further analysis. Conclusion The results demonstrate that the proposed methodology could be used as a pharmacovigilance decision support tool to facilitate ADE detection. PMID:21946238

The Role of Rumination and Stressful Life Events in the Relationship between the Qi Stagnation Constitution and Depression in Women: A Moderated Mediation Model

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Mingfan Liu

2017-01-01

Full Text Available The qi stagnation constitution is associated with depression in traditional Chinese medicine. It is unclear how rumination and stressful life events affect the relationship between the qi stagnation constitution and depression. The Qi Stagnation Constitution Scale, Ruminative Response Scale, Center for Epidemiologic Studies Depression Scale, and Adolescent Self-Rating Life Events Checklist were used to assess this association in 1200 female college students. The results revealed that the qi stagnation constitution was positively associated with depression. Furthermore, rumination was a partial mediator of the relationship between the qi stagnation constitution and depression. In addition, stressful life events moderated the direct effect and mediating effect of the qi stagnation constitution on depression. These findings indicate that rumination and stressful life events may affect the relationship between the qi stagnation constitution and depression in women.

Molecular insights into the m-AAA protease-mediated dislocation of transmembrane helices in the mitochondrial inner membrane.

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Lee, Seoeun; Lee, Hunsang; Yoo, Suji; Kim, Hyun

2017-12-08

Protein complexes involved in respiration, ATP synthesis, and protein import reside in the mitochondrial inner membrane; thus, proper regulation of these proteins is essential for cell viability. The m -AAA protease, a conserved hetero-hexameric AAA (ATPase associated with diverse cellular activities) protease, composed of the Yta10 and Yta12 proteins, regulates mitochondrial proteostasis by mediating protein maturation and degradation. It also recognizes and mediates the dislocation of membrane-embedded substrates, including foreign transmembrane (TM) segments, but the molecular mechanism involved in these processes remains elusive. This study investigated the role of the TM domains in the m -AAA protease by systematic replacement of one TM domain at a time in yeast. Our data indicated that replacement of the Yta10 TM2 domain abolishes membrane dislocation for only a subset of substrates, whereas replacement of the Yta12 TM2 domain impairs membrane dislocation for all tested substrates, suggesting different roles of the TM domains in each m -AAA protease subunit. Furthermore, m -AAA protease-mediated membrane dislocation was impaired in the presence of a large downstream hydrophilic moiety in a membrane substrate. This finding suggested that the m -AAA protease cannot dislocate large hydrophilic domains across the membrane, indicating that the membrane dislocation probably occurs in a lipid environment. In summary, this study highlights previously underappreciated biological roles of TM domains of the m -AAA proteases in mediating the recognition and dislocation of membrane-embedded substrates. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Delicate regulation of the cGAS-MITA-mediated innate immune response.

Science.gov (United States)

Luo, Wei-Wei; Shu, Hong-Bing

2018-02-19

Although it has long been demonstrated that cytosolic DNA is a potent immune stimulant, it is only in recent years that the molecular mechanisms of DNA-stimulated innate immune responses have emerged. Studies have established critical roles for the DNA sensor cyclic GMP-AMP synthase (cGAS) and the adapter protein MITA/STING in the innate immune response to cytosolic DNA or DNA viruses. Although the regulation of cGAS-MITA/STING-mediated signaling remains to be fully investigated, understanding the processes involved may help to explain the mechanisms of innate immune signaling events and perhaps autoinflammatory diseases and to provide potential therapeutic targets for drug intervention. In this review, we summarize recent progress on the regulation of the cGAS-MITA/STING-mediated innate immune response to DNA viruses at the organelle-trafficking, post-translational and transcriptional levels.Cellular & Molecular Immunology advance online publication, 19 February 2018; doi:10.1038/cmi.2016.51.

The effects of poverty on childhood brain development: the mediating effect of caregiving and stressful life events.

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Luby, Joan; Belden, Andy; Botteron, Kelly; Marrus, Natasha; Harms, Michael P; Babb, Casey; Nishino, Tomoyuki; Barch, Deanna

2013-12-01

IMPORTANCE The study provides novel data to inform the mechanisms by which poverty negatively impacts childhood brain development. OBJECTIVE To investigate whether the income-to-needs ratio experienced in early childhood impacts brain development at school age and to explore the mediators of this effect. DESIGN, SETTING, AND PARTICIPANTS This study was conducted at an academic research unit at the Washington University School of Medicine in St Louis. Data from a prospective longitudinal study of emotion development in preschool children who participated in neuroimaging at school age were used to investigate the effects of poverty on brain development. Children were assessed annually for 3 to 6 years prior to the time of a magnetic resonance imaging scan, during which they were evaluated on psychosocial, behavioral, and other developmental dimensions. Preschoolers included in the study were 3 to 6 years of age and were recruited from primary care and day care sites in the St Louis metropolitan area; they were annually assessed behaviorally for 5 to 10 years. Healthy preschoolers and those with clinical symptoms of depression participated in neuroimaging at school age/early adolescence. EXPOSURE Household poverty as measured by the income-to-needs ratio. MAIN OUTCOMES AND MEASURES Brain volumes of children's white matter and cortical gray matter, as well as hippocampus and amygdala volumes, obtained using magnetic resonance imaging. Mediators of interest were caregiver support/hostility measured observationally during the preschool period and stressful life events measured prospectively. RESULTS Poverty was associated with smaller white and cortical gray matter and hippocampal and amygdala volumes. The effects of poverty on hippocampal volume were mediated by caregiving support/hostility on the left and right, as well as stressful life events on the left. CONCLUSIONS AND RELEVANCE The finding that exposure to poverty in early childhood materially impacts brain

Anxiety symptoms mediate the relationship between exposure to stressful negative life events and depressive symptoms: A conditional process modelling of the protective effects of resilience.

Science.gov (United States)

Anyan, Frederick; Worsley, Lyn; Hjemdal, Odin

2017-10-01

Resilience has provided a useful framework that elucidates the effects of protective factors to overcome psychological adversities but studies that address the potential contingencies of resilience to protect against direct and indirect negative effects are lacking. These obvious gaps have also resulted in oversimplification of complex processes that can be clarified by moderated mediation associations. This study examines a conditional process modelling of the protective effects of resilience against indirect effects. Two separate samples were recruited in a cross-sectional survey from Australia and Norway to complete the Patient Health Questionnaire -9, Generalized Anxiety Disorder, Stressful Negative Life Events Questionnaire and the Resilience Scale for Adults. The final sample sizes were 206 (females=114; males=91; other=1) and 210 (females=155; males=55) for Australia and Norway respectively. Moderated mediation analyses were conducted across the samples. Anxiety symptoms mediated the relationship between exposure to stressful negative life events and depressive symptoms in both samples. Conditional indirect effects of exposure to stressful negative life events on depressive symptoms mediated by anxiety symptoms showed that high subgroup of resilience was associated with less effect of exposure to stressful negative life events through anxiety symptoms on depressive symptoms than the low subgroup of resilience. As a cross-sectional survey, the present study does not answer questions about causal processes despite the use of a conditional process modelling. These findings support that, resilience protective resources can protect against both direct and indirect - through other channels - psychological adversities. Copyright © 2017 Elsevier B.V. All rights reserved.

Cellular and molecular events leading to the development of skin cancer

International Nuclear Information System (INIS)

Melnikova, Vladislava O.; Ananthaswamy, Honnavara N.

2005-01-01

The transition from a normal cell to a neoplastic cell is a complex process and involves both genetic and epigenetic changes. The process of carcinogenesis begins when the DNA is damaged, which then leads to a cascade of events leading to the development of a tumor. Ultraviolet (UV) radiation causes DNA damage, inflammation, erythema, sunburn, immunosuppression, photoaging, gene mutations, and skin cancer. Upon DNA damage, the p53 tumor suppressor protein undergoes phosphorylation and translocation to the nucleus and aids in DNA repair or causes apoptosis. Excessive UV exposure overwhelms DNA repair mechanisms leading to induction of p53 mutations and loss of Fas-FasL interaction. Keratinocytes carrying p53 mutations acquire a growth advantage by virtue of their increased resistance to apoptosis. Thus, resistance to cell death is a key event in photocarcinogenesis and conversely, elimination of cells containing excessive UV-induced DNA damage is a key step in protecting against skin cancer development. Apoptosis-resistant keratinocytes undergo clonal expansion that eventually leads to formation of actinic keratoses and squamous cell carcinomas. In this article, we will review some of the cellular and molecular mechanisms involved in initiation and progression of UV-induced skin cancer

Cellular and molecular events leading to the development of skin cancer

Energy Technology Data Exchange (ETDEWEB)

Melnikova, Vladislava O. [Department of Immunology, University of Texas M.D. Anderson Cancer Center, P.O. Box 301402, Unit 902, Houston, TX 77030 (United States); Ananthaswamy, Honnavara N. [Department of Immunology, University of Texas M.D. Anderson Cancer Center, P.O. Box 301402, Unit 902, Houston, TX 77030 (United States)]. E-mail: hanantha@mdanderson.org

2005-04-01

The transition from a normal cell to a neoplastic cell is a complex process and involves both genetic and epigenetic changes. The process of carcinogenesis begins when the DNA is damaged, which then leads to a cascade of events leading to the development of a tumor. Ultraviolet (UV) radiation causes DNA damage, inflammation, erythema, sunburn, immunosuppression, photoaging, gene mutations, and skin cancer. Upon DNA damage, the p53 tumor suppressor protein undergoes phosphorylation and translocation to the nucleus and aids in DNA repair or causes apoptosis. Excessive UV exposure overwhelms DNA repair mechanisms leading to induction of p53 mutations and loss of Fas-FasL interaction. Keratinocytes carrying p53 mutations acquire a growth advantage by virtue of their increased resistance to apoptosis. Thus, resistance to cell death is a key event in photocarcinogenesis and conversely, elimination of cells containing excessive UV-induced DNA damage is a key step in protecting against skin cancer development. Apoptosis-resistant keratinocytes undergo clonal expansion that eventually leads to formation of actinic keratoses and squamous cell carcinomas. In this article, we will review some of the cellular and molecular mechanisms involved in initiation and progression of UV-induced skin cancer.

The multitalented Mediator complex.

Science.gov (United States)

Carlsten, Jonas O P; Zhu, Xuefeng; Gustafsson, Claes M

2013-11-01

The Mediator complex is needed for regulated transcription of RNA polymerase II (Pol II)-dependent genes. Initially, Mediator was only seen as a protein bridge that conveyed regulatory information from enhancers to the promoter. Later studies have added many other functions to the Mediator repertoire. Indeed, recent findings show that Mediator influences nearly all stages of transcription and coordinates these events with concomitant changes in chromatin organization. We review the multitude of activities associated with Mediator and discuss how this complex coordinates transcription with other cellular events. We also discuss the inherent difficulties associated with in vivo characterization of a coactivator complex that can indirectly affect diverse cellular processes via changes in gene transcription. Copyright © 2013 Elsevier Ltd. All rights reserved.

Search for supersymmetry with gauge-mediated breaking in diphoton events with missing transverse energy at CDF II.

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Aaltonen, T; Adelman, J; Alvarez González, B; Amerio, S; Amidei, D; Anastassov, A; Annovi, A; Antos, J; Apollinari, G; Apresyan, A; Arisawa, T; Artikov, A; Asaadi, J; Ashmanskas, W; Attal, A; Aurisano, A; Azfar, F; Badgett, W; Barbaro-Galtieri, A; Barnes, V E; Barnett, B A; Barria, P; Bartos, P; Bauer, G; Beauchemin, P-H; Bedeschi, F; Beecher, D; Behari, S; Bellettini, G; Bellinger, J; Benjamin, D; Beretvas, A; Bhatti, A; Binkley, M; Bisello, D; Bizjak, I; Blair, R E; Blocker, C; Blumenfeld, B; Bocci, A; Bodek, A; Boisvert, V; Bortoletto, D; Boudreau, J; Boveia, A; Brau, B; Bridgeman, A; Brigliadori, L; Bromberg, C; Brubaker, E; Budagov, J; Budd, H S; Budd, S; Burkett, K; Busetto, G; Bussey, P; Buzatu, A; Byrum, K L; Cabrera, S; Calancha, C; Camarda, S; Campanelli, M; Campbell, M; Canelli, F; Canepa, A; Carls, B; Carlsmith, D; Carosi, R; Carrillo, S; Carron, S; Casal, B; Casarsa, M; Castro, A; Catastini, P; Cauz, D; Cavaliere, V; Cavalli-Sforza, M; Cerri, A; Cerrito, L; Chang, S H; Chen, Y C; Chertok, M; Chiarelli, G; Chlachidze, G; Chlebana, F; Cho, K; Chokheli, D; Chou, J P; Choudalakis, G; Chung, K; Chung, W H; Chung, Y S; Chwalek, T; Ciobanu, C I; Ciocci, M A; Clark, A; Clark, D; Compostella, G; Convery, M E; Conway, J; Corbo, M; Cordelli, M; Cox, C A; Cox, D J; Crescioli, F; Cuenca Almenar, C; Cuevas, J; Culbertson, R; Cully, J C; Dagenhart, D; Datta, M; Davies, T; de Barbaro, P; De Cecco, S; Deisher, A; De Lorenzo, G; Dell'Orso, M; Deluca, C; Demortier, L; Deng, J; Deninno, M; d'Errico, M; Di Canto, A; di Giovanni, G P; Di Ruzza, B; Dittmann, J R; D'Onofrio, M; Donati, S; Dong, P; Dorigo, T; Dube, S; Ebina, K; Elagin, A; Erbacher, R; Errede, D; Errede, S; Ershaidat, N; Eusebi, R; Fang, H C; Farrington, S; Fedorko, W T; Feild, R G; Feindt, M; Fernandez, J P; Ferrazza, C; Field, R; Flanagan, G; Forrest, R; Frank, M J; Franklin, M; Freeman, J C; Furic, I; Gallinaro, M; Galyardt, J; Garberson, F; Garcia, J E; Garfinkel, A F; Garosi, P; Genser, K; Gerberich, H; Gerdes, D; Gessler, A; Giagu, S; Giakoumopoulou, V; Giannetti, P; Gibson, K; Gimmell, J L; Ginsburg, C M; Giokaris, N; Giordani, M; Giromini, P; Giunta, M; Giurgiu, G; Glagolev, V; Glenzinski, D; Gold, M; Goldschmidt, N; Golossanov, A; Gomez, G; Gomez-Ceballos, G; Goncharov, M; González, O; Gorelov, I; Goshaw, A T; Goulianos, K; Gresele, A; Grinstein, S; Grosso-Pilcher, C; Group, R C; Grundler, U; Guimaraes da Costa, J; Gunay-Unalan, Z; Haber, C; Hahn, K; Hahn, S R; Halkiadakis, E; Han, B-Y; Han, J Y; Happacher, F; Hara, K; Hare, D; Hare, M; Harr, R F; Hartz, M; Hatakeyama, K; Hays, C; Heck, M; Heinrich, J; Henderson, C; Herndon, M; Heuser, J; Hewamanage, S; Hidas, D; Hill, C S; Hirschbuehl, D; Hocker, A; Hou, S; Houlden, M; Hsu, S-C; Huffman, B T; Hughes, R E; Hurwitz, M; Husemann, U; Hussein, M; Huston, J; Incandela, J; Introzzi, G; Iori, M; Ivanov, A; James, E; Jang, D; Jayatilaka, B; Jeon, E J; Jha, M K; Jindariani, S; Johnson, W; Jones, M; Joo, K K; Jun, S Y; Jung, J E; Junk, T R; Kamon, T; Kar, D; Karchin, P E; Kato, Y; Kephart, R; Ketchum, W; Keung, J; Khotilovich, V; Kilminster, B; Kim, D H; Kim, H S; Kim, H W; Kim, J E; Kim, M J; Kim, S B; Kim, S H; Kim, Y K; Kimura, N; Kirsch, L; Klimenko, S; Knuteson, B; Kondo, K; Kong, D J; Konigsberg, J; Korytov, A; Kotwal, A V; Kreps, M; Kroll, J; Krop, D; Krumnack, N; Kruse, M; Krutelyov, V; Kuhr, T; Kulkarni, N P; Kurata, M; Kwang, S; Laasanen, A T; Lami, S; Lammel, S; Lancaster, M; Lander, R L; Lannon, K; Lath, A; Latino, G; Lazzizzera, I; LeCompte, T; Lee, E; Lee, H S; Lee, J S; Lee, S W; Leone, S; Lewis, J D; Lin, C-J; Linacre, J; Lindgren, M; Lipeles, E; Lister, A; Litvintsev, D O; Liu, C; Liu, T; Lockyer, N S; Loginov, A; Lovas, L; Lucchesi, D; Lueck, J; Lujan, P; Lukens, P; Lungu, G; Lys, J; Lysak, R; MacQueen, D; Madrak, R; Maeshima, K; Makhoul, K; Maksimovic, P; Malde, S; Malik, S; Manca, G; Manousakis-Katsikakis, A; Margaroli, F; Marino, C; Marino, C P; Martin, A; Martin, V; Martínez, M; Martínez-Ballarín, R; Mastrandrea, P; Mathis, M; Mattson, M E; Mazzanti, P; McFarland, K S; McIntyre, P; McNulty, R; Mehta, A; Mehtala, P; Menzione, A; Mesropian, C; Miao, T; Mietlicki, D; Miladinovic, N; Miller, R; Mills, C; Milnik, M; Mitra, A; Mitselmakher, G; Miyake, H; Moed, S; Moggi, N; Mondragon, M N; Moon, C S; Moore, R; Morello, M J; Morlock, J; Movilla Fernandez, P; Mülmenstädt, J; Mukherjee, A; Muller, Th; Murat, P; Mussini, M; Nachtman, J; Nagai, Y; Naganoma, J; Nakamura, K; Nakano, I; Napier, A; Nett, J; Neu, C; Neubauer, M S; Neubauer, S; Nielsen, J; Nodulman, L; Norman, M; Norniella, O; Nurse, E; Oakes, L; Oh, S H; Oh, Y D; Oksuzian, I; Okusawa, T; Orava, R; Osterberg, K; Pagan Griso, S; Pagliarone, C; Palencia, E; Papadimitriou, V; Papaikonomou, A; Paramanov, A A; Parks, B; Pashapour, S; Patrick, J; Pauletta, G; Paulini, M; Paus, C; Peiffer, T; Pellett, D E; Penzo, A; Phillips, T J; Piacentino, G; Pianori, E; Pinera, L; Pitts, K; Plager, C; Pondrom, L; Potamianos, K; Poukhov, O; Prokoshin, F; Pronko, A; Ptohos, F; Pueschel, E; Punzi, G; Pursley, J; Rademacker, J; Rahaman, A; Ramakrishnan, V; Ranjan, N; Redondo, I; Renton, P; Renz, M; Rescigno, M; Richter, S; Rimondi, F; Ristori, L; Robson, A; Rodrigo, T; Rodriguez, T; Rogers, E; Rolli, S; Roser, R; Rossi, M; Rossin, R; Roy, P; Ruiz, A; Russ, J; Rusu, V; Rutherford, B; Saarikko, H; Safonov, A; Sakumoto, W K; Santi, L; Sartori, L; Sato, K; Savoy-Navarro, A; Schlabach, P; Schmidt, A; Schmidt, E E; Schmidt, M A; Schmidt, M P; Schmitt, M; Schwarz, T; Scodellaro, L; Scribano, A; Scuri, F; Sedov, A; Seidel, S; Seiya, Y; Semenov, A; Sexton-Kennedy, L; Sforza, F; Sfyrla, A; Shalhout, S Z; Shears, T; Shepard, P F; Shimojima, M; Shiraishi, S; Shochet, M; Shon, Y; Shreyber, I; Simonenko, A; Sinervo, P; Sisakyan, A; Slaughter, A J; Slaunwhite, J; Sliwa, K; Smith, J R; Snider, F D; Snihur, R; Soha, A; Somalwar, S; Sorin, V; Spreitzer, T; Squillacioti, P; Stanitzki, M; St Denis, R; Stelzer, B; Stelzer-Chilton, O; Stentz, D; Strologas, J; Strycker, G L; Suh, J S; Sukhanov, A; Suslov, I; Taffard, A; Takashima, R; Takeuchi, Y; Tanaka, R; Tang, J; Tecchio, M; Teng, P K; Thom, J; Thome, J; Thompson, G A; Thomson, E; Tipton, P; Ttito-Guzmán, P; Tkaczyk, S; Toback, D; Tokar, S; Tollefson, K; Tomura, T; Tonelli, D; Torre, S; Torretta, D; Totaro, P; Tourneur, S; Trovato, M; Tsai, S-Y; Tu, Y; Turini, N; Ukegawa, F; Uozumi, S; van Remortel, N; Varganov, A; Vataga, E; Vázquez, F; Velev, G; Vellidis, C; Vidal, M; Vila, I; Vilar, R; Vogel, M; Volobouev, I; Volpi, G; Wagner, P; Wagner, R G; Wagner, R L; Wagner, W; Wagner-Kuhr, J; Wakisaka, T; Wallny, R; Wang, S M; Warburton, A; Waters, D; Weinberger, M; Weinelt, J; Wester, W C; Whitehouse, B; Whiteson, D; Wicklund, A B; Wicklund, E; Wilbur, S; Williams, G; Williams, H H; Wilson, P; Winer, B L; Wittich, P; Wolbers, S; Wolfe, C; Wolfe, H; Wright, T; Wu, X; Würthwein, F; Xie, S; Yagil, A; Yamamoto, K; Yamaoka, J; Yang, U K; Yang, Y C; Yao, W M; Yeh, G P; Yi, K; Yoh, J; Yorita, K; Yoshida, T; Yu, G B; Yu, I; Yu, S S; Yun, J C; Zanetti, A; Zeng, Y; Zhang, X; Zheng, Y; Zucchelli, S

2010-01-08

We present the results of a search for supersymmetry with gauge-mediated breaking and chi(1)(0) --> gammaG in the gammagamma + missing transverse energy final state. In 2.6+/-0.2 fb(-1) of pp collisions at square root(s) = 1.96 TeV recorded by the CDF II detector we observe no candidate events, consistent with a standard model background expectation of 1.4+/-0.4 events. We set limits on the cross section at the 95% C.L. and place the world's best limit of 149 GeV/c2 on the chi(1)(0) mass at tau(chi(1)(0)) < 1 ns. We also exclude regions in the chi(1)(0) mass-lifetime plane for tau(chi(1)(0)) approximately < 2 ns.

Cannabis-Related Problems and Social Anxiety: The Mediational Role of Post-Event Processing.

Science.gov (United States)

Ecker, Anthony H; Buckner, Julia D

2018-01-02

Cannabis is the most commonly used illicit drug in the US, and is associated with a range of psychological, social, and physical health-related problems. Individuals who endorse elevated levels of social anxiety are especially at risk for experiencing cannabis-related problems, including cannabis use disorder, despite not using cannabis more often than those with more normative social anxiety. Identification of mechanisms that underlie the relationship between social anxiety and cannabis-related problems may inform treatment and prevention efforts. Post-event processing (PEP, i.e., cognitively reviewing past social interactions/performances) is a social anxiety-related phenomenon that may be one such mechanism. The current study sought to test PEP as a mediator of the relationship between social anxiety and cannabis-related problems, adjusting for cannabis use frequency. Cannabis-using (past 3-month) undergraduate students recruited in 2015 (N = 244; 76.2% female; 74.2% Non-Hispanic Caucasian) completed an online survey of cannabis use, cannabis-related problems, social anxiety, and PEP. Bootstrap estimate of the indirect effect of social anxiety through PEP was significant, suggesting PEP is a mediator of the social anxiety-cannabis-related problems relationship. Conclusions/Importance: Treatment and prevention efforts may benefit from targeting PEP among individuals with elevated social anxiety and cannabis-related problems.

Distinct and shared cognitive functions mediate event- and time-based prospective memory impairment in normal ageing

Science.gov (United States)

Gonneaud, Julie; Kalpouzos, Grégoria; Bon, Laetitia; Viader, Fausto; Eustache, Francis; Desgranges, Béatrice

2011-01-01

Prospective memory (PM) is the ability to remember to perform an action at a specific point in the future. Regarded as multidimensional, PM involves several cognitive functions that are known to be impaired in normal aging. In the present study, we set out to investigate the cognitive correlates of PM impairment in normal aging. Manipulating cognitive load, we assessed event- and time-based PM, as well as several cognitive functions, including executive functions, working memory and retrospective episodic memory, in healthy subjects covering the entire adulthood. We found that normal aging was characterized by PM decline in all conditions and that event-based PM was more sensitive to the effects of aging than time-based PM. Whatever the conditions, PM was linked to inhibition and processing speed. However, while event-based PM was mainly mediated by binding and retrospective memory processes, time-based PM was mainly related to inhibition. The only distinction between high- and low-load PM cognitive correlates lays in an additional, but marginal, correlation between updating and the high-load PM condition. The association of distinct cognitive functions, as well as shared mechanisms with event- and time-based PM confirms that each type of PM relies on a different set of processes. PMID:21678154

Insights into the Molecular Events That Regulate Heat-Induced Chilling Tolerance in Citrus Fruits.

Science.gov (United States)

Lafuente, María T; Establés-Ortíz, Beatriz; González-Candelas, Luis

2017-01-01

Low non-freezing temperature may cause chilling injury (CI), which is responsible for external quality deterioration in many chilling-sensitive horticultural crops. Exposure of chilling-sensitive citrus cultivars to non-lethal high-temperature conditioning may increase their chilling tolerance. Very little information is available about the molecular events involved in such tolerance. In this work, the molecular events associated with the low temperature tolerance induced by heating Fortune mandarin, which is very sensitive to chilling, for 3 days at 37°C prior to cold storage is presented. A transcriptomic analysis reveals that heat-conditioning has an important impact favoring the repression of genes in cold-stored fruit, and that long-term heat-induced chilling tolerance is an active process that requires activation of transcription factors involved in transcription initiation and of the WRKY family. The analysis also shows that chilling favors degradation processes, which affect lipids and proteins, and that the protective effect of the heat-conditioning treatment is more likely to be related to the repression of the genes involved in lipid degradation than to the modification of fatty acids unsaturation, which affects membrane permeability. Another major factor associated with the beneficial effect of the heat treatment on reducing CI is the regulation of stress-related proteins. Many of the genes that encoded such proteins are involved in secondary metabolism and in oxidative stress-related processes.

Insights into the Molecular Events That Regulate Heat-Induced Chilling Tolerance in Citrus Fruits

Directory of Open Access Journals (Sweden)

María T. Lafuente

2017-06-01

Full Text Available Low non-freezing temperature may cause chilling injury (CI, which is responsible for external quality deterioration in many chilling-sensitive horticultural crops. Exposure of chilling-sensitive citrus cultivars to non-lethal high-temperature conditioning may increase their chilling tolerance. Very little information is available about the molecular events involved in such tolerance. In this work, the molecular events associated with the low temperature tolerance induced by heating Fortune mandarin, which is very sensitive to chilling, for 3 days at 37°C prior to cold storage is presented. A transcriptomic analysis reveals that heat-conditioning has an important impact favoring the repression of genes in cold-stored fruit, and that long-term heat-induced chilling tolerance is an active process that requires activation of transcription factors involved in transcription initiation and of the WRKY family. The analysis also shows that chilling favors degradation processes, which affect lipids and proteins, and that the protective effect of the heat-conditioning treatment is more likely to be related to the repression of the genes involved in lipid degradation than to the modification of fatty acids unsaturation, which affects membrane permeability. Another major factor associated with the beneficial effect of the heat treatment on reducing CI is the regulation of stress-related proteins. Many of the genes that encoded such proteins are involved in secondary metabolism and in oxidative stress-related processes.

Interference between Coulombic and CT-mediated couplings in molecular aggregates: H- to J-aggregate transformation in perylene-based π-stacks

Energy Technology Data Exchange (ETDEWEB)

Hestand, Nicholas J.; Spano, Frank C. [Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122 (United States)

2015-12-28

The spectroscopic differences between J and H-aggregates are traditionally attributed to the spatial dependence of the Coulombic coupling, as originally proposed by Kasha. However, in tightly packed molecular aggregates wave functions on neighboring molecules overlap, leading to an additional charge transfer (CT) mediated exciton coupling with a vastly different spatial dependence. The latter is governed by the nodal patterns of the molecular LUMOs and HOMOs from which the electron (t{sub e}) and hole (t{sub h}) transfer integrals derive. The sign of the CT-mediated coupling depends on the sign of the product t{sub e}t{sub h} and is therefore highly sensitive to small (sub-Angstrom) transverse displacements or slips. Given that Coulombic and CT-mediated couplings exist simultaneously in tightly packed molecular systems, the interference between the two must be considered when defining J and H-aggregates. Generally, such π-stacked aggregates do not abide by the traditional classification scheme of Kasha: for example, even when the Coulomb coupling is strong the presence of a similarly strong but destructively interfering CT-mediated coupling results in “null-aggregates” which spectroscopically resemble uncoupled molecules. Based on a Frenkel/CT Holstein Hamiltonian that takes into account both sources of electronic coupling as well as intramolecular vibrations, vibronic spectral signatures are developed for integrated Frenkel/CT systems in both the perturbative and resonance regimes. In the perturbative regime, the sign of the lowest exciton band curvature, which rigorously defines J and H-aggregation, is directly tracked by the ratio of the first two vibronic peak intensities. Even in the resonance regime, the vibronic ratio remains a useful tool to evaluate the J or H nature of the system. The theory developed is applied to the reversible H to J-aggregate transformations recently observed in several perylene bisimide systems.

Interference between Coulombic and CT-mediated couplings in molecular aggregates: H- to J-aggregate transformation in perylene-based π-stacks

International Nuclear Information System (INIS)

Hestand, Nicholas J.; Spano, Frank C.

2015-01-01

The spectroscopic differences between J and H-aggregates are traditionally attributed to the spatial dependence of the Coulombic coupling, as originally proposed by Kasha. However, in tightly packed molecular aggregates wave functions on neighboring molecules overlap, leading to an additional charge transfer (CT) mediated exciton coupling with a vastly different spatial dependence. The latter is governed by the nodal patterns of the molecular LUMOs and HOMOs from which the electron (t e ) and hole (t h ) transfer integrals derive. The sign of the CT-mediated coupling depends on the sign of the product t e t h and is therefore highly sensitive to small (sub-Angstrom) transverse displacements or slips. Given that Coulombic and CT-mediated couplings exist simultaneously in tightly packed molecular systems, the interference between the two must be considered when defining J and H-aggregates. Generally, such π-stacked aggregates do not abide by the traditional classification scheme of Kasha: for example, even when the Coulomb coupling is strong the presence of a similarly strong but destructively interfering CT-mediated coupling results in “null-aggregates” which spectroscopically resemble uncoupled molecules. Based on a Frenkel/CT Holstein Hamiltonian that takes into account both sources of electronic coupling as well as intramolecular vibrations, vibronic spectral signatures are developed for integrated Frenkel/CT systems in both the perturbative and resonance regimes. In the perturbative regime, the sign of the lowest exciton band curvature, which rigorously defines J and H-aggregation, is directly tracked by the ratio of the first two vibronic peak intensities. Even in the resonance regime, the vibronic ratio remains a useful tool to evaluate the J or H nature of the system. The theory developed is applied to the reversible H to J-aggregate transformations recently observed in several perylene bisimide systems

Molecular Structures and Dynamics of the Stepwise Activation Mechanism of a Matrix Metalloproteinase Zymogen: Challenging the Cysteine Switch Dogma

International Nuclear Information System (INIS)

Rosenblum, G.; Meroueh, S.; Toth, M.; Fisher, J.; Fridman, R.; Mobashery, S.; Sagi, I.

2007-01-01

Activation of matrix metalloproteinase zymogen (pro-MMP) is a vital homeostatic process, yet its molecular basis remains unresolved. Using stopped-flow X-ray spectroscopy of the active site zinc ion, we determined the temporal sequence of pro-MMP-9 activation catalyzed by tissue kallikrein protease in milliseconds to several minutes. The identity of three intermediates seen by X-ray spectroscopy was corroborated by molecular dynamics simulations and quantum mechanics/molecular mechanics calculations. The cysteine-zinc interaction that maintains enzyme latency is disrupted via active-site proton transfers that mediate transient metal-protein coordination events and eventual binding of water. Unexpectedly, these events ensue as a direct result of complexation of pro-MMP-9 and kallikrein and occur before proteolysis and eventual dissociation of the pro-peptide from the catalytic site. Here we demonstrate the synergism among long-range protein conformational transitions, local structural rearrangements, and fine atomic events in the process of zymogen activation.

The molecular mechanism of mediation of adsorbed serum proteins to endothelial cells adhesion and growth on biomaterials.

Science.gov (United States)

Yang, Dayun; Lü, Xiaoying; Hong, Ying; Xi, Tingfei; Zhang, Deyuan

2013-07-01

To explore molecular mechanism of mediation of adsorbed proteins to cell adhesion and growth on biomaterials, this study examined endothelial cell adhesion, morphology and viability on bare and titanium nitride (TiN) coated nickel titanium (NiTi) alloys and chitosan film firstly, and then identified the type and amount of serum proteins adsorbed on the three surfaces by proteomic technology. Subsequently, the mediation role of the identified proteins to cell adhesion and growth was investigated with bioinformatics analyses, and further confirmed by a series of cellular and molecular biological experiments. Results showed that the type and amount of adsorbed serum proteins associated with cell adhesion and growth was obviously higher on the alloys than on the chitosan film, and these proteins mediated endothelial cell adhesion and growth on the alloys via four ways. First, proteins such as adiponectin in the adsorbed protein layer bound with cell surface receptors to generate signal transduction, which activated cell surface integrins through increasing intracellular calcium level. Another way, thrombospondin 1 in the adsorbed protein layer promoted TGF-β signaling pathway activation and enhanced integrins expression. The third, RGD sequence containing proteins such as fibronectin 1, vitronectin and thrombospondin 1 in the adsorbed protein layer bound with activated integrins to activate focal adhesion pathway, increased focal adhesion formation and actin cytoskeleton organization and mediated cell adhesion and spreading. In addition, the activated focal adhesion pathway promoted the expression of cell growth related genes and resulted in cell proliferation. The fourth route, coagulation factor II (F2) and fibronectin 1 in the adsorbed protein layer bound with cell surface F2 receptor and integrin, activated regulation of actin cytoskeleton pathway and regulated actin cytoskeleton organization. Copyright © 2013 Elsevier Ltd. All rights reserved.

Palladium-mediated strategies for functionalizing the dihydroazulene photoswitch: paving the way for its exploitation in molecular electronics.

Science.gov (United States)

Jevric, Martyn; Broman, Søren Lindbæk; Nielsen, Mogens Brøndsted

2013-05-03

The dihydroazulene (DHA)/vinylheptafulvene (VHF) photo/thermoswitch has attracted interest as a molecular switch for advanced materials and molecular electronics. We report here two synthetic approaches using palladium catalysis for synthesizing dihydroazulene (DHA) photoswitches with thioacetate anchoring groups intended for molecular electronics applications. The first methodology involves a Suzuki coupling using tert-butyl thioether protecting groups. Conversion to the thioacetate using boron tribromide/acetyl chloride results in the formation of the product as a mixture of regioisomers mediated by a ring-opening reaction. The second approach circumvents isomerization by the synthesis of stannanes as intermediates and their use in a Stille coupling. Although fully unsaturated azulenes are formed as byproducts during the synthesis of the DHA stannanes, this approach allowed the regioselective incorporation of the thioacetate anchoring group in either one of the two ends (positions 2 or 7) or at both.

Novel molecular events associated with altered steroidogenesis induced by exposure to atrazine in the intact and castrate male rat

Science.gov (United States)

Toxicology is increasingly focused on molecular events comprising adverse outcome pathways. Atrazine activates the hypothalamic-pituitary adrenal axis, but relationships to gonadal alterations are unknown. We characterized hormone profiles and adrenal (intact and castrate) and te...

Molecular profiling of angiogenesis in hypericin mediated photodynamic therapy

Directory of Open Access Journals (Sweden)

Ali Seyed M

2008-06-01

Full Text Available Abstract Background Photodynamic therapy (PDT involves the administration of a tumor-localizing photosensitizing drug, which is activated by light of specific wavelength in the presence of molecular oxygen thus generating reactive oxygen species that is toxic to the tumor cells. PDT selectively destroys photosensitized tissue leading to various cellular and molecular responses. The present study was designed to examine the angiogenic responses at short (0.5 h and long (6 h drug light interval (DLI hypericin-PDT (HY-PDT treatment at 24 h and 30 days post treatment in a human bladder carcinoma xenograft model. As short DLI targets tumor vasculature and longer DLI induces greater cellular damage, we hypothesized a differential effect of these treatments on the expression of angiogenic factors. Results Immunohistochemistry (IHC results showed minimal CD31 stained endothelium at 24 h post short DLI PDT indicating extensive vascular damage. Angiogenic proteins such as vascular endothelial growth factor (VEGF, tumor necrosis growth factor-α (TNF-α, interferon-α (IFN-α and basic fibroblast growth factor (bFGF were expressed to a greater extent in cellular targeting long DLI PDT compared to vascular mediated short DLI PDT. Gene expression profiling for angiogenesis pathway demonstrated downregulation of adhesion molecules – cadherin 5, collagen alpha 1 and 3 at 24 h post treatment. Hepatocyte growth factor (HGF and Ephrin-A3 (EFNA3 were upregulated in all treatment groups suggesting a possible activation of c-Met and Ephrin-Eph signaling pathways. Conclusion In conclusion, long DLI HY-PDT induces upregulation of angiogenic proteins. Differential expression of genes involved in the angiogenesis pathway was observed in the various groups treated with HY-PDT.

Necroptosis Mediates TNF-Induced Toxicity of Hippocampal Neurons

Directory of Open Access Journals (Sweden)

Shan Liu

2014-01-01

Full Text Available Tumor necrosis factor-α (TNF-α is a critical proinflammatory cytokine regulating neuroinflammation. Elevated levels of TNF-α have been associated with various neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. However, the signaling events that lead to TNF-α-initiated neurotoxicity are still unclear. Here, we report that RIP3-mediated necroptosis, a form of regulated necrosis, is activated in the mouse hippocampus after intracerebroventricular injection of TNF-α. RIP3 deficiency attenuates TNF-α-initiated loss of hippocampal neurons. Furthermore, we characterized the molecular mechanism of TNF-α-induced neurotoxicity in HT-22 hippocampal neuronal cells. HT-22 cells are sensitive to TNF-α only upon caspase blockage and subsequently undergo necrosis. The cell death is suppressed by knockdown of CYLD or RIP1 or RIP3 or MLKL, suggesting that this necrosis is necroptosis and mediated by CYLD-RIP1-RIP3-MLKL signaling pathway. TNF-α-induced necroptosis of HT-22 cells is largely independent of both ROS accumulation and calcium influx although these events have been shown to be critical for necroptosis in certain cell lines. Taken together, these data not only provide the first in vivo evidence for a role of RIP3 in TNF-α-induced toxicity of hippocampal neurons, but also demonstrate that TNF-α promotes CYLD-RIP1-RIP3-MLKL-mediated necroptosis of hippocampal neurons largely bypassing ROS accumulation and calcium influx.

A novel heat shock protein alpha 8 (Hspa8) molecular network mediating responses to stress- and ethanol-related behaviors.

Science.gov (United States)

Urquhart, Kyle R; Zhao, Yinghong; Baker, Jessica A; Lu, Ye; Yan, Lei; Cook, Melloni N; Jones, Byron C; Hamre, Kristin M; Lu, Lu

2016-04-01

Genetic differences mediate individual differences in susceptibility and responses to stress and ethanol, although, the specific molecular pathways that control these responses are not fully understood. Heat shock protein alpha 8 (Hspa8) is a molecular chaperone and member of the heat shock protein family that plays an integral role in the stress response and that has been implicated as an ethanol-responsive gene. Therefore, we assessed its role in mediating responses to stress and ethanol across varying genetic backgrounds. The hippocampus is an important mediator of these responses, and thus, was examined in the BXD family of mice in this study. We conducted bioinformatic analyses to dissect genetic factors modulating Hspa8 expression, identify downstream targets of Hspa8, and examined its role. Hspa8 is trans-regulated by a gene or genes on chromosome 14 and is part of a molecular network that regulates stress- and ethanol-related behaviors. To determine additional components of this network, we identified direct or indirect targets of Hspa8 and show that these genes, as predicted, participate in processes such as protein folding and organic substance metabolic processes. Two phenotypes that map to the Hspa8 locus are anxiety-related and numerous other anxiety- and/or ethanol-related behaviors significantly correlate with Hspa8 expression. To more directly assay this relationship, we examined differences in gene expression following exposure to stress or alcohol and showed treatment-related differential expression of Hspa8 and a subset of the members of its network. Our findings suggest that Hspa8 plays a vital role in genetic differences in responses to stress and ethanol and their interactions.

Molecular Mechanisms Underlying Renin-Angiotensin-Aldosterone System Mediated Regulation of BK Channels

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Zhen-Ye Zhang

2017-09-01

Full Text Available Large-conductance calcium-activated potassium channels (BK channels belong to a family of Ca2+-sensitive voltage-dependent potassium channels and play a vital role in various physiological activities in the human body. The renin-angiotensin-aldosterone system is acknowledged as being vital in the body's hormone system and plays a fundamental role in the maintenance of water and electrolyte balance and blood pressure regulation. There is growing evidence that the renin-angiotensin-aldosterone system has profound influences on the expression and bioactivity of BK channels. In this review, we focus on the molecular mechanisms underlying the regulation of BK channels mediated by the renin-angiotensin-aldosterone system and its potential as a target for clinical drugs.

An Event-Driven Hybrid Molecular Dynamics and Direct Simulation Monte Carlo Algorithm

Energy Technology Data Exchange (ETDEWEB)

Donev, A; Garcia, A L; Alder, B J

2007-07-30

A novel algorithm is developed for the simulation of polymer chains suspended in a solvent. The polymers are represented as chains of hard spheres tethered by square wells and interact with the solvent particles with hard core potentials. The algorithm uses event-driven molecular dynamics (MD) for the simulation of the polymer chain and the interactions between the chain beads and the surrounding solvent particles. The interactions between the solvent particles themselves are not treated deterministically as in event-driven algorithms, rather, the momentum and energy exchange in the solvent is determined stochastically using the Direct Simulation Monte Carlo (DSMC) method. The coupling between the solvent and the solute is consistently represented at the particle level, however, unlike full MD simulations of both the solvent and the solute, the spatial structure of the solvent is ignored. The algorithm is described in detail and applied to the study of the dynamics of a polymer chain tethered to a hard wall subjected to uniform shear. The algorithm closely reproduces full MD simulations with two orders of magnitude greater efficiency. Results do not confirm the existence of periodic (cycling) motion of the polymer chain.

Computational exploration of single-protein mechanics by steered molecular dynamics

Energy Technology Data Exchange (ETDEWEB)

Sotomayor, Marcos [Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio (United States)

2015-12-31

Hair cell mechanotransduction happens in tens of microseconds, involves forces of a few picoNewtons, and is mediated by nanometer-scale molecular conformational changes. As proteins involved in this process become identified and their high resolution structures become available, multiple tools are being used to explore their “single-molecule responses” to force. Optical tweezers and atomic force microscopy offer exquisite force and extension resolution, but cannot reach the high loading rates expected for high frequency auditory stimuli. Molecular dynamics (MD) simulations can reach these fast time scales, and also provide a unique view of the molecular events underlying protein mechanics, but its predictions must be experimentally verified. Thus a combination of simulations and experiments might be appropriate to study the molecular mechanics of hearing. Here I review the basics of MD simulations and the different methods used to apply force and study protein mechanics in silico. Simulations of tip link proteins are used to illustrate the advantages and limitations of this method.

Detection of DNA damage based on metal-mediated molecular beacon and DNA strands displacement reaction

Science.gov (United States)

Xiong, Yanxiang; Wei, Min; Wei, Wei; Yin, Lihong; Pu, Yuepu; Liu, Songqin

2014-01-01

DNA hairpin structure probes are usually designed by forming intra-molecular duplex based on Watson-Crick hydrogen bonds. In this paper, a molecular beacon based on silver ions-mediated cytosine-Ag+-cytosine base pairs was used to detect DNA. The inherent characteristic of the metal ligation facilitated the design of functional probe and the adjustment of its binding strength compared to traditional DNA hairpin structure probes, which make it be used to detect DNA in a simple, rapid and easy way with the help of DNA strands displacement reaction. The method was sensitive and also possesses the good specificity to differentiate the single base mismatched DNA from the complementary DNA. It was also successfully applied to study the damage effect of classic genotoxicity chemicals such as styrene oxide and sodium arsenite on DNA, which was significant in food science, environmental science and pharmaceutical science.

Diagnostic and molecular evaluation of three iridovirus-associated salamander mortality events

Science.gov (United States)

Docherty, D.E.; Meteyer, C.U.; Wang, Jingyuan; Mao, J.; Case, S.T.; Chinchar, V.G.

2003-01-01

In 1998 viruses were isolated from tiger salamander larvae (Ambystoma tigrinum diaboli and A. tigrinum melanostictum) involved in North Dakota and Utah (USA) mortality events and spotted salamander (A. maculatum) larvae in a third event in Maine (USA). Although sympatric caudates and anurans were present at all three sites only ambystomid larvae appeared to be affected. Mortality at the North Dakota site was in the thousands while at the Utah and Maine sites mortality was in the hundreds. Sick larvae were lethargic and slow moving. They swam in circles with obvious buoyancy problems and were unable to remain upright. On the ventral surface, near the gills and hind limbs, red spots or swollen areas were noted. Necropsy findings included: hemorrhages and ulceration of the skin, subcutaneous and intramuscular edema, swollen and pale livers with multifocal hemorrhage, and distended fluid-filled intestines with areas of hemorrhage. Light microscopy revealed intracytoplasmic inclusions, suggestive of a viral infection, in a variety of organs. Electron microscopy of ultra thin sections of the same tissues revealed iridovirus-like particles within the inclusions. These viruses were isolated from a variety of organs, indicating a systemic infection. Representative viral isolates from the three mortality events were characterized using molecular assays. Characterization confirmed that the viral isolates were iridoviruses and that the two tiger salamander isolates were similar and could be distinguished from the spotted salamander isolate. The spotted salamander isolate was similar to frog virus 3, the type species of the genus Ranavirus, while the tiger salamander isolates were not. These data indicate that different species of salamanders can become infected and die in association with different iridoviruses. Challenge assays are required to determine the fish and amphibian host range of these isolates and to assess the susceptibility of tiger and spotted salamanders to

Global mapping of protein phosphorylation events identifies novel signalling hubs mediating fatty acid starvation responses in Saccharomyces cerevisiae

DEFF Research Database (Denmark)

Pultz, Dennis; Bennetzen, Martin; Rødkær, Steven Vestergaard

2011-01-01

Dietary restriction (DR) extends the life span of multiple species, ranging from single-celled organisms like yeast to mammals. This increase in longevity by dietary restriction is coupled to profound beneficial effects on age-related pathology. Despite the number of studies on DR...... and the physiological changes DR induces, only little is known about the genetics and signalling networks, which regulate the DR response. We have recently shown that inhibition of fatty acid synthesis in Saccharomyces cerevisiae induces autophagy mediated by TORC1 signalling and affects life span. In the present study...... in a temporal manner in response to inhibition of fatty acid synthesis by cerulenin. By in silico analysis of these phosphorylation events, we have identified the major downstream regulated processes and signalling networks mediating the cellular response to fatty acid starvation. The analysis further...

[Compassion as a mediator between stressful events and perceived stress in Greek students].

Science.gov (United States)

Tholouli, E; Maridaki-Kassotaki, A; Varvogli, L; Chrousos, G P

2016-01-01

Compassion is closely related with human's survival as a mammal and has been developed through evolution for pain reduction, for forming affiliative bonds and alliances with non kin in order to increase protection and cope with external threats. Compassion seems to influence people's ability to deal with life's adverse situations such as stress and it is linked with lower psychopathology and greater wellbeing. Compassion is closely related to empathy and altruism and it is defined as the recognition of the pain of the self or others' that is accompanied with the will to take action in order to relieve the person from pain. Its main features are kindness instead of self-judgment and indifference, the recognition of common humanity instead of the feeling of separation and mindfulness when facing adverse conditions instead of over-identification with one's pain or disengagement with the pain of others. According to the biopsychosocial approach, stress can be defined by three dimensions such as the cause or stressful factors that can be major life events or daily hassles, the perception of stress that is manifested through cognitive, emotional and behavioural reactions and the physiological response for achieving homeostasis. The purpose of the present study was to investigate the role of compassion for self and others in the occurrence of stressful events and levels of perceived stress in students. Participants were 280 undergraduate students from two Greek universities. Results indicated that students who had experienced a greater amount of stressful events during the past year reported having higher levels of perceived stress and that higher self-compassion was correlated with less perceived stress. Moreover, the adverse effect of stressful events on perceived stress was partially explained by the mediating role of self-compassion. Students who reported more stressful events showed higher compassion for others in opposition to compassion towards themselves but

Positive-negative-selection-mediated gene targeting in rice

Directory of Open Access Journals (Sweden)

Zenpei eShimatani

2015-01-01

Full Text Available Gene targeting (GT refers to the designed modification of genomic sequence(s through homologous recombination (HR. GT is a powerful tool both for the study of gene function and for molecular breeding. However, in transformation of higher plants, non-homologous end joining (NHEJ occurs overwhelmingly in somatic cells, masking HR-mediated GT. Positive-negative selection (PNS is an approach for finding HR-mediated GT events because it can eliminate NHEJ effectively by expression of a negative-selection marker gene. In rice—a major crop worldwide—reproducible PNS-mediated GT of endogenous genes has now been successfully achieved. The procedure is based on strong PNS using diphtheria toxin A-fragment as a negative marker, and has succeeded in the directed modification of several endogenous rice genes in various ways. In addition to gene knock-outs and knock-ins, a nucleotide substitution in a target gene was also achieved recently. This review presents a summary of the development of the rice PNS system, highlighting its advantages. Different types of gene modification and gene editing aimed at developing new plant breeding technology (NPBT based on PNS are discussed.

Analogies Between Digital Radio and Chemical Orthogonality as a Method for Enhanced Analysis of Molecular Recognition Events

Directory of Open Access Journals (Sweden)

Sang-Hun Lee

2008-02-01

Full Text Available Acoustic wave biosensors are a real-time, label-free biosensor technology, which have been exploited for the detection of proteins and cells. One of the conventional biosensor approaches involves the immobilization of a monolayer of antibodies onto the surface of the acoustic wave device for the detection of a specific analyte. The method described within includes at least two immobilizations of two different antibodies onto the surfaces of two separate acoustic wave devices for the detection of several analogous analytes. The chemical specificity of the molecular recognition event is achieved by virtue of the extremely high (nM to pM binding affinity between the antibody and its antigen. In a standard ELISA (Enzyme-Linked ImmunoSorbent Assay test, there are multiple steps and the end result is a measure of what is bound so tightly that it does not wash away easily. The fact that this “gold standard” is very much not real time, masks the dance that is the molecular recognition event. X-Ray Crystallographer, Ian Wilson, demonstrated more than a decade ago that antibodies undergo conformational change during a binding event[1, 2]. Further, it is known in the arena of immunochemistry that some antibodies exhibit significant cross-reactivity and this is widely termed antibody promiscuity. A third piece of the puzzle that we will exploit in our system of acoustic wave biosensors is the notion of chemical orthogonality. These three biochemical constructs, the dance, antibody promiscuity and chemical orthogonality will be combined in this paper with the notions of Int. J. Mol. Sci. 2008, 9 155 in-phase (I and quadrature (Q signals from digital radio to manifest an approach to molecular recognition that allows a level of discrimination and analysis unobtainable without the aggregate. As an example we present experimental data on the detection of TNT, RDX, C4, ammonium nitrate and musk oil from a system of antibody-coated acoustic

Study of gene expression alteration in male androgenetic alopecia: evidence of predominant molecular signalling pathways.

Science.gov (United States)

Michel, L; Reygagne, P; Benech, P; Jean-Louis, F; Scalvino, S; Ly Ka So, S; Hamidou, Z; Bianovici, S; Pouch, J; Ducos, B; Bonnet, M; Bensussan, A; Patatian, A; Lati, E; Wdzieczak-Bakala, J; Choulot, J-C; Loing, E; Hocquaux, M

2017-11-01

Male androgenetic alopecia (AGA) is the most common form of hair loss in men. It is characterized by a distinct pattern of progressive hair loss starting from the frontal area and the vertex of the scalp. Although several genetic risk loci have been identified, relevant genes for AGA remain to be defined. To identify biomarkers associated with AGA. Molecular biomarkers associated with premature AGA were identified through gene expression analysis using cDNA generated from scalp vertex biopsies of hairless or bald men with premature AGA, and healthy volunteers. This monocentric study reveals that genes encoding mast cell granule enzymes, inflammatory mediators and immunoglobulin-associated immune mediators were significantly overexpressed in AGA. In contrast, underexpressed genes appear to be associated with the Wnt/β-catenin and bone morphogenic protein/transforming growth factor-β signalling pathways. Although involvement of these pathways in hair follicle regeneration is well described, functional interpretation of the transcriptomic data highlights different events that account for their inhibition. In particular, one of these events depends on the dysregulated expression of proopiomelanocortin, as confirmed by polymerase chain reaction and immunohistochemistry. In addition, lower expression of CYP27B1 in patients with AGA supports the notion that changes in vitamin D metabolism contributes to hair loss. This study provides compelling evidence for distinct molecular events contributing to alopecia that may pave the way for new therapeutic approaches. © 2017 British Association of Dermatologists.

Molecular architecture of the yeast Mediator complex

Science.gov (United States)

Robinson, Philip J; Trnka, Michael J; Pellarin, Riccardo; Greenberg, Charles H; Bushnell, David A; Davis, Ralph; Burlingame, Alma L; Sali, Andrej; Kornberg, Roger D

2015-01-01

The 21-subunit Mediator complex transduces regulatory information from enhancers to promoters, and performs an essential role in the initiation of transcription in all eukaryotes. Structural information on two-thirds of the complex has been limited to coarse subunit mapping onto 2-D images from electron micrographs. We have performed chemical cross-linking and mass spectrometry, and combined the results with information from X-ray crystallography, homology modeling, and cryo-electron microscopy by an integrative modeling approach to determine a 3-D model of the entire Mediator complex. The approach is validated by the use of X-ray crystal structures as internal controls and by consistency with previous results from electron microscopy and yeast two-hybrid screens. The model shows the locations and orientations of all Mediator subunits, as well as subunit interfaces and some secondary structural elements. Segments of 20–40 amino acid residues are placed with an average precision of 20 Å. The model reveals roles of individual subunits in the organization of the complex. DOI: http://dx.doi.org/10.7554/eLife.08719.001 PMID:26402457

Intrathymic laminin-mediated interactions: role in T cell migration and development

Directory of Open Access Journals (Sweden)

Wilson eSavino

2015-11-01

Full Text Available Intrathymic T cell differentiation is a key process for the development and maintenance of cell-mediated immunity, and occurs concomitantly to highly regulated migratory events. We have proposed a multivectorial model for describing intrathymic thymocyte migration. One of the individual vectors comprises interactions mediated by laminins, a heterotrimeric protein family of the extracellular matrix. Several laminins are expressed in the thymus, being produced by microenvironmental cells, particularly thymic epithelial cells. Also, thymocytes and epithelial cells express integrin-type laminin receptors. Functionally, it has been reported that the dy/dy mutant mouse (lacking the laminin isoform 211 exhibits defective thymocyte differentiation. Several data show haptotactic effects of laminins upon thymocytes, as well as their adhesion on thymic epithelial cells; both effects being prevented by anti-laminin or anti-laminin receptor antibodies. Interestingly, laminin synergizes with chemokines to enhance thymocyte migration, whereas classe-3 semaphorins and B ephrins, which exhibit chemorepulsive effects in the thymus, downregulate laminin-mediated migratory responses of thymocytes. More recently, we showed that knocking down the ITGA6 gene (which encodes the α6 integrin chain of laminin receptors in human thymic epithelial cells, modulates a large number of cell-migration related genes, and results in changes of adhesion pattern of thymocytes onto the thymic epithelium. Overall, laminin-mediated interactions can be placed at the cross-road of the multivectorial process of thymocyte migration, with a direct influence per se, as well as by modulating other molecular interactions associated with the intrathymic trafficking events.

Ab initio molecular dynamics simulations of low energy recoil events in MgO

International Nuclear Information System (INIS)

Petersen, B. A.; Liu, B.; Weber, W. J.; Oak Ridge National Laboratory; Zhang, Y.; Oak Ridge National Laboratory

2017-01-01

In this paper, low-energy recoil events in MgO are studied using ab initio molecular dynamics simulations to reveal the dynamic displacement processes and final defect configurations. Threshold displacement energies, E_d, are obtained for Mg and O along three low-index crystallographic directions, [100], [110], and [111]. The minimum values for E_d are found along the [110] direction consisting of the same element, either Mg or O atoms. Minimum threshold values of 29.5 eV for Mg and 25.5 eV for O, respectively, are suggested from the calculations. For other directions, the threshold energies are considerably higher, 65.5 and 150.0 eV for O along [111] and [100], and 122.5 eV for Mg along both [111] and [100] directions, respectively. These results show that the recoil events in MgO are partial-charge transfer assisted processes where the charge transfer plays an important role. Finally, there is a similar trend found in other oxide materials, where the threshold displacement energy correlates linearly with the peak partial-charge transfer, suggesting this behavior might be universal in ceramic oxides.

Chronic Antibody-Mediated Rejection in Nonhuman Primate Renal Allografts: Validation of Human Histological and Molecular Phenotypes.

Science.gov (United States)

Adam, B A; Smith, R N; Rosales, I A; Matsunami, M; Afzali, B; Oura, T; Cosimi, A B; Kawai, T; Colvin, R B; Mengel, M

2017-11-01

Molecular testing represents a promising adjunct for the diagnosis of antibody-mediated rejection (AMR). Here, we apply a novel gene expression platform in sequential formalin-fixed paraffin-embedded samples from nonhuman primate (NHP) renal transplants. We analyzed 34 previously described gene transcripts related to AMR in humans in 197 archival NHP samples, including 102 from recipients that developed chronic AMR, 80 from recipients without AMR, and 15 normal native nephrectomies. Three endothelial genes (VWF, DARC, and CAV1), derived from 10-fold cross-validation receiver operating characteristic curve analysis, demonstrated excellent discrimination between AMR and non-AMR samples (area under the curve = 0.92). This three-gene set correlated with classic features of AMR, including glomerulitis, capillaritis, glomerulopathy, C4d deposition, and DSAs (r = 0.39-0.63, p < 0.001). Principal component analysis confirmed the association between three-gene set expression and AMR and highlighted the ambiguity of v lesions and ptc lesions between AMR and T cell-mediated rejection (TCMR). Elevated three-gene set expression corresponded with the development of immunopathological evidence of rejection and often preceded it. Many recipients demonstrated mixed AMR and TCMR, suggesting that this represents the natural pattern of rejection. These data provide NHP animal model validation of recent updates to the Banff classification including the assessment of molecular markers for diagnosing AMR. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

Cohesin Rad21 Mediates Loss of Heterozygosity and Is Upregulated via Wnt Promoting Transcriptional Dysregulation in Gastrointestinal Tumors

Directory of Open Access Journals (Sweden)

Huiling Xu

2014-12-01

Full Text Available Summary: Loss of heterozygosity (LOH of the adenomatous polyposis coli (APC gene triggers a series of molecular events leading to intestinal adenomagenesis. Haploinsufficiency of the cohesin Rad21 influences multiple initiating events in colorectal cancer (CRC. We identify Rad21 as a gatekeeper of LOH and a β-catenin target gene and provide evidence that Wnt pathway activation drives RAD21 expression in human CRC. Genome-wide analyses identified Rad21 as a key transcriptional regulator of critical CRC genes and long interspersed element (LINE-1 or L1 retrotransposons. Elevated RAD21 expression tracks with reactivation of L1 expression in human sporadic CRC, implicating cohesin-mediated L1 expression in global genomic instability and gene dysregulation in cancer. : Rad21 holds the cohesin complex together as part of its role in chromosome partitioning and DNA repair. Xu et al. identify Rad21 as a key mediator of Apc gene heterozygous loss, the event initiating intestinal tumorigenesis. The subsequent activation of the Wnt pathway further induces Rad21, global gene dysregulation, chromosome instability, and pervasive retrotransposon activation.

Rational Design of a Green-Light-Mediated Unimolecular Platform for Fast Switchable Acidic Sensing.

Science.gov (United States)

Zhou, Yunyun; Zou, Qi; Qiu, Jing; Wang, Linjun; Zhu, Liangliang

2018-02-01

A controllable sensing ability strongly connects to complex and precise events in diagnosis and treatment. However, imposing visible light into the molecular-scale mediation of sensing processes is restricted by the lack of structural relevance. To address this critical challenge, we present the rational design, synthesis, and in vitro studies of a novel cyanostyryl-modified azulene system for green-light-mediated fast switchable acidic sensing. The advantageous features of the design include a highly efficient green-light-driven Z/E-isomerization (a quantum yield up to 61.3%) for fast erasing chromatic and luminescent expressions and a superior compatibility with control of ratiometric protonation. Significantly, these merits of the design enable the development of a microfluidic system to perform a green-light-mediated reusable sensing function toward a gastric acid analyte in a miniaturized platform. The results may provide new insights for building future integrated green materials.

Lower prevalence of carotid plaque hemorrhage in women, and its mediator effect on sex differences in recurrent cerebrovascular events.

Directory of Open Access Journals (Sweden)

Neghal Kandiyil

Full Text Available Women are at lower risk of stroke, and appear to benefit less from carotid endarterectomy (CEA than men. We hypothesised that this is due to more benign carotid disease in women mediating a lower risk of recurrent cerebrovascular events. To test this, we investigated sex differences in the prevalence of MRI detectable plaque hemorrhage (MRI PH as an index of plaque instability, and secondly whether MRI PH mediates sex differences in the rate of cerebrovascular recurrence.Prevalence of PH between sexes was analysed in a single centre pooled cohort of 176 patients with recently symptomatic, significant carotid stenosis (106 severe [≥70%], 70 moderate [50-69%] who underwent prospective carotid MRI scanning for identification of MRI PH. Further, a meta-analysis of published evidence was undertaken. Recurrent events were noted during clinical follow up for survival analysis.Women with symptomatic carotid stenosis (50%≥ were less likely to have plaque hemorrhage (PH than men (46% vs. 70% with an adjusted OR of 0.23 [95% CI 0.10-0.50, P<0.0001] controlling for other known vascular risk factors. This negative association was only significant for the severe stenosis subgroup (adjusted OR 0.18, 95% CI 0.067-0.50 not the moderate degree stenosis. Female sex in this subgroup also predicted a longer time to recurrent cerebral ischemic events (HR 0.38 95% CI 0.15-0.98, P = 0.045. Further addition of MRI PH or smoking abolished the sex effects with only MRI PH exerting a direct effect. Meta-analysis confirmed a protective effect of female sex on development of PH: unadjusted OR for presence of PH = 0.54 (95% CI 0.45-0.67, p<0.00001.MRI PH is significantly less prevalent in women. Women with MRI PH and severe stenosis have a similar risk as men for recurrent cerebrovascular events. MRI PH thus allows overcoming the sex bias in selection for CEA.

Ethylene-Mediated Acclimations to Flooding Stress1

Science.gov (United States)

Sasidharan, Rashmi; Voesenek, Laurentius A.C.J.

2015-01-01

Flooding is detrimental for plants, primarily because of restricted gas exchange underwater, which leads to an energy and carbohydrate deficit. Impeded gas exchange also causes rapid accumulation of the volatile ethylene in all flooded plant cells. Although several internal changes in the plant can signal the flooded status, it is the pervasive and rapid accumulation of ethylene that makes it an early and reliable flooding signal. Not surprisingly, it is a major regulator of several flood-adaptive plant traits. Here, we discuss these major ethylene-mediated traits, their functional relevance, and the recent progress in identifying the molecular and signaling events underlying these traits downstream of ethylene. We also speculate on the role of ethylene in postsubmergence recovery and identify several questions for future investigations. PMID:25897003

De-Virtualizing Social Events: Understanding the Gap between Online and Offline Participation for Event Invitations

OpenAIRE

Huang, Ai-Ju; Wang, Hao-Chuan; Yuan, Chien Wen

2013-01-01

One growing use of computer-based communication media is for gathering people to initiate or sustain social events. Although the use of computer-mediated communication and social network sites such as Facebook for event promotion is becoming popular, online participation in an event does not always translate to offline attendance. In this paper, we report on an interview study of 31 participants that examines how people handle online event invitations and what influences their online and offl...

A molecular mechanism for diacylglycerol-mediated promotion of negative caloric balance

Directory of Open Access Journals (Sweden)

Yanai H

2009-12-01

Full Text Available Hidekatsu Yanai1,2, Yoshiharu Tomono3, Kumie Ito1,2, Yuji Hirowatari4, Hiroshi Yoshida1,5, Norio Tada1,21Department of Internal Medicine, 2Institute of Clinical Medicine and Research, 3Department of Nutrition, 5Department of Laboratory Medicine, Jikei University School of Medicine, chiba, Japan; 4Bioscience Division, Tosoh Corporation, Kanagawa, JapanAims: A substitution of diacylglycerol (DAG oil for triacylglycerol (TAG oil in diet has been reported to reduce body fat and body weight, possibly by increasing postprandial energy expenditure (EE. We have previously studied plasma serotonin, which increases EE and exists in the small intestine, in individuals who ingested TAG and DAG oil, and found that DAG ingestion elevates plasma serotonin levels by about 50% compared with TAG ingestion. We studied the molecular mechanisms for DAG-mediated increase in serotonin and EE.Methods: We studied effects of 1-monoacylglycerol and 2-monoacylglycerol, distinct digestive products of DAG and TAG, respectively, on serotonin release from the Caco-2 cells (the human intestinal cell line, n = 8. Further, we studied effects of 1- and 2-monoacylglycerol, and serotonin on expression of mRNA associated with β-oxidation, FA metabolism, and thermogenesis, in the Caco-2 cells (n = 5.Results: 1-monoacylglycerol (100 µM 1-monooleyl glycerol [1-MOG] significantly increased serotonin release from the Caco-2 cells compared with 2-monoacylglycerol (100 µM 2-MOG by 36.6%. Expression of mRNA of acyl-CoA oxidase (ACO, fatty acid translocase (FAT, and uncoupling protein-2 (UCP-2 were significantly higher in 100 µM 1-MOG-treated Caco-2 cells than 100 µM 2-MOG-treated cells by 12.8%, 23.7%, and 35.1%, respectively. Further, expression of mRNA of ACO, medium-chain acyl-CoA dehydrogenase, FAT, and UCP-2 were significantly elevated in serotonin (400 nM-treated Caco-2 cells compared with cells incubated without serotonin by 28.7%, 30.1%, and 39.2%, respectively.Conclusions: Our

Angry thoughts in Spanish drivers and their relationship with crash-related events. The mediation effect of aggressive and risky driving.

Science.gov (United States)

Herrero-Fernández, David; Fonseca-Baeza, Sara

2017-09-01

Several studies have related aggressive and risky driving behaviours to accidents. However, the cognitive processes associated with driving aggression have received very little attention in the scientific literature. With the aim of shedding light on this topic, the present research was carried out on a sample of 414 participants in order to validate the Driver's Angry Thoughts Questionnaire (DATQ) with a sample of Spanish drivers and to test the hypothesis of the mediation effect of aggressive and risky driving on the relationship between drivers' angry thoughts and crash-related events. The results showed a good fit with the five-factor model of the questionnaire (Judgmental and Disbelieving Thinking, Pejorative Labelling and Verbally Aggressive Thinking, Revenge and Retaliatory Thinking, Physically Aggressive Thinking, and Coping Self-Instruction). Moreover, slight gender differences were observed in drivers' angry thoughts, with women scoring higher than men (η 2 =0.03). However, younger drivers had higher scores than older drivers in general (η 2 =0.06). Finally, several mediation effects of aggressive driving and risky driving on the relationship between aggressive thinking and the crash-related events were found. Implications of the results for research in traffic psychology and clinical assessment of aggressive drivers as well as limitations of the study are discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Single-cell analysis of pyroptosis dynamics reveals conserved GSDMD-mediated subcellular events that precede plasma membrane rupture.

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de Vasconcelos, Nathalia M; Van Opdenbosch, Nina; Van Gorp, Hanne; Parthoens, Eef; Lamkanfi, Mohamed

2018-04-17

Pyroptosis is rapidly emerging as a mechanism of anti-microbial host defense, and of extracellular release of the inflammasome-dependent cytokines interleukin (IL)-1β and IL-18, which contributes to autoinflammatory pathology. Caspases 1, 4, 5 and 11 trigger this regulated form of necrosis by cleaving the pyroptosis effector gasdermin D (GSDMD), causing its pore-forming amino-terminal domain to oligomerize and perforate the plasma membrane. However, the subcellular events that precede pyroptotic cell lysis are ill defined. In this study, we triggered primary macrophages to undergo pyroptosis from three inflammasome types and recorded their dynamics and morphology using high-resolution live-cell spinning disk confocal laser microscopy. Based on quantitative analysis of single-cell subcellular events, we propose a model of pyroptotic cell disintegration that is initiated by opening of GSDMD-dependent ion channels or pores that are more restrictive than recently proposed GSDMD pores, followed by osmotic cell swelling, commitment of mitochondria and other membrane-bound organelles prior to sudden rupture of the plasma membrane and full permeability to intracellular proteins. This study provides a dynamic framework for understanding cellular changes that occur during pyroptosis, and charts a chronological sequence of GSDMD-mediated subcellular events that define pyroptotic cell death at the single-cell level.

The Molecular Circadian Clock and Alcohol-Induced Liver Injury

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Uduak S. Udoh

2015-10-01

Full Text Available Emerging evidence from both experimental animal studies and clinical human investigations demonstrates strong connections among circadian processes, alcohol use, and alcohol-induced tissue injury. Components of the circadian clock have been shown to influence the pathophysiological effects of alcohol. Conversely, alcohol may alter the expression of circadian clock genes and the rhythmic behavioral and metabolic processes they regulate. Therefore, we propose that alcohol-mediated disruption in circadian rhythms likely underpins many adverse health effects of alcohol that cut across multiple organ systems. In this review, we provide an overview of the circadian clock mechanism and showcase results from new studies in the alcohol field implicating the circadian clock as a key target of alcohol action and toxicity in the liver. We discuss various molecular events through which alcohol may work to negatively impact circadian clock-mediated processes in the liver, and contribute to tissue pathology. Illuminating the mechanistic connections between the circadian clock and alcohol will be critical to the development of new preventative and pharmacological treatments for alcohol use disorders and alcohol-mediated organ diseases.

The role of attributions in the cognitive appraisal of work-related stressful events : An event-recording approach

NARCIS (Netherlands)

Peeters, MCW; Schaufeli, WB; Buunk, BP

1995-01-01

This paper describes a micro-analysis of the cognitive appraisal of daily stressful events in a sample of correctional officers (COs). More specifically, the authors examined whether three attribution dimensions mediated the relationship between the occurrence of stressful events and the

NK cell cytotoxicity mediated by 2B4 and NTB-A is dependent on SAP acting downstream of receptor phosphorylation

Directory of Open Access Journals (Sweden)

Stephan eMeinke

2013-01-01

Full Text Available 2B4 (CD244 and NK-T-B-antigen (NTB-A, CD352 are activating receptors on human NK cells and belong to the family of SLAM-related receptors. Engagement of these receptors leads to phosphorylation of their cytoplasmic tails and recruitment of the adapter proteins SAP and EAT-2. X-linked lymphoproliferative syndrome (XLP is a severe immunodeficiency that results from mutations in the SAP gene. 2B4 and NTB-A-mediated cytotoxicity are abrogated in XLP NK cells. To elucidate the molecular basis for this defect we analyzed early signaling events in SAP knockdown cells. Similar to XLP NK cells, knockdown of SAP in primary human NK cells leads to a reduction of 2B4 and NTB-A-mediated cytotoxicity. We found that early signaling events such as raft recruitment and receptor phosphorylation are not affected by the absence of SAP, indicating the defect in the absence of SAP is downstream of these events. In addition, knockdown of EAT-2 does not impair 2B4 or NTB-A-mediated cytotoxicity. Surprisingly, EAT-2 recruitment to both receptors is abrogated in the absence of SAP, revealing a novel cooperativity between these adapters.

Gargamelle: neutral current event

CERN Multimedia

1973-01-01

This event shows real tracks of particles from the 1200 litre Gargamelle bubble chamber that ran on the PS from 1970 to 1976 and on the SPS from 1976 to 1979. In this image a neutrino passes close to a nucleon and reemerges as a neutrino. Such events are called neutral curent, as they are mediated by the Z0 boson which has no electric charge.

Search for SUSY in gauge mediated and anomaly mediated supersymmetry breaking models

International Nuclear Information System (INIS)

Nunnnemann, Thomas

2004-01-01

In this note, recent results on the search for Gauge Mediated Supersymmetry Breaking (GMSB) and Anomaly Mediated Supersymmetry Breaking (AMSB) at the LEP and Tevatron colliders are summarized. We report on DOe's search for GMSB in di-photon events with large missing transverse energy and discuss the sensitivity of similar searches based on future Tevatron integrated luminosities. (orig.)

Molecular events basic to cellular radiation response

International Nuclear Information System (INIS)

Kolodny, G.M.

The initiation and control of the division process in normal cells is studied to gain insight into changes in these regards caused by x-irradiation and neoplasia. The Primer Hypothesis for eukaryotic gene regulation proposes that small molecular weight RNA acts as primer for new RNA synthesis by hybridizing with DNA and there initiating the transcription of a new RNA chain. The experiments reported here indicate that small molecular weight RNA will induce the production of new proteins. These results are consistent with the Primer Hypothesis, and demonstrate that RNA can be taken up from the media by cells in culture and can induce in vitro the production of differentiated cell products

Event-governed and verbally-governed behavior.

Science.gov (United States)

Vargas, E A

1988-01-01

A NUMBER OF STATEMENTS PRESCRIBE BEHAVIOR: apothegms, maxims, proverbs, instructions, and so on. These differing guides to conduct present varieties of the dictionary definition of "rules." The term "rules" thus defines a category of language usage. Such a term, and its derivative, "rule-governed," does not address a controlling relation in the analysis of verbal behavior. The prevailing confounding of a category of language with a category of verbal behavior appears related to a lack of understanding as to what distinguishes verbal behavior from other behavior. Verbal behavior is a behavior-behavior relation in which events are contacted through the mediation of another organism's behavior specifically shaped for such mediation by a verbal community. It contrasts with behavior that contacts events directly, and shaped directly by the features of those events. Thus we may distinguish between two large classes of behavior by whether it is behavior controlled by events, or behavior controlled verbally. However, the functional controls operative with both classes of behavior do not differ.

Photoperiod- and temperature-mediated control of growth cessation and dormancy in trees: a molecular perspective.

Science.gov (United States)

Maurya, Jay P; Bhalerao, Rishikesh P

2017-09-01

How plants adapt their developmental patterns to regular seasonal changes is an important question in biology. The annual growth cycle in perennial long-lived trees is yet another example of how plants can adapt to seasonal changes. The two main signals that plants rely on to respond to seasonal changes are photoperiod and temperature, and these signals have critical roles in the temporal regulation of the annual growth cycle of trees. This review presents the latest findings to provide insight into the molecular mechanisms that underlie how photoperiodic and temperature signals regulate seasonal growth in trees. The results point to a high level of conservation in the signalling pathways that mediate photoperiodic control of seasonal growth in trees and flowering in annual plants such as arabidopsis. Furthermore, the data indicate that symplastic communication may mediate certain aspects of seasonal growth. Although considerable insight into the control of phenology in model plants such as poplar and spruce has been obtained, the future challenge is extending these studies to other, non-model trees. © The Author 2017. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Inhibition of Ubc13-mediated Ubiquitination by GPS2 Regulates Multiple Stages of B Cell Development.

Science.gov (United States)

Lentucci, Claudia; Belkina, Anna C; Cederquist, Carly T; Chan, Michelle; Johnson, Holly E; Prasad, Sherry; Lopacinski, Amanda; Nikolajczyk, Barbara S; Monti, Stefano; Snyder-Cappione, Jennifer; Tanasa, Bogdan; Cardamone, M Dafne; Perissi, Valentina

2017-02-17

Non-proteolytic ubiquitin signaling mediated by Lys 63 ubiquitin chains plays a critical role in multiple pathways that are key to the development and activation of immune cells. Our previous work indicates that GPS2 (G-protein Pathway Suppressor 2) is a multifunctional protein regulating TNFα signaling and lipid metabolism in the adipose tissue through modulation of Lys 63 ubiquitination events. However, the full extent of GPS2-mediated regulation of ubiquitination and the underlying molecular mechanisms are unknown. Here, we report that GPS2 is required for restricting the activation of TLR and BCR signaling pathways and the AKT/FOXO1 pathway in immune cells based on direct inhibition of Ubc13 enzymatic activity. Relevance of this regulatory strategy is confirmed in vivo by B cell-targeted deletion of GPS2, resulting in developmental defects at multiple stages of B cell differentiation. Together, these findings reveal that GPS2 genomic and non-genomic functions are critical for the development and cellular homeostasis of B cells. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Twisted molecular excitons as mediators for changing the angular momentum of light

Science.gov (United States)

Zang, Xiaoning; Lusk, Mark T.

2017-07-01

Molecules with CN or CN h symmetry can absorb quanta of optical angular momentum to generate twisted excitons with well-defined quasiangular momenta of their own. Angular momentum is conserved in such interactions at the level of a paraxial approximation for the light beam. A sequence of absorption events can thus be used to create a range of excitonic angular momenta. Subsequent decay can produce radiation with a single angular momentum equal to that accumulated. Such molecules can thus be viewed as mediators for changing the angular momentum of light. This sidesteps the need to exploit nonlinear light-matter interactions based on higher-order susceptibilities. A tight-binding paradigm is used to verify angular momentum conservation and demonstrate how it can be exploited to change the angular momentum of light. The approach is then extended to a time-dependent density functional theory setting where the key results are shown to hold in a many-body, multilevel setting.

The past and the future of Alzheimer’s disease CSF biomarkers – a journey towards validated biochemical tests covering the whole spectra of molecular events

Directory of Open Access Journals (Sweden)

Kaj eBlennow

2015-09-01

Full Text Available This paper gives a short review on cerebrospinal fluid (CSF biomarkers for Alzheimer’s disease (AD, from early developments to high-precision validated assays on fully automated lab analyzers. We also discuss developments on novel biomarkers, such as synaptic proteins and Aβ oligomers. Our vision for the future is that assaying a set of biomarkers in a single CSF tube can monitor the whole spectra of AD molecular pathogenic events. CSF biomarkers will have a central position not only for clinical diagnosis, but also for the understanding of the sequence of molecular events in the pathogenic process underlying AD and as tools to monitor the effects of novel drug candidates targeting these different mechanisms.

Multiple proviral integration events after virological synapse-mediated HIV-1 spread

International Nuclear Information System (INIS)

Russell, Rebecca A.; Martin, Nicola; Mitar, Ivonne; Jones, Emma; Sattentau, Quentin J.

2013-01-01

HIV-1 can move directly between T cells via virological synapses (VS). Although aspects of the molecular and cellular mechanisms underlying this mode of spread have been elucidated, the outcomes for infection of the target cell remain incompletely understood. We set out to determine whether HIV-1 transfer via VS results in productive, high-multiplicity HIV-1 infection. We found that HIV-1 cell-to-cell spread resulted in nuclear import of multiple proviruses into target cells as seen by fluorescence in-situ hybridization. Proviral integration into the target cell genome was significantly higher than that seen in a cell-free infection system, and consequent de novo viral DNA and RNA production in the target cell detected by quantitative PCR increased over time. Our data show efficient proviral integration across VS, implying the probability of multiple integration events in target cells that drive productive T cell infection. - Highlights: • Cell-to-cell HIV-1 infection delivers multiple vRNA copies to the target cell. • Cell-to-cell infection results in productive infection of the target cell. • Cell-to-cell transmission is more efficient than cell-free HIV-1 infection. • Suggests a mechanism for recombination in cells infected with multiple viral genomes

Defining molecular initiating events in the adverse outcome pathway framework for risk assessment.

Science.gov (United States)

Allen, Timothy E H; Goodman, Jonathan M; Gutsell, Steve; Russell, Paul J

2014-12-15

Consumer and environmental safety decisions are based on exposure and hazard data, interpreted using risk assessment approaches. The adverse outcome pathway (AOP) conceptual framework has been presented as a logical sequence of events or processes within biological systems which can be used to understand adverse effects and refine current risk assessment practices in ecotoxicology. This framework can also be applied to human toxicology and is explored on the basis of investigating the molecular initiating events (MIEs) of compounds. The precise definition of the MIE has yet to reach general acceptance. In this work we present a unified MIE definition: an MIE is the initial interaction between a molecule and a biomolecule or biosystem that can be causally linked to an outcome via a pathway. Case studies are presented, and issues with current definitions are addressed. With the development of a unified MIE definition, the field can look toward defining, classifying, and characterizing more MIEs and using knowledge of the chemistry of these processes to aid AOP research and toxicity risk assessment. We also present the role of MIE research in the development of in vitro and in silico toxicology and suggest how, by using a combination of biological and chemical approaches, MIEs can be identified and characterized despite a lack of detailed reports, even for some of the most studied molecules in toxicology.

Molecular mechanism underlying juvenile hormone-mediated repression of precocious larval-adult metamorphosis.

Science.gov (United States)

Kayukawa, Takumi; Jouraku, Akiya; Ito, Yuka; Shinoda, Tetsuro

2017-01-31

Juvenile hormone (JH) represses precocious metamorphosis of larval to pupal and adult transitions in holometabolous insects. The early JH-inducible gene Krüppel homolog 1 (Kr-h1) plays a key role in the repression of metamorphosis as a mediator of JH action. Previous studies demonstrated that Kr-h1 inhibits precocious larval-pupal transition in immature larva via direct transcriptional repression of the pupal specifier Broad-Complex (BR-C). JH was recently reported to repress the adult specifier gene Ecdysone-induced protein 93F (E93); however, its mechanism of action remains unclear. Here, we found that JH suppressed ecdysone-inducible E93 expression in the epidermis of the silkworm Bombyx mori and in a B. mori cell line. Reporter assays in the cell line revealed that the JH-dependent suppression was mediated by Kr-h1. Genome-wide ChIP-seq analysis identified a consensus Kr-h1 binding site (KBS, 14 bp) located in the E93 promoter region, and EMSA confirmed that Kr-h1 directly binds to the KBS. Moreover, we identified a C-terminal conserved domain in Kr-h1 essential for the transcriptional repression of E93 Based on these results, we propose a mechanism in which JH-inducible Kr-h1 directly binds to the KBS site upstream of the E93 locus to repress its transcription in a cell-autonomous manner, thereby preventing larva from bypassing the pupal stage and progressing to precocious adult development. These findings help to elucidate the molecular mechanisms regulating the metamorphic genetic network, including the functional significance of Kr-h1, BR-C, and E93 in holometabolous insect metamorphosis.

Reinforcing the membrane-mediated mechanism of action of the anti-tuberculosis candidate drug thioridazine with molecular simulations

DEFF Research Database (Denmark)

Kopec, Wojciech; Khandelia, Himanshu

2014-01-01

Thioridazine is a well-known dopamine-antagonist drug with a wide range of pharmacological properties ranging from neuroleptic to antimicrobial and even anticancer activity. Thioridazine is a critical component of a promising multi-drug therapy against M. tuberculosis. Amongst the various propose......-membrane interactions, and reinforce the wider, emerging view of action of many small, bioactive compounds....... mechanisms of action, the cell membrane-mediated one is peculiarly tempting due to the distinctive feature of phenothiazine drug family to accumulate in selected body tissues. In this study, we employ long-scale molecular dynamics simulations to investigate the interactions of three different concentrations...

Rumination mediates the relationship between structural variations in ventrolateral prefrontal cortex and sensitivity to negative life events.

Science.gov (United States)

Qiao, L; Wei, D T; Li, W F; Chen, Q L; Che, X W; Li, B B; Li, Y D; Qiu, J; Zhang, Q L; Liu, Y J

2013-01-01

Individuals have different levels of stress sensitivity. An individual's predisposition to experience negative life events (NLEs) may make him/her more vulnerable to a series of psychopathological and physical diseases. However, the neuroanatomical correlates of individual differences in sensitivity to NLEs remain unknown. In this study, voxel-based morphometry was used to identify the gray matter (GM) associations of individual differences in sensitivity to NLEs measured by adolescent self-rating life events checklist. Results showed that there was a positive association between individual NLEs sensitivity and regional GM volume (rGMV) in the ventrolateral prefrontal cortex (VLPFC). GM was mostly evident in the left frontal operculum and a small part of the left middle frontal gyrus. This region was thought to play an important role in introception. Importantly, our study revealed that rumination served as a mediator between the rGMV of the VLPFC and individual NLEs sensitivity. These findings suggest that people with greater VLPFC might be more inclined to ruminate and the ruminative response style might make them more sensitive to NLEs. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Effects of cadmium on olfactory mediated behaviors and molecular biomarkers in coho salmon (Oncorhynchus kisutch)

Energy Technology Data Exchange (ETDEWEB)

Williams, Chase R.; Gallagher, Evan P., E-mail: evang3@u.washington.edu

2013-09-15

Highlights: •Low Cd exposures elicited significant olfactory mediated behavioral changes independent of histological injury. •The olfactory behavioral deficits persisted following a 16-day depuration. •Olfactory molecular biomarkers expression was strongly linked to injury to the olfactory epithelium. •Cd induced a strong antioxidant response in the coho salmon olfactory system. •Results suggest a sensitivity of salmonids to waterborne Cd. -- Abstract: The olfactory system of salmonids is sensitive to the adverse effects of metals such as copper and cadmium. In the current study, we analyzed olfactory-mediated alarm responses, epithelial injury and recovery, and a suite of olfactory molecular biomarkers encoding genes critical in maintaining olfactory function in juvenile coho salmon receiving acute exposures to cadmium (Cd). The molecular biomarkers analyzed included four G-protein coupled receptors (GPCRs) representing the two major classes of odorant receptors (salmon olfactory receptor sorb and vomeronasal receptors svra, svrb, and gpr27), as well as markers of neurite outgrowth (nrn1) and antioxidant responses to metals, including heme oxygenase 1 (hmox1), and peroxiredoxin 1 (prdx1). Coho received acute (8–168 h) exposures to 3.7 ppb and 347 ppb Cd, and a subset of fish was analyzed following a 16-day depuration. Coho exposed to 347 ppb Cd over 48 h exhibited a reduction in freeze responses, and an extensive loss of olfaction accompanied by histological injury to the olfactory epithelium. The olfactory injury in coho exposed to 347 ppb Cd was accompanied at the gene level by significant decreases in expression of the olfactory GPCRs and increased expression of hmox1. Persistent behavioral deficits, histological injury and altered expression of a subset of olfactory biomarkers were still evident in Cd-exposed coho following a 16-day depuration in clean water. Exposure to 3.7 ppb Cd also resulted in reduced freeze responses and histological changes

microRNA-mediated R gene regulation: molecular scabbards for double-edged swords.

Science.gov (United States)

Deng, Yingtian; Liu, Minglei; Li, Xiaofei; Li, Feng

2018-02-01

Plant resistance (R) proteins are immune receptors that recognize pathogen effectors and trigger rapid defense responses, namely effector-triggered immunity. R protein-mediated pathogen resistance is usually race specific. During plant-pathogen coevolution, plant genomes accumulated large numbers of R genes. Even though plant R genes provide important natural resources for breeding disease-resistant crops, their presence in the plant genome comes at a cost. Misregulation of R genes leads to developmental defects, such as stunted growth and reduced fertility. In the past decade, many microRNAs (miRNAs) have been identified to target various R genes in plant genomes. miRNAs reduce R gene levels under normal conditions and allow induction of R gene expression under various stresses. For these reasons, we consider R genes to be double-edged "swords" and miRNAs as molecular "scabbards". In the present review, we summarize the contributions and potential problems of these "swords" and discuss the features and production of the "scabbards", as well as the mechanisms used to pull the "sword" from the "scabbard" when needed.

Synthesis of homochiral tris-indanyl molecular rods

DEFF Research Database (Denmark)

Kjeldsen, Niels Due; Funder, Erik Daa; Gothelf, Kurt Vesterager

2014-01-01

Homochiral tris-indanyl molecular rods designed for supramolecular surface self-assembly were synthesized. The chiral indanol moiety was constructed via a Ti-mediated alkyne trimerization. Further manipulations resulted in a homochiral indanol monomer. This was employed as the precursor for succe...... for successive Sonogashira and Ohira-Bestman reactions towards the homochiral tris-indanyl molecular rods. The molecular rods will be applied for scanning tunnelling microscopy studies of their surface self-assembly and chirality.......Homochiral tris-indanyl molecular rods designed for supramolecular surface self-assembly were synthesized. The chiral indanol moiety was constructed via a Ti-mediated alkyne trimerization. Further manipulations resulted in a homochiral indanol monomer. This was employed as the precursor...

Bringing molecules back into molecular evolution.

Directory of Open Access Journals (Sweden)

Claus O Wilke

Full Text Available Much molecular-evolution research is concerned with sequence analysis. Yet these sequences represent real, three-dimensional molecules with complex structure and function. Here I highlight a growing trend in the field to incorporate molecular structure and function into computational molecular-evolution work. I consider three focus areas: reconstruction and analysis of past evolutionary events, such as phylogenetic inference or methods to infer selection pressures; development of toy models and simulations to identify fundamental principles of molecular evolution; and atom-level, highly realistic computational modeling of molecular structure and function aimed at making predictions about possible future evolutionary events.

Extracellular histones disarrange vasoactive mediators release through a COX-NOS interaction in human endothelial cells.

Science.gov (United States)

Pérez-Cremades, Daniel; Bueno-Betí, Carlos; García-Giménez, José Luis; Ibañez-Cabellos, José Santiago; Hermenegildo, Carlos; Pallardó, Federico V; Novella, Susana

2017-08-01

Extracellular histones are mediators of inflammation, tissue injury and organ dysfunction. Interactions between circulating histones and vascular endothelial cells are key events in histone-mediated pathologies. Our aim was to investigate the implication of extracellular histones in the production of the major vasoactive compounds released by human endothelial cells (HUVECs), prostanoids and nitric oxide (NO). HUVEC exposed to increasing concentrations of histones (0.001 to 100 μg/ml) for 4 hrs induced prostacyclin (PGI2) production in a dose-dependent manner and decreased thromboxane A2 (TXA2) release at 100 μg/ml. Extracellular histones raised cyclooxygenase-2 (COX-2) and prostacyclin synthase (PGIS) mRNA and protein expression, decreased COX-1 mRNA levels and did not change thromboxane A2 synthase (TXAS) expression. Moreover, extracellular histones decreased both, eNOS expression and NO production in HUVEC. The impaired NO production was related to COX-2 activity and superoxide production since was reversed after celecoxib (10 μmol/l) and tempol (100 μmol/l) treatments, respectively. In conclusion, our findings suggest that extracellular histones stimulate the release of endothelial-dependent mediators through an up-regulation in COX-2-PGIS-PGI2 pathway which involves a COX-2-dependent superoxide production that decreases the activity of eNOS and the NO production. These effects may contribute to the endothelial cell dysfunction observed in histone-mediated pathologies. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

The mediating effect of depression between exposure to potentially traumatic events and PTSD in news journalists

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Klas Backholm

2012-08-01

Full Text Available Background: News journalists are an occupational group with a unique task at the scene of an unfolding crisis—to collect information and inform the public about the event. By being on location, journalists put themselves at risk for being exposed to the potentially traumatic event. Objective: To compare potentially traumatic exposure during work assignments at a crisis scene and in personal life as predictors of the development of post-traumatic stress disorder (PTSD in news journalists. Further, to investigate the mediating effect of depression between the predictor and predicted variables. Method: With a web-based questionnaire, information from a sample of Finnish news journalists (n=407 was collected. The data collected included details on the range of potentially traumatic assignments (PTAs at the crisis scene during the past 12 months, lifetime potentially traumatic events (PTEs in personal life, PTSD symptoms, and level of depression. Results: Approximately 50% of the participants had worked with a PTA during the past 12 months. Depression had a significant indirect effect on the relationship between PTAs at the scene and symptoms of PTSD. A similar result was found regarding the relationship between personal life PTEs and PTSD. Depression had a complete indirect effect in the case of PTAs and a partial indirect effect in regard to PTE exposure in personal life. Conclusions: Exposure to PTAs is common within journalistic work. The results reflect the importance of understanding the underlying mechanisms of the measured symptoms (PTSD, depression in relation to trauma history. The main limitations of the study include the cross-sectional design and the nature of the instruments used for the collection of work-related trauma history.

Role of stressful life events, avoidant coping styles, and neuroticism in online game addiction among college students: a moderated mediation model

Directory of Open Access Journals (Sweden)

Li Huanhuan

2016-11-01

Full Text Available Online game addiction (OGA is becoming a significant problem worldwide. The aim of this study was to explore the incidence of OGA and the roles of stressful life events, avoidant coping styles (ACSs, and neuroticism in OGA. A total of 651 Chinese college students were selected by random cluster sampling. Subjects completed the Chinese version of Young’s eight-item Internet Addiction Scale (CIAS, Online Game Cognition Addiction Scale (OGCAS, Revised Eysenck Personality Questionnaire Short Scale in Chinese (EPQ-RSC, Chinese College-student Stress Questionnaire (CCSQ, and Coping Style Questionnaire (CSQ. Structural equation modeling (SEM was used to explore the interactive effects of stressful life events, ACSs, and neuroticism on OGA. Of the 651 participants in the sample, 31 (4.8% were identified as addicts. The incidence of OGA was two times higher for males than females. The addicts had markedly higher scores on the neuroticism subscale of the EPQ-RSC than non-addicts. Compared to non-addicts, addicts were more apt to use ACSs. Having an avoidant coping strategy mediated the effect of stressful life events on OGA. Furthermore, neuroticism moderated the indirect effect of stressful life events on OGA via ACSs. Applications of these findings to etiological research and clinical treatment programs are discussed.

Role of Stressful Life Events, Avoidant Coping Styles, and Neuroticism in Online Game Addiction among College Students: A Moderated Mediation Model.

Science.gov (United States)

Li, Huanhuan; Zou, Yingmin; Wang, Jiaqi; Yang, Xuelin

2016-01-01

Online game addiction (OGA) is becoming a significant problem worldwide. The aim of this study was to explore the incidence of OGA and the roles of stressful life events, avoidant coping styles (ACSs), and neuroticism in OGA. A total of 651 Chinese college students were selected by random cluster sampling. Subjects completed the Chinese version of Young's eight-item Internet Addiction Scale (CIAS), Online Game Cognition Addiction Scale (OGCAS), Revised Eysenck Personality Questionnaire Short Scale in Chinese (EPQ-RSC), Chinese College-student Stress Questionnaire, and Coping Style Questionnaire. Structural equation modeling (SEM) was used to explore the interactive effects of stressful life events, ACSs, and neuroticism on OGA. Of the 651 participants in the sample, 31 (4.8%) were identified as addicts. The incidence of OGA was two times higher for males than females. The addicts had markedly higher scores on the neuroticism subscale of the EPQ-RSC than non-addicts. Compared to non-addicts, addicts were more apt to use ACSs. Having an avoidant coping strategy mediated the effect of stressful life events on OGA. Furthermore, neuroticism moderated the indirect effect of stressful life events on OGA via ACSs. Applications of these findings to etiological research and clinical treatment programs are discussed.

Role of Stressful Life Events, Avoidant Coping Styles, and Neuroticism in Online Game Addiction among College Students: A Moderated Mediation Model

Science.gov (United States)

Li, Huanhuan; Zou, Yingmin; Wang, Jiaqi; Yang, Xuelin

2016-01-01

Online game addiction (OGA) is becoming a significant problem worldwide. The aim of this study was to explore the incidence of OGA and the roles of stressful life events, avoidant coping styles (ACSs), and neuroticism in OGA. A total of 651 Chinese college students were selected by random cluster sampling. Subjects completed the Chinese version of Young’s eight-item Internet Addiction Scale (CIAS), Online Game Cognition Addiction Scale (OGCAS), Revised Eysenck Personality Questionnaire Short Scale in Chinese (EPQ-RSC), Chinese College-student Stress Questionnaire, and Coping Style Questionnaire. Structural equation modeling (SEM) was used to explore the interactive effects of stressful life events, ACSs, and neuroticism on OGA. Of the 651 participants in the sample, 31 (4.8%) were identified as addicts. The incidence of OGA was two times higher for males than females. The addicts had markedly higher scores on the neuroticism subscale of the EPQ-RSC than non-addicts. Compared to non-addicts, addicts were more apt to use ACSs. Having an avoidant coping strategy mediated the effect of stressful life events on OGA. Furthermore, neuroticism moderated the indirect effect of stressful life events on OGA via ACSs. Applications of these findings to etiological research and clinical treatment programs are discussed. PMID:27920734

Characterization of nanoparticle mediated laser transfection by femtosecond laser pulses for applications in molecular medicine.

Science.gov (United States)

Schomaker, Markus; Heinemann, Dag; Kalies, Stefan; Willenbrock, Saskia; Wagner, Siegfried; Nolte, Ingo; Ripken, Tammo; Murua Escobar, Hugo; Meyer, Heiko; Heisterkamp, Alexander

2015-02-03

In molecular medicine, the manipulation of cells is prerequisite to evaluate genes as therapeutic targets or to transfect cells to develop cell therapeutic strategies. To achieve these purposes it is essential that given transfection techniques are capable of handling high cell numbers in reasonable time spans. To fulfill this demand, an alternative nanoparticle mediated laser transfection method is presented herein. The fs-laser excitation of cell-adhered gold nanoparticles evokes localized membrane permeabilization and enables an inflow of extracellular molecules into cells. The parameters for an efficient and gentle cell manipulation are evaluated in detail. Efficiencies of 90% with a cell viability of 93% were achieved for siRNA transfection. The proof for a molecular medical approach is demonstrated by highly efficient knock down of the oncogene HMGA2 in a rapidly proliferating prostate carcinoma in vitro model using siRNA. Additionally, investigations concerning the initial perforation mechanism are conducted. Next to theoretical simulations, the laser induced effects are experimentally investigated by spectrometric and microscopic analysis. The results indicate that near field effects are the initial mechanism of membrane permeabilization. This methodical approach combined with an automated setup, allows a high throughput targeting of several 100,000 cells within seconds, providing an excellent tool for in vitro applications in molecular medicine. NIR fs lasers are characterized by specific advantages when compared to lasers employing longer (ps/ns) pulses in the visible regime. The NIR fs pulses generate low thermal impact while allowing high penetration depths into tissue. Therefore fs lasers could be used for prospective in vivo applications.

Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging.

Science.gov (United States)

Ben-Zvi, Anat; Miller, Elizabeth A; Morimoto, Richard I

2009-09-01

Protein damage contributes prominently to cellular aging. To address whether this occurs at a specific period during aging or accumulates gradually, we monitored the biochemical, cellular, and physiological properties of folding sensors expressed in different tissues of C. elegans. We observed the age-dependent misfolding and loss of function of diverse proteins harboring temperature-sensitive missense mutations in all somatic tissues at the permissive condition. This widespread failure in proteostasis occurs rapidly at an early stage of adulthood, and coincides with a severely reduced activation of the cytoprotective heat shock response and the unfolded protein response. Enhancing stress responsive factors HSF-1 or DAF-16 suppresses misfolding of these metastable folding sensors and restores the ability of the cell to maintain a functional proteome. This suggests that a compromise in the regulation of proteostatic stress responses occurs early in adulthood and tips the balance between the load of damaged proteins and the proteostasis machinery. We propose that the collapse of proteostasis represents an early molecular event of aging that amplifies protein damage in age-associated diseases of protein conformation.

Quantification of pancreatic cancer proteome and phosphorylome: indicates molecular events likely contributing to cancer and activity of drug targets.

Directory of Open Access Journals (Sweden)

David Britton

Full Text Available LC-MS/MS phospho-proteomics is an essential technology to help unravel the complex molecular events that lead to and propagate cancer. We have developed a global phospho-proteomic workflow to determine activity of signaling pathways and drug targets in pancreatic cancer tissue for clinical application.Peptides resulting from tryptic digestion of proteins extracted from frozen tissue of pancreatic ductal adenocarcinoma and background pancreas (n = 12, were labelled with tandem mass tags (TMT 8-plex, separated by strong cation exchange chromatography, then were analysed by LC-MS/MS directly or first enriched for phosphopeptides using IMAC and TiO2, prior to analysis. In-house, commercial and freeware bioinformatic platforms were used to identify relevant biological events from the complex dataset.Of 2,101 proteins identified, 152 demonstrated significant difference in abundance between tumor and non-tumor tissue. They included proteins that are known to be up-regulated in pancreatic cancer (e.g. Mucin-1, but the majority were new candidate markers such as HIPK1 & MLCK. Of the 6,543 unique phosphopeptides identified (6,284 unique phosphorylation sites, 635 showed significant regulation, particularly those from proteins involved in cell migration (Rho guanine nucleotide exchange factors & MRCKα and formation of focal adhesions. Activator phosphorylation sites on FYN, AKT1, ERK2, HDAC1 and other drug targets were found to be highly modulated (≥2 fold in different cases highlighting their predictive power.Here we provided critical information enabling us to identify the common and unique molecular events likely contributing to cancer in each case. Such information may be used to help predict more bespoke therapy suitable for an individual case.

Quantification of pancreatic cancer proteome and phosphorylome: indicates molecular events likely contributing to cancer and activity of drug targets.

Science.gov (United States)

Britton, David; Zen, Yoh; Quaglia, Alberto; Selzer, Stefan; Mitra, Vikram; Löβner, Christopher; Jung, Stephan; Böhm, Gitte; Schmid, Peter; Prefot, Petra; Hoehle, Claudia; Koncarevic, Sasa; Gee, Julia; Nicholson, Robert; Ward, Malcolm; Castellano, Leandro; Stebbing, Justin; Zucht, Hans Dieter; Sarker, Debashis; Heaton, Nigel; Pike, Ian

2014-01-01

LC-MS/MS phospho-proteomics is an essential technology to help unravel the complex molecular events that lead to and propagate cancer. We have developed a global phospho-proteomic workflow to determine activity of signaling pathways and drug targets in pancreatic cancer tissue for clinical application. Peptides resulting from tryptic digestion of proteins extracted from frozen tissue of pancreatic ductal adenocarcinoma and background pancreas (n = 12), were labelled with tandem mass tags (TMT 8-plex), separated by strong cation exchange chromatography, then were analysed by LC-MS/MS directly or first enriched for phosphopeptides using IMAC and TiO2, prior to analysis. In-house, commercial and freeware bioinformatic platforms were used to identify relevant biological events from the complex dataset. Of 2,101 proteins identified, 152 demonstrated significant difference in abundance between tumor and non-tumor tissue. They included proteins that are known to be up-regulated in pancreatic cancer (e.g. Mucin-1), but the majority were new candidate markers such as HIPK1 & MLCK. Of the 6,543 unique phosphopeptides identified (6,284 unique phosphorylation sites), 635 showed significant regulation, particularly those from proteins involved in cell migration (Rho guanine nucleotide exchange factors & MRCKα) and formation of focal adhesions. Activator phosphorylation sites on FYN, AKT1, ERK2, HDAC1 and other drug targets were found to be highly modulated (≥2 fold) in different cases highlighting their predictive power. Here we provided critical information enabling us to identify the common and unique molecular events likely contributing to cancer in each case. Such information may be used to help predict more bespoke therapy suitable for an individual case.

Molecular initiating events of the intersex phenotype: Low-dose exposure to 17α-ethinylestradiol rapidly regulates molecular networks associated with gonad differentiation in the adult fathead minnow testis

International Nuclear Information System (INIS)

Feswick, April; Loughery, Jennifer R.; Isaacs, Meghan A.; Munkittrick, Kelly R.; Martyniuk, Christopher J.

2016-01-01

Highlights: • Male fathead minnow were exposed to 17alpha ethinylestradiol (EE2). • Both 11-ketotestosterone and testosterone production was decreased relative to controls. • A gene network associated with doublesex and mab-3 related transcription factor 1 were suppressed. • Genes involved in granulosa cell development were increased and sensitive to EE2 exposure. • Molecular initiating events that may be related to the intersex condition were identified. - Abstract: Intersex, or the presence of oocytes in the testes, has been documented in fish following exposure to wastewater effluent and estrogenic compounds. However, the molecular networks underlying the intersex condition are not completely known. To address this, we exposed male fathead minnows to a low, environmentally-relevant concentration of 17alpha-ethinylestradiol (EE2) (15 ng/L) and measured the transcriptome response in the testis after 96 h to identify early molecular initiating events that may proceed the intersex condition. The short-term exposure to EE2 did not affect gonadosomatic index and proportion of gametes within the testes. However, the production of 11-ketotestosterone and testosterone from the testis in vitro was decreased relative to controls. Expression profiling using a 8 × 60 K fathead minnow microarray identified 10 transcripts that were differentially expressed in the testes, the most dramatic change being that of coagulation factor XIII A chain (20-fold increase). Transcripts that included guanine nucleotide binding protein (Beta Polypeptide 2), peroxisome proliferator-activated receptor delta, and WNK lysine deficient protein kinase 1a, were down-regulated by EE2. Subnetwork enrichment analysis revealed that EE2 suppressed transcriptional networks associated with steroid metabolism, hormone biosynthesis, and sperm mobility. Most interesting was that gene networks associated with doublesex and mab-3 related transcription factor 1 (dmrt1) were suppressed in the adult

Molecular initiating events of the intersex phenotype: Low-dose exposure to 17α-ethinylestradiol rapidly regulates molecular networks associated with gonad differentiation in the adult fathead minnow testis

Energy Technology Data Exchange (ETDEWEB)

Feswick, April; Loughery, Jennifer R.; Isaacs, Meghan A.; Munkittrick, Kelly R.; Martyniuk, Christopher J., E-mail: cmartyni@yahoo.ca

2016-12-15

Highlights: • Male fathead minnow were exposed to 17alpha ethinylestradiol (EE2). • Both 11-ketotestosterone and testosterone production was decreased relative to controls. • A gene network associated with doublesex and mab-3 related transcription factor 1 were suppressed. • Genes involved in granulosa cell development were increased and sensitive to EE2 exposure. • Molecular initiating events that may be related to the intersex condition were identified. - Abstract: Intersex, or the presence of oocytes in the testes, has been documented in fish following exposure to wastewater effluent and estrogenic compounds. However, the molecular networks underlying the intersex condition are not completely known. To address this, we exposed male fathead minnows to a low, environmentally-relevant concentration of 17alpha-ethinylestradiol (EE2) (15 ng/L) and measured the transcriptome response in the testis after 96 h to identify early molecular initiating events that may proceed the intersex condition. The short-term exposure to EE2 did not affect gonadosomatic index and proportion of gametes within the testes. However, the production of 11-ketotestosterone and testosterone from the testis in vitro was decreased relative to controls. Expression profiling using a 8 × 60 K fathead minnow microarray identified 10 transcripts that were differentially expressed in the testes, the most dramatic change being that of coagulation factor XIII A chain (20-fold increase). Transcripts that included guanine nucleotide binding protein (Beta Polypeptide 2), peroxisome proliferator-activated receptor delta, and WNK lysine deficient protein kinase 1a, were down-regulated by EE2. Subnetwork enrichment analysis revealed that EE2 suppressed transcriptional networks associated with steroid metabolism, hormone biosynthesis, and sperm mobility. Most interesting was that gene networks associated with doublesex and mab-3 related transcription factor 1 (dmrt1) were suppressed in the adult

Life Event Stress and Binge Eating Among Adolescents: The Roles of Early Maladaptive Schemas and Impulsivity.

Science.gov (United States)

Zhu, Hong; Luo, Xingwei; Cai, Taisheng; He, Jinbo; Lu, Yao; Wu, Siyao

2016-10-01

This study examined the relationships between life event stress, early maladaptive schemas, impulsivity and binge eating among adolescents and investigated the effects of early maladaptive schemas and impulsivity on the relationship between life event stress and binge eating. Specifically, we examined a moderated mediation model in which early maladaptive schemas mediated this relationship and impulsivity moderated the mediation effect. Life event stress, early maladaptive schemas, impulsivity and binge eating were investigated in a sample of 2172 seventh-, eighth- and tenth-grade middle and high school students (mean age = 14.55 years, standard deviation = 1.29). The results indicated that adolescents with greater life event stress, more early maladaptive schemas and higher levels of impulsivity displayed more severe binge eating. In addition, early maladaptive schemas mediated the relationship between life event stress and binge eating, while impulsivity moderated this relationship. Furthermore, impulsivity also moderated the mediation effect of early maladaptive schemas; as impulsivity levels increased, the strength of the association between life event stress and early maladaptive schemas increased. This study illustrates the importance of understanding individual differences and their effects on the relationship between life event stress and binge eating. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Molecular Mechanisms Underlying Curcumin-Mediated Therapeutic Effects in Type 2 Diabetes and Cancer

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Marzena Wojcik

2018-01-01

Full Text Available The growing prevalence of age-related diseases, especially type 2 diabetes mellitus (T2DM and cancer, has become global health and economic problems. Due to multifactorial nature of both diseases, their pathophysiology is not completely understood so far. Compelling evidence indicates that increased oxidative stress, resulting from an imbalance between production of reactive oxygen species (ROS and their clearance by antioxidant defense mechanisms, as well as the proinflammatory state contributes to the development and progression of the diseases. Curcumin (CUR; diferuloylmethane, a well-known polyphenol derived from the rhizomes of turmeric Curcuma longa, has attracted a great deal of attention as a natural compound with beneficial antidiabetic and anticancer properties, partly due to its antioxidative and anti-inflammatory actions. Although this polyphenolic compound is increasingly being recognized for its growing number of protective health effects, the precise molecular mechanisms through which it reduces diabetes- and cancer-related pathological events have not been fully unraveled. Hence, CUR is the subject of intensive research in the fields Diabetology and Oncology as a potential candidate in the treatment of both T2DM and cancer, particularly since current therapeutic options for their treatment are not satisfactory in clinics. In this review, we summarize the recent progress made on the molecular targets and pathways involved in antidiabetic and anticancer activities of CUR that are responsible for its beneficial health effects.

General perspectives for molecular nuclear imaging

International Nuclear Information System (INIS)

Chung, June Key

2004-01-01

Molecular imaging provides a visualization of normal as well as abnormal cellular processes at a molecular or genetic level rather than at an anatomical level. Conventional medical imaging methods utilize the imaging signals produced by nonspecific physico-chemical interaction. However, molecular imaging methods utilize the imaging signals derived from specific cellular or molecular events. Because molecular and genetic changes precede anatomical change in the course of disease development, molecular imaging can detect early events in disease progression. In the near future, through molecular imaging we can understand basic mechanisms of disease, and diagnose earlier and, subsequently, treat earlier intractable disease such as cancer, neuro-degenerative diseases, and immunologic disorders. In beginning period, nuclear medicine started as a molecular imaging, and has had a leading role in the field of molecular imaging. But recently molecular imaging has been rapidly developed. Besides nuclear imaging, molecular imaging methods such as optical imaging, magnetic resonance imaging are emerging. Each imaging modalities have their advantages and weaknesses. The opportunities from molecular imaging look bright. We should try nuclear medicine continues to have a leading role in molecular imaging

Mechanistic Insights into Radical-Mediated Oxidation of Tryptophan from ab Initio Quantum Chemistry Calculations and QM/MM Molecular Dynamics Simulations.

Science.gov (United States)

Wood, Geoffrey P F; Sreedhara, Alavattam; Moore, Jamie M; Wang, John; Trout, Bernhardt L

2016-05-12

An assessment of the mechanisms of (•)OH and (•)OOH radical-mediated oxidation of tryptophan was performed using density functional theory calculations and ab initio plane-wave Quantum Mechanics/Molecular Mechanics (QM/MM) molecular dynamics simulations. For the (•)OH reactions, addition to the pyrrole ring at position 2 is the most favored site with a barrierless reaction in the gas phase. The subsequent degradation of this adduct through a H atom transfer to water was intermittently observed in aqueous-phase molecular dynamics simulations. For the (•)OOH reactions, addition to the pyrrole ring at position 2 is the most favored pathway, in contrast to the situation in the model system ethylene, where concerted addition to the double bond is preferred. From the (•)OOH position 2 adduct QM/MM simulations show that formation of oxy-3-indolanaline occurs readily in an aqueous environment. The observed transformation starts from an initial rupture of the O-O bond followed by a H atom transfer with the accompanying loss of an (•)OH radical to solution. Finally, classical molecular dynamics simulations were performed to equate observed differential oxidation rates of various tryptophan residues in monoclonal antibody fragments. It was found that simple parameters derived from simulation correlate well with the experimental data.

Characterization of GM events by insert knowledge adapted re-sequencing approaches

OpenAIRE

Yang, Litao; Wang, Congmao; Holst-Jensen, Arne; Morisset, Dany; Lin, Yongjun; Zhang, Dabing

2013-01-01

Detection methods and data from molecular characterization of genetically modified (GM) events are needed by stakeholders of public risk assessors and regulators. Generally, the molecular characteristics of GM events are incomprehensively revealed by current approaches and biased towards detecting transformation vector derived sequences. GM events are classified based on available knowledge of the sequences of vectors and inserts (insert knowledge). Herein we present three insert knowledge-ad...

Reprogramming the Dynamin 2 mRNA by Spliceosome-mediated RNA Trans-splicing

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Delphine Trochet

2016-01-01

Full Text Available Dynamin 2 (DNM2 is a large GTPase, ubiquitously expressed, involved in membrane trafficking and regulation of actin and microtubule cytoskeletons. DNM2 mutations cause autosomal dominant centronuclear myopathy which is a rare congenital myopathy characterized by skeletal muscle weakness and histopathological features including nuclear centralization in absence of regeneration. No curative treatment is currently available for the DNM2-related autosomal dominant centronuclear myopathy. In order to develop therapeutic strategy, we evaluated here the potential of Spliceosome-Mediated RNA Trans-splicing technology to reprogram the Dnm2-mRNA in vitro and in vivo in mice. We show that classical 3′-trans-splicing strategy cannot be considered as accurate therapeutic strategy regarding toxicity of the pre-trans-splicing molecules leading to low rate of trans-splicing in vivo. Thus, we tested alternative strategies devoted to prevent this toxicity and enhance frequency of trans-splicing events. We succeeded to overcome the toxicity through a 5′-trans-splicing strategy which also allows detection of trans-splicing events at mRNA and protein levels in vitro and in vivo. These results suggest that the Spliceosome-Mediated RNA Trans-splicing strategy may be used to reprogram mutated Dnm2-mRNA but highlight the potential toxicity linked to the molecular tools which have to be carefully investigated during preclinical development.

The dorsolateral periaqueductal gray and its role in mediating fear learning to life threatening events.

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Grasielle C Kincheski

Full Text Available The dorsolateral column of the periaqueductal gray (dlPAG integrates aversive emotional experiences and represents an important site responding to life threatening situations, such as hypoxia, cardiac pain and predator threats. Previous studies have shown that the dorsal PAG also supports fear learning; and we have currently explored how the dlPAG influences associative learning. We have first shown that N-methyl-D-aspartate (NMDA 100 pmol injection in the dlPAG works as a valuable unconditioned stimulus (US for the acquisition of olfactory fear conditioning (OFC using amyl acetate odor as conditioned stimulus (CS. Next, we revisited the ascending projections of the dlPAG to the thalamus and hypothalamus to reveal potential paths that could mediate associative learning during OFC. Accordingly, the most important ascending target of the dlPAG is the hypothalamic defensive circuit, and we were able to show that pharmacological inactivation using β-adrenoceptor blockade of the dorsal premammillary nucleus, the main exit way for the hypothalamic defensive circuit to thalamo-cortical circuits involved in fear learning, impaired the acquisition of the OFC promoted by NMDA stimulation of the dlPAG. Moreover, our tracing study revealed multiple parallel paths from the dlPAG to several thalamic targets linked to cortical-hippocampal-amygdalar circuits involved in fear learning. Overall, the results point to a major role of the dlPAG in the mediation of aversive associative learning via ascending projections to the medial hypothalamic defensive circuit, and perhaps, to other thalamic targets, as well. These results provide interesting perspectives to understand how life threatening events impact on fear learning, and should be useful to understand pathological fear memory encoding in anxiety disorders.

Characterization of GM events by insert knowledge adapted re-sequencing approaches.

Science.gov (United States)

Yang, Litao; Wang, Congmao; Holst-Jensen, Arne; Morisset, Dany; Lin, Yongjun; Zhang, Dabing

2013-10-03

Detection methods and data from molecular characterization of genetically modified (GM) events are needed by stakeholders of public risk assessors and regulators. Generally, the molecular characteristics of GM events are incomprehensively revealed by current approaches and biased towards detecting transformation vector derived sequences. GM events are classified based on available knowledge of the sequences of vectors and inserts (insert knowledge). Herein we present three insert knowledge-adapted approaches for characterization GM events (TT51-1 and T1c-19 rice as examples) based on paired-end re-sequencing with the advantages of comprehensiveness, accuracy, and automation. The comprehensive molecular characteristics of two rice events were revealed with additional unintended insertions comparing with the results from PCR and Southern blotting. Comprehensive transgene characterization of TT51-1 and T1c-19 is shown to be independent of a priori knowledge of the insert and vector sequences employing the developed approaches. This provides an opportunity to identify and characterize also unknown GM events.

An exploration of the relationship among valence, fading affect, rehearsal frequency, and memory vividness for past personal events.

Science.gov (United States)

Lindeman, Meghan I H; Zengel, Bettina; Skowronski, John J

2017-07-01

The affect associated with negative (or unpleasant) memories typically tends to fade faster than the affect associated with positive (or pleasant) memories, a phenomenon called the fading affect bias (FAB). We conducted a study to explore the mechanisms related to the FAB. A retrospective recall procedure was used to obtain three self-report measures (memory vividness, rehearsal frequency, affective fading) for both positive events and negative events. Affect for positive events faded less than affect for negative events, and positive events were recalled more vividly than negative events. The perceived vividness of an event (memory vividness) and the extent to which an event has been rehearsed (rehearsal frequency) were explored as possible mediators of the relation between event valence and affect fading. Additional models conceived of affect fading and rehearsal frequency as contributors to a memory's vividness. Results suggested that memory vividness was a plausible mediator of the relation between an event's valence and affect fading. Rehearsal frequency was also a plausible mediator of this relation, but only via its effects on memory vividness. Additional modelling results suggested that affect fading and rehearsal frequency were both plausible mediators of the relation between an event's valence and the event's rated memory vividness.

MOLECULAR DIAGNOSTICS - ANOTHER PIECE IN THE ENVIRONMENTAL PUZZLE

Science.gov (United States)

Molecular biology offers sensitive and expedient tools for the detection of exposure to environmental stressors. Molecular approaches provide the means for detection of the "first cellular event(s)" in response to environmental changes-specifically, immediate changes in gene expr...

Molecular simulations of lipid-mediated protein-protein interactions

NARCIS (Netherlands)

de Meyer, F.J.M.; Venturoli, M.; Smit, B.

2008-01-01

Recent experimental results revealed that lipid-mediated interactions due to hydrophobic forces may be important in determining the protein topology after insertion in the membrane, in regulating the protein activity, in protein aggregation and in signal transduction. To gain insight into the

Tyrosine kinase chromosomal translocations mediate distinct and overlapping gene regulation events

International Nuclear Information System (INIS)

Kim, Hani; Gillis, Lisa C; Jarvis, Jordan D; Yang, Stuart; Huang, Kai; Der, Sandy; Barber, Dwayne L

2011-01-01

Leukemia is a heterogeneous disease commonly associated with recurrent chromosomal translocations that involve tyrosine kinases including BCR-ABL, TEL-PDGFRB and TEL-JAK2. Most studies on the activated tyrosine kinases have focused on proximal signaling events, but little is known about gene transcription regulated by these fusions. Oligonucleotide microarray was performed to compare mRNA changes attributable to BCR-ABL, TEL-PDGFRB and TEL-JAK2 after 1 week of activation of each fusion in Ba/F3 cell lines. Imatinib was used to control the activation of BCR-ABL and TEL-PDGFRB, and TEL-JAK2-mediated gene expression was examined 1 week after Ba/F3-TEL-JAK2 cells were switched to factor-independent conditions. Microarray analysis revealed between 800 to 2000 genes induced or suppressed by two-fold or greater by each tyrosine kinase, with a subset of these genes commonly induced or suppressed among the three fusions. Validation by Quantitative PCR confirmed that eight genes (Dok2, Mrvi1, Isg20, Id1, gp49b, Cxcl10, Scinderin, and collagen Vα1(Col5a1)) displayed an overlapping regulation among the three tested fusion proteins. Stat1 and Gbp1 were induced uniquely by TEL-PDGFRB. Our results suggest that BCR-ABL, TEL-PDGFRB and TEL-JAK2 regulate distinct and overlapping gene transcription profiles. Many of the genes identified are known to be involved in processes associated with leukemogenesis, including cell migration, proliferation and differentiation. This study offers the basis for further work that could lead to an understanding of the specificity of diseases caused by these three chromosomal translocations

Mediation Analysis: A Practitioner's Guide.

Science.gov (United States)

VanderWeele, Tyler J

2016-01-01

This article provides an overview of recent developments in mediation analysis, that is, analyses used to assess the relative magnitude of different pathways and mechanisms by which an exposure may affect an outcome. Traditional approaches to mediation in the biomedical and social sciences are described. Attention is given to the confounding assumptions required for a causal interpretation of direct and indirect effect estimates. Methods from the causal inference literature to conduct mediation in the presence of exposure-mediator interactions, binary outcomes, binary mediators, and case-control study designs are presented. Sensitivity analysis techniques for unmeasured confounding and measurement error are introduced. Discussion is given to extensions to time-to-event outcomes and multiple mediators. Further flexible modeling strategies arising from the precise counterfactual definitions of direct and indirect effects are also described. The focus throughout is on methodology that is easily implementable in practice across a broad range of potential applications.

New insights into the molecular mechanism of E-cadherin-mediated cell adhesion by free energy calculations

DEFF Research Database (Denmark)

Doro, Fabio; Saladino, Giorgio; Belvisi, Laura

2015-01-01

Three-dimensional domain swapping is an important mode of protein association leading to the formation of stable dimers. Monomers associating via this mechanism mutually exchange a domain to form a homodimer. Classical cadherins, an increasingly important target for anticancer therapy, use domain...... swapping to mediate cell adhesion. However, despite its importance, the molecular mechanism of domain swapping is still debated. Here, we study the conformational changes that lead to activation and dimerization via domain swapping of E-cadherin. Using state-of-the-art enhanced sampling atomistic......" mechanism in which monomers in an active conformational state bind to form a homodimer, analogous to the conformational selection mechanism often observed in ligand-target binding. Moreover, we find that the open state population is increased in the presence of calcium ions at the extracellular boundary...

Mediating Business

DEFF Research Database (Denmark)

"Mediating Business" is a study of the expansion of business journalism. Building on evidence from Denmark, Finland, Norway and Sweden, "Mediating Business" is a comparative and multidisciplinary study of one of the major transformations of the mass media and the realm of business - nationally...... and globally. The book explores the history of key innovations and innovators in the business press. It analyzes changes in the discourse of business journalism associated with the growth in business news and the development of new ways of framing business issues and events. Finally, it examines...... the organizational implications of the increased media visibility of business and, in particular, the development of corporate governance and media relations....

The effect of consumer pressure and abiotic stress on positive plant interactions are mediated by extreme climatic events.

Science.gov (United States)

Filazzola, Alessandro; Liczner, Amanda Rae; Westphal, Michael; Lortie, Christopher J

2018-01-01

Environmental extremes resulting from a changing climate can have profound implications for plant interactions in desert communities. Positive interactions can buffer plant communities from abiotic stress and consumer pressure caused by climatic extremes, but limited research has explored this empirically. We tested the hypothesis that the mechanism of shrub facilitation on an annual plant community can change with precipitation extremes in deserts. During years of extreme drought and above-average rainfall in a desert, we measured plant interactions and biomass while manipulating a soil moisture gradient and reducing consumer pressure. Shrubs facilitated the annual plant community at all levels of soil moisture through reductions in microclimatic stress in both years and herbivore protection in the wet year only. Shrub facilitation and the high rainfall year contributed to the dominance of a competitive annual species in the plant community. Precipitation patterns in deserts determine the magnitude and type of facilitation mechanisms. Moreover, shrub facilitation mediates the interspecific competition within the associated annual community between years with different rainfall amounts. Examining multiple drivers during extreme climate events is a challenging area of research, but it is a necessary consideration given forecasts predicting that these events will increase in frequency and magnitude. © 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.

p53-Mediated Molecular Control of Autophagy in Tumor Cells

Directory of Open Access Journals (Sweden)

Maria Mrakovcic

2018-03-01

Full Text Available Autophagy is an indispensable mechanism of the eukaryotic cell, facilitating the removal and renewal of cellular components and thereby balancing the cell’s energy consumption and homeostasis. Deregulation of autophagy is now regarded as one of the characteristic key features contributing to the development of tumors. In recent years, the suppression of autophagy in combination with chemotherapeutic treatment has been approached as a novel therapy in cancer treatment. However, depending on the type of cancer and context, interference with the autophagic machinery can either promote or disrupt tumorigenesis. Therefore, disclosure of the major signaling pathways that regulate autophagy and control tumorigenesis is crucial. To date, several tumor suppressor proteins and oncogenes have emerged as eminent regulators of autophagy whose depletion or mutation favor tumor formation. The mammalian cell “janitor” p53 belongs to one of these tumor suppressors that are most commonly mutated in human tumors. Experimental evidence over the last decade convincingly reports that p53 can act as either an activator or an inhibitor of autophagy depending on its subcellular localization and its mode of action. This finding gains particular significance as p53 deficiency or mutant variants of p53 that accumulate in the cytoplasm of tumor cells enable activation of autophagy. Accordingly, we recently identified p53 as a molecular hub that regulates autophagy and apoptosis in histone deacetylase inhibitor-treated uterine sarcoma cells. In light of this novel experimental evidence, in this review, we focus on p53 signaling as a mediator of the autophagic pathway in tumor cells.

A Network of AOPs for reduced thyroid hormone synthesis derived from inhibition of Thyroperoxidase - A common Molecular Initiating Event Leading to Species-Specific Indices of Adversity.

Science.gov (United States)

This collection of 3 AOPs describe varying outcomes of adversity dependent upon species in response to inhibition of thyroperoxidase (TPO) during development. Chemical inhibition of TPO, the molecular-initiating event (MIE), results in decreased thyroid hormone (TH) synthesis, a...

The study of the mechanism of arsenite toxicity in respiration-deficient cells reveals that NADPH oxidase-derived superoxide promotes the same downstream events mediated by mitochondrial superoxide in respiration-proficient cells

Energy Technology Data Exchange (ETDEWEB)

Guidarelli, Andrea; Fiorani, Mara; Carloni, Silvia; Cerioni, Liana; Balduini, Walter; Cantoni, Orazio, E-mail: orazio.cantoni@uniurb.it

2016-09-15

We herein report the results from a comparative study of arsenite toxicity in respiration-proficient (RP) and -deficient (RD) U937 cells. An initial characterization of these cells led to the demonstration that the respiration-deficient phenotype is not associated with apparent changes in mitochondrial mass and membrane potential. In addition, similar levels of superoxide (O{sub 2}{sup .-}) were generated by RP and RD cells in response to stimuli specifically triggering respiratory chain-independent mitochondrial mechanisms or extramitochondrial, NADPH-oxidase dependent, mechanisms. At the concentration of 2.5 μM, arsenite elicited selective formation of O{sub 2}{sup .-} in the respiratory chain of RP cells, with hardly any contribution of the above mechanisms. Under these conditions, O{sub 2}{sup .-} triggered downstream events leading to endoplasmic reticulum (ER) stress, autophagy and apoptosis. RD cells challenged with similar levels of arsenite failed to generate O{sub 2}{sup .-} because of the lack of a functional respiratory chain and were therefore resistant to the toxic effects mediated by the metalloid. Their resistance, however, was lost after exposure to four fold greater concentrations of arsenite, coincidentally with the release of O{sub 2}{sup .-} mediated by NADPH oxidase. Interestingly, extramitochondrial O{sub 2}{sup .-} triggered the same downstream events and an identical mode of death previously observed in RP cells. Taken together, the results obtained in this study indicate that arsenite toxicity is strictly dependent on O{sub 2}{sup .-} availability that, regardless of whether generated in the mitochondrial or extramitochondrial compartments, triggers similar downstream events leading to ER stress, autophagy and apoptosis. - Highlights: • Mitochondrial superoxide mediates arsenite toxicity in respiration-proficient cells. • NADPH-derived superoxide mediates arsenite toxicity in respiration-deficient cells. • Arsenite causes apoptosis

Parent-adolescent relationship and adolescent internet addiction: A moderated mediation model.

Science.gov (United States)

Wang, Wei; Li, Dongping; Li, Xian; Wang, Yanhui; Sun, Wenqiang; Zhao, Liyan; Qiu, Lilan

2018-09-01

Substantial research has found that positive parent-adolescent relationship is associated with low levels of adolescent Internet addiction (IA). However, little is known about the mediating and moderating mechanisms underlying this relation. The present study examined a moderated mediation model that included the parent-adolescent relationship (predictor variable), emotion regulation ability (mediator), stressful life events (moderator), and IA (outcome variable) simultaneously. A total of 998 (M age  = 15.15 years, SD = 1.57) Chinese adolescents completed the Parent-Adolescent Relationship Scale, Emotion Regulation Ability Scale, Adolescent Stressful Life Events Scale, and Internet Addiction Diagnostic Questionnaire. After controlling for adolescent gender, age, and family socioeconomic status, results revealed that good parent-adolescent relationship was positively associated with adolescent emotion regulation ability, which in turn was negatively associated with their IA. Moreover, stressful life events moderated the second part of the mediation process. In accordance with the reverse stress-buffering model, the relation between emotion regulation ability and adolescent IA was stronger for adolescents who experienced lower levels of stressful life events. The findings and their implications are discussed and a resilient contextual perspective proposed. Copyright © 2018 Elsevier Ltd. All rights reserved.

The Mediating Role Of Coping Styles In Personal, Environmental and Event Related Factors and Posttraumatic Growth Relationships Among Women With Breast Cancer (English

Directory of Open Access Journals (Sweden)

Zumrut Bellur

2018-03-01

Full Text Available Object: The aim of this study was to examine the effects of environmental, personal and event related factors on posttraumatic growth in breast cancer patients. Methods: The study was conducted with 134 women who are undergoing chemotherapy treatment or coming to the hospital for their routine controls. Revised Dyadic Adjustment Scale, The Impact of Event Scale, Posttraumatic Growth Inventory, Ways of Coping Inventory, Multidimensional Scale of Perceived Social Support, The General Self-Efficacy Scale-Turkish Form and Demographic Information Form was used. Results: Acoording to t-test analyses as the time passage from the diagnosis increases the perceived social support from the family members is increasing. Also while the group that had previous trauma experiences uses more helplessness coping styles, the group that had no previous trauma experience uses more problem focused coping style and showed greater posttraumatic growth. Results of the mediation analyses showed that problem focused coping has a mediator role in dyadic adjustment- posttraumatic growth; perceived social support from the family- posttraumatic growth; and self-efficacy- posttraumatic growth relationships. Discussion: The results of the current study are important in terms of developing new intervention programs that will help breast cancer patients to develop posttraumatic growth and also to better cope with cancer. This study is also important because the effect of marital adjustment and marital satisfaction on posttraumatic growth in breast cancer patients is an issue which is not well studied with Turkish sample.

Molecular orientation and electronic structure at organic heterojunction interfaces

Energy Technology Data Exchange (ETDEWEB)

Zhong, Shu [Department of Chemistry, National University of Singapore, 3 Science Drive 3, 117543 Singapore (Singapore); Zhong, Jian Qiang; Wee, Andrew T.S. [Department of Physics, National University of Singapore, 2 Science Drive 3, 117542 Singapore (Singapore); Chen, Wei, E-mail: phycw@nus.edu.sg [Department of Chemistry, National University of Singapore, 3 Science Drive 3, 117543 Singapore (Singapore); Department of Physics, National University of Singapore, 2 Science Drive 3, 117542 Singapore (Singapore); National University of Singapore (Suzhou) Research Institute, Suzhou (China)

2015-10-01

Highlights: • Molecular orientation at the organic heterojunction interfaces. • Energy level alignments at the organic heterojunction interfaces. • Gap-states mediated interfacial energy level alignment. - Abstract: Due to the highly anisotropic nature of π-conjugated molecules, the molecular orientation in organic thin films can significantly affect light absorption, charge transport, energy level alignment (ELA) and hence device performance. Synchrotron-based near-edge X-ray absorption fine structure (NEXAFS) spectroscopy represents a powerful technique for probing molecular orientation. The aim of this review paper is to provide a balanced assessment on the investigation of molecular orientation at the organic–organic heterojunction (OOH) interface by NEXAFS, as well as the gap-states mediated orientation dependent energy level alignment at OOH interfaces. We highlight recent progress in elucidating molecular orientation at OOH interfaces dominated by various interfacial interactions, gap-states controlled orientation dependent energy level alignments at OOH interfaces, and the manipulations of molecular orientation and ELA in OOH.

The molecular basis for stability of heterochromatin-mediated silencing in mammals.

Science.gov (United States)

Hiragami-Hamada, Kyoko; Xie, Sheila Q; Saveliev, Alexander; Uribe-Lewis, Santiago; Pombo, Ana; Festenstein, Richard

2009-11-04

The archetypal epigenetic phenomenon of position effect variegation (PEV) in Drosophila occurs when a gene is brought abnormally close to heterochromatin, resulting in stochastic silencing of the affected gene in a proportion of cells that would normally express it. PEV has been instrumental in unraveling epigenetic mechanisms. Using an in vivo mammalian model for PEV we have extensively investigated the molecular basis for heterochromatin-mediated gene silencing. Here we distinguish 'epigenetic effects' from other cellular differences by studying ex vivo cells that are identical, apart from the expression of the variegating gene which is silenced in a proportion of the cells. By separating cells according to transgene expression we show here that silencing appears to be associated with histone H3 lysine 9 trimethylation (H3K9me3), DNA methylation and the localization of the silenced gene to a specific nuclear compartment enriched in these modifications. In contrast, histone H3 acetylation (H3Ac) and lysine 4 di or tri methylation (H3K4me2/3) are the predominant modifications associated with expression where we see the gene in a euchromatic compartment. Interestingly, DNA methylation and inaccessibility, rather than H3K9me3, correlated most strongly with resistance to de-repression by cellular activation. These results have important implications for understanding the contribution of specific factors involved in the establishment and maintenance of gene silencing and activation in vivo.

Uncovering molecular structural mechanisms of signaling mediated by the prion protein

International Nuclear Information System (INIS)

Romano, Sebastian A.; Linden, Rafael; Silva, Jerson L.; Foguel, Debora

2009-01-01

The glycosyl phosphatidylinositol (GPI) - anchored prion protein (PrP c ), usually associated with neurodegenerative diseases, modulates various cellular responses and may scaffold multiprotein cell surface signaling complexes. Engagement of PrP c with the secretable cochaperone hop/STI 1 induces neurotrophic transmembrane signals through unknown molecular mechanisms. We addressed whether interaction of Pr P c and hop STI 1 entails structural rearrangements relevant for signaling. Circular dichroism and fluorescence spectroscopy showed that PrP c :hop/STI 1 interaction triggers loss of PrP helical structures, involving at least a perturbation of the Pr P c 143-153 beta-helix. Novel SAXS models revealed a significant C-terminal compaction of hop/STI 1 when bound to PrP c . Differing from a recent dimeric model of human hop/STI 1, both size exclusion chromatography and SAXS data support a monomeric form of free murine hop/STI 1. Changes in the Pr P c 143-153 beta-helix may engage the transmembrane signaling protein laminin receptor precursor and neural cell adhesion molecule, both of which bind that domain of Pr P c , and further ligands may be engaged by the tertiary structural changes of hop/STI 1. These reciprocal structural modifications indicate a versatile mechanism for signaling mediated by Pr P c :hop/STI 1 interaction, consistent with the hypothesis that Pr P c scaffolds multiprotein signaling complexes at the cell surface. (author)

Uncovering molecular structural mechanisms of signaling mediated by the prion protein

Energy Technology Data Exchange (ETDEWEB)

Romano, Sebastian A.; Linden, Rafael [Universidade Federal do Rio de Janeiro (IBCCF/UFRl), RJ (Brazil). Inst. de Biofisica Carlos Chagas Filho; Cordeiro, Yraima; Rocha e Lima, Luis M.T. da [Universidade Federal do Rio de Janeiro (FF/UFRl), RJ (Brazil). Fac. de Farmacia; Lopes, Marilene H. [Instituto Ludwig de Pesquisa de Cancer, Sao Paulo, SP (Brazil); Silva, Jerson L.; Foguel, Debora [Universidade Federal do Rio de Janeiro (IBqM/UFRl), RJ (Brazil). Inst. de Bioquimica Medica

2009-07-01

The glycosyl phosphatidylinositol (GPI) - anchored prion protein (PrP{sup c}), usually associated with neurodegenerative diseases, modulates various cellular responses and may scaffold multiprotein cell surface signaling complexes. Engagement of PrP{sup c} with the secretable cochaperone hop/STI 1 induces neurotrophic transmembrane signals through unknown molecular mechanisms. We addressed whether interaction of Pr P{sup c} and hop STI 1 entails structural rearrangements relevant for signaling. Circular dichroism and fluorescence spectroscopy showed that PrP{sup c}:hop/STI 1 interaction triggers loss of PrP helical structures, involving at least a perturbation of the Pr P{sup c}{sub 143-153} beta-helix. Novel SAXS models revealed a significant C-terminal compaction of hop/STI 1 when bound to PrP{sup c}. Differing from a recent dimeric model of human hop/STI 1, both size exclusion chromatography and SAXS data support a monomeric form of free murine hop/STI 1. Changes in the Pr P{sup c}{sub 143-153} beta-helix may engage the transmembrane signaling protein laminin receptor precursor and neural cell adhesion molecule, both of which bind that domain of Pr P{sup c}, and further ligands may be engaged by the tertiary structural changes of hop/STI 1. These reciprocal structural modifications indicate a versatile mechanism for signaling mediated by Pr P{sup c}:hop/STI 1 interaction, consistent with the hypothesis that Pr P{sup c} scaffolds multiprotein signaling complexes at the cell surface. (author)

The molecular basis for stability of heterochromatin-mediated silencing in mammals

Directory of Open Access Journals (Sweden)

Hiragami-Hamada Kyoko

2009-11-01

Full Text Available Abstract The archetypal epigenetic phenomenon of position effect variegation (PEV in Drosophila occurs when a gene is brought abnormally close to heterochromatin, resulting in stochastic silencing of the affected gene in a proportion of cells that would normally express it. PEV has been instrumental in unraveling epigenetic mechanisms. Using an in vivo mammalian model for PEV we have extensively investigated the molecular basis for heterochromatin-mediated gene silencing. Here we distinguish 'epigenetic effects' from other cellular differences by studying ex vivo cells that are identical, apart from the expression of the variegating gene which is silenced in a proportion of the cells. By separating cells according to transgene expression we show here that silencing appears to be associated with histone H3 lysine 9 trimethylation (H3K9me3, DNA methylation and the localization of the silenced gene to a specific nuclear compartment enriched in these modifications. In contrast, histone H3 acetylation (H3Ac and lysine 4 di or tri methylation (H3K4me2/3 are the predominant modifications associated with expression where we see the gene in a euchromatic compartment. Interestingly, DNA methylation and inaccessibility, rather than H3K9me3, correlated most strongly with resistance to de-repression by cellular activation. These results have important implications for understanding the contribution of specific factors involved in the establishment and maintenance of gene silencing and activation in vivo.

Molecular recognition of naphthalene diimide ligands by telomeric quadruplex-DNA: the importance of the protonation state and mediated hydrogen bonds.

Science.gov (United States)

Spinello, A; Barone, G; Grunenberg, J

2016-01-28

In depth Monte Carlo conformational scans in combination with molecular dynamics (MD) simulations and electronic structure calculations were applied in order to study the molecular recognition process between tetrasubstituted naphthalene diimide (ND) guests and G-quadruplex (G4) DNA receptors. ND guests are a promising class of telomere stabilizers due to which they are used in novel anticancer therapeutics. Though several ND guests have been studied experimentally in the past, the protonation state under physiological conditions is still unclear. Based on chemical intuition, in the case of N-methyl-piperazine substitution, different protonation states are possible and might play a crucial role in the molecular recognition process by G4-DNA. Depending on the proton concentration, different nitrogen atoms of the N-methyl-piperazine might (or might not) be protonated. This fact was considered in our simulation in terms of a case by case analysis, since the process of molecular recognition is determined by possible donor or acceptor positions. The results of our simulations show that the electrostatic interactions between the ND ligands and the G4 receptor are maximized in the case of the protonation of the terminal nitrogen atoms, forming compact ND G4 complexes inside the grooves. The influence of different protonation states in terms of the ability to form hydrogen bonds with the sugar-phosphate backbone, as well as the importance of mediated vs. direct hydrogen bonding, was analyzed in detail by MD and relaxed force constant (compliance constant) simulations.

Crosstalk between Rac1-mediated actin regulation and ROS production.

Science.gov (United States)

Acevedo, Alejandro; González-Billault, Christian

2018-02-20

The small RhoGTPase Rac1 is implicated in a variety of events related to actin cytoskeleton rearrangement. Remarkably, another event that is completely different from those related to actin regulation has the same relevance; the Rac1-mediated production of reactive oxygen species (ROS) through NADPH oxidases (NOX). Each outcome involves different Rac1 downstream effectors; on one hand, events related to the actin cytoskeleton require Rac1 to bind to WAVEs proteins and PAKs that ultimately promote actin branching and turnover, on the other, NOX-derived ROS production demands active Rac1 to be bound to a cytosolic activator of NOX. How Rac1-mediated signaling ends up promoting actin-related events, NOX-derived ROS, or both is poorly understood. Rac1 regulators, including scaffold proteins, are known to exert tight control over its functions. Hence, evidence of Rac1 regulatory events leading to both actin remodeling and NOX-mediated ROS generation are discussed. Moreover, cellular functions linked to physiological and pathological conditions that exhibit crosstalk between Rac1 outcomes are analyzed, while plausible roles in neuronal functions (and dysfunctions) are highlighted. Together, discussed evidence shed light on cellular mechanisms which requires Rac1 to direct either actin- and/or ROS-related events, helping to understand crucial roles of Rac1 dual functionality. Copyright © 2018 Elsevier Inc. All rights reserved.

The progress of molecular biology in radiation research

International Nuclear Information System (INIS)

Wei Kang

1989-01-01

The recent progress in application of molecular biology techniques in the study of radiation biology is reviewed. The three sections are as follows: (1) the study of DNA damage on molecular level, (2) the molecular mechanism of radiation cell genetics, including chromosome abberation and cell mutation, (3) the study on DNA repair gene with DNA mediated gene transfer techniques

Regulation of metabolism by the Mediator complex.

Science.gov (United States)

Youn, Dou Yeon; Xiaoli, Alus M; Pessin, Jeffrey E; Yang, Fajun

2016-01-01

The Mediator complex was originally discovered in yeast, but it is conserved in all eukaryotes. Its best-known function is to regulate RNA polymerase II-dependent gene transcription. Although the mechanisms by which the Mediator complex regulates transcription are often complicated by the context-dependent regulation, this transcription cofactor complex plays a pivotal role in numerous biological pathways. Biochemical, molecular, and physiological studies using cancer cell lines or model organisms have established the current paradigm of the Mediator functions. However, the physiological roles of the mammalian Mediator complex remain poorly defined, but have attracted a great interest in recent years. In this short review, we will summarize some of the reported functions of selective Mediator subunits in the regulation of metabolism. These intriguing findings suggest that the Mediator complex may be an important player in nutrient sensing and energy balance in mammals.

Immunomodulatory role of interleukin-10 in visceral leishmaniasis: defective activation of protein kinase C-mediated signal transduction events.

Science.gov (United States)

Bhattacharyya, S; Ghosh, S; Jhonson, P L; Bhattacharya, S K; Majumdar, S

2001-03-01

Leishmania donovani, an intracellular protozoan parasite, challenges host defense mechanisms by impairing the signal transduction of macrophages. In this study we investigated whether interleukin-10 (IL-10)-mediated alteration of signaling events in a murine model of visceral leishmaniasis is associated with macrophage deactivation. Primary in vitro cultures of macrophages infected with leishmanial parasites markedly elevated the endogenous release of IL-10. Treatment with either L. donovani or recombinant IL-10 (rIL-10) inhibited both the activity and expression of the Ca2+-dependent protein kinase C (PKC) isoform. However, preincubation with neutralizing anti-IL-10 monoclonal antibody (MAb) restored the PKC activity in the parasitized macrophage. Furthermore, we observed that coincubation of macrophages with rIL-10 and L. donovani increased the intracellular parasite burden, which was abrogated by anti-IL-10 MAb. Consistent with these observations, generation of superoxide (O2-) and nitric oxide and the release of murine tumor necrosis factor-alpha were attenuated in response to L. donovani or rIL-10 treatment. On the other hand, preincubation of the infected macrophages with neutralizing anti-IL-10 MAb significantly blocked the inhibition of nitric oxide and murine tumor necrosis factor-alpha release by the infected macrophages. These findings imply that infection with L. donovani induces endogenous secretion of murine IL-10, which in turn facilitates the intracellular survival of the protozoan and orchestrates several immunomodulatory roles via selective impairment of PKC-mediated signal transduction.

Molecular Pharmacology of VEGF-A Isoforms: Binding and Signalling at VEGFR2.

Science.gov (United States)

Peach, Chloe J; Mignone, Viviane W; Arruda, Maria Augusta; Alcobia, Diana C; Hill, Stephen J; Kilpatrick, Laura E; Woolard, Jeanette

2018-04-23

Vascular endothelial growth factor-A (VEGF-A) is a key mediator of angiogenesis, signalling via the class IV tyrosine kinase receptor family of VEGF Receptors (VEGFRs). Although VEGF-A ligands bind to both VEGFR1 and VEGFR2, they primarily signal via VEGFR2 leading to endothelial cell proliferation, survival, migration and vascular permeability. Distinct VEGF-A isoforms result from alternative splicing of the Vegfa gene at exon 8, resulting in VEGF xxx a or VEGF xxx b isoforms. Alternative splicing events at exons 5⁻7, in addition to recently identified posttranslational read-through events, produce VEGF-A isoforms that differ in their bioavailability and interaction with the co-receptor Neuropilin-1. This review explores the molecular pharmacology of VEGF-A isoforms at VEGFR2 in respect to ligand binding and downstream signalling. To understand how VEGF-A isoforms have distinct signalling despite similar affinities for VEGFR2, this review re-evaluates the typical classification of these isoforms relative to the prototypical, “pro-angiogenic” VEGF 165 a. We also examine the molecular mechanisms underpinning the regulation of VEGF-A isoform signalling and the importance of interactions with other membrane and extracellular matrix proteins. As approved therapeutics targeting the VEGF-A/VEGFR signalling axis largely lack long-term efficacy, understanding these isoform-specific mechanisms could aid future drug discovery efforts targeting VEGF receptor pharmacology.

Proteinaceous molecules mediating Bifidobacterium-host interactions

Directory of Open Access Journals (Sweden)

Lorena Ruiz

2016-08-01

Full Text Available Bifidobacteria are commensal microoganisms found in the gastrointestinal tract.Several strains have been attributed beneficial traits at local and systemic levels, through pathogen exclusion or immune modulation, among other benefits. This has promoted a growing industrial and scientific interest in bifidobacteria as probiotic supplements. However, the molecular mechanisms mediating this cross-talk with the human host remain unknown. High-throughput technologies, from functional genomics to transcriptomics, proteomics and interactomics coupled to the development of both in vitro and in vivo models to study the dynamics of the intestinal microbiota and their effects on host cells, have eased the identification of key molecules in these interactions. Numerous secreted or surface-associated proteins or peptides have been identified as potential mediators of bifidobacteria-host interactions and molecular cross-talk, directly participating in sensing environmental factors, promoting intestinal colonization or mediating a dialogue with mucosa-associated immune cells. On the other hand, bifidobacteria induce the production of proteins in the intestine, by epithelial or immune cells, and other gut bacteria, which are key elements in orchestrating interactions among bifidobacteria, gut microbiota and host cells. This review aims to give a comprehensive overview on proteinaceous molecules described and characterized to date, as mediators of the dynamic interplay between bifidobacteria and the human host, providing a framework to identify knowledge gaps and future research needs.

Voltammetric determination of attomolar levels of a sequence derived from the genom of hepatitis B virus by using molecular beacon mediated circular strand displacement and rolling circle amplification.

Science.gov (United States)

Huang, Shan; Feng, Mengmeng; Li, Jiawen; Liu, Yi; Xiao, Qi

2018-03-03

The authors describe an electrochemical method for the determination of the single-stranded DNA (ssDNA) oligonucleotide with a sequence derived from the genom of hepatitis B virus (HBV). It is making use of circular strand displacement (CSD) and rolling circle amplification (RCA) strategies mediated by a molecular beacon (MB). This ssDNA hybridizes with the loop portion of the MB immobilized on the surface of a gold electrode, while primer DNA also hybridizes with the rest of partial DNA sequences of MB. This triggers the MB-mediated CSD. The RCA is then initiated to produce a long DNA strand with multiple tandem-repeat sequences, and this results in a significant increase of the differential pulse voltammetric response of the electrochemical probe Methylene Blue at a rather low working potential of -0.24 V (vs. Ag/AgCl). Under optimal experimental conditions, the assay displays an ultrahigh sensitivity (with a 2.6 aM detection limit) and excellent selectivity. Response is linear in the 10 to 700 aM DNA concentration range. Graphical abstract Schematic of a voltammetric method for the determination of attomolar levels of target DNA. It is based on molecular beacon mediated circular strand displacement and rolling circle amplification strategies. Under optimal experimental conditions, the assay displays an ultrahigh sensitivity with a 2.6 aM detection limit and excellent selectivity.

Molecular signals into the insular cortex and amygdala during aversive gustatory memory formation.

Science.gov (United States)

Bermúdez-Rattoni, Federico; Ramírez-Lugo, Leticia; Gutiérrez, Ranier; Miranda, María Isabel

2004-02-01

In this paper, we will provide evidence of the putative molecular signals and biochemical events that mediate the formation of long-lasting gustatory memory trace. When an animal drinks a novel taste (the conditioned stimulus; CS) and it is later associated with malaise (unconditioned stimulus; US), the animal will reject it in the next presentation, developing a long-lasting taste aversion, i.e., the taste cue becomes an aversive signal, and this is referred to as conditioning taste aversion. Different evidence indicates that the novel stimulus (taste) induces a rapid and strong cortical acetylcholine activity that decreases when the stimulus becomes familiar after several presentations. Cholinergic activation via muscarinic receptors initiates a series of intracellular events leading to plastic changes that could be related to short- and/or long-term memory gustatory trace. Such plastic changes facilitate the incoming US signals carried out by, in part, the glutamate release induced by the US. Altogether, these events could produce the cellular changes related to the switch from safe to aversive taste memory trace. A proposed working model to explain the biochemical sequence of signals during taste memory formation will be discussed.

A Modified Glycosaminoglycan, GM-0111, Inhibits Molecular Signaling Involved in Periodontitis.

Directory of Open Access Journals (Sweden)

Justin R Savage

Full Text Available Periodontitis is characterized by microbial infection, inflammation, tissue breakdown, and accelerated loss of alveolar bone matrix. Treatment targeting these multiple stages of the disease provides ways to treat or prevent periodontitis. Certain glycosaminoglycans (GAGs block multiple inflammatory mediators as well as suppress bacterial growth, suggesting that these GAGs may be exploited as a therapeutic for periodontitis.We investigated the effects of a synthetic GAG, GM-0111, on various molecular events associated with periodontitis: growth of Porphyromonas gingivalis (P. gingivalis and Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans pathogenic bacteria associated with periodontitis; activation of pro-inflammatory signaling through TLR2 and TLR4 in mouse macrophage RAW 264.7 cells and heterologously expressed HEK 293 cells; osteoclast formation and bone matrix resorption in cultured mouse pre-osteoclasts.(1 GM-0111 suppressed the growth of P. gingivalis and A. actinomycetemcomitans even at 1% (w/v solution. The antibacterial effects of GM-0111 were stronger than hyaluronic acid (HA or xylitol in P. gingivalis at all concentrations and comparable to xylitol in A. actinomycetemcomitans at ≥2% (w/v solution. We also observed that GM-0111 suppressed biofilm formation of P. gingivalis and these effects were much stronger than HA. (2 GM-0111 inhibited TLR-mediated pro-inflammatory cellular signaling both in macrophage and HEK 293 cells with higher selectivity for TLR2 than TLR4 (IC50 of 1-10 ng/mL vs. > 100 μg/mL, respectively. (3 GM-0111 blocked RANKL-induced osteoclast formation (as low as 300 ng/mL and bone matrix resorption. While GM-0111 showed high affinity binding to RANKL, it did not interfere with RANKL/RANK/NF-κB signaling, suggesting that GM-0111 inhibits osteoclast formation by a RANKL-RANK-independent mechanism.We report that GM-0111 inhibits multiple molecular events involved in periodontitis, spanning from the

The Mediator Complex and Lipid Metabolism.

Science.gov (United States)

Zhang, Yi; Xiaoli; Zhao, Xiaoping; Yang, Fajun

2013-03-01

The precise control of gene expression is essential for all biological processes. In addition to DNA-binding transcription factors, numerous transcription cofactors contribute another layer of regulation of gene transcription in eukaryotic cells. One of such transcription cofactors is the highly conserved Mediator complex, which has multiple subunits and is involved in various biological processes through directly interacting with relevant transcription factors. Although the current understanding on the biological functions of Mediator remains incomplete, research in the past decade has revealed an important role of Mediator in regulating lipid metabolism. Such function of Mediator is dependent on specific transcription factors, including peroxisome proliferator-activated receptor-gamma (PPARγ) and sterol regulatory element-binding proteins (SREBPs), which represent the master regulators of lipid metabolism. The medical significance of these findings is apparent, as aberrant lipid metabolism is intimately linked to major human diseases, such as type 2 diabetes and cardiovascular disease. Here, we briefly review the functions and molecular mechanisms of Mediator in regulation of lipid metabolism.

Novel High-Viscosity Polyacrylamidated Chitosan for Neural Tissue Engineering: Fabrication of Anisotropic Neurodurable Scaffold via Molecular Disposition of Persulfate-Mediated Polymer Slicing and Complexation

Directory of Open Access Journals (Sweden)

Viness Pillay

2012-10-01

Full Text Available Macroporous polyacrylamide-grafted-chitosan scaffolds for neural tissue engineering were fabricated with varied synthetic and viscosity profiles. A novel approach and mechanism was utilized for polyacrylamide grafting onto chitosan using potassium persulfate (KPS mediated degradation of both polymers under a thermally controlled environment. Commercially available high molecular mass polyacrylamide was used instead of the acrylamide monomer for graft copolymerization. This grafting strategy yielded an enhanced grafting efficiency (GE = 92%, grafting ratio (GR = 263%, intrinsic viscosity (IV = 5.231 dL/g and viscometric average molecular mass (MW = 1.63 × 106 Da compared with known acrylamide that has a GE = 83%, GR = 178%, IV = 3.901 dL/g and MW = 1.22 × 106 Da. Image processing analysis of SEM images of the newly grafted neurodurable scaffold was undertaken based on the polymer-pore threshold. Attenuated Total Reflectance-FTIR spectral analyses in conjugation with DSC were used for the characterization and comparison of the newly grafted copolymers. Static Lattice Atomistic Simulations were employed to investigate and elucidate the copolymeric assembly and reaction mechanism by exploring the spatial disposition of chitosan and polyacrylamide with respect to the reactional profile of potassium persulfate. Interestingly, potassium persulfate, a peroxide, was found to play a dual role initially degrading the polymers—“polymer slicing”—thereby initiating the formation of free radicals and subsequently leading to synthesis of the high molecular mass polyacrylamide-grafted-chitosan (PAAm-g-CHT—“polymer complexation”. Furthermore, the applicability of the uniquely grafted scaffold for neural tissue engineering was evaluated via PC12 neuronal cell seeding. The novel PAAm-g-CHT exhibited superior neurocompatibility in terms of cell infiltration owing to the anisotropic porous architecture, high molecular mass mediated robustness

Molecular Recognition in the Colloidal World.

Science.gov (United States)

Elacqua, Elizabeth; Zheng, Xiaolong; Shillingford, Cicely; Liu, Mingzhu; Weck, Marcus

2017-11-21

Colloidal self-assembly is a bottom-up technique to fabricate functional nanomaterials, with paramount interest stemming from programmable assembly of smaller building blocks into dynamic crystalline domains and photonic materials. Multiple established colloidal platforms feature diverse shapes and bonding interactions, while achieving specific orientations along with short- and long-range order. A major impediment to their universal use as building blocks for predesigned architectures is the inability to precisely dictate and control particle functionalization and concomitant reversible self-assembly. Progress in colloidal self-assembly necessitates the development of strategies that endow bonding specificity and directionality within assemblies. Methodologies that emulate molecular and polymeric three-dimensional (3D) architectures feature elements of covalent bonding, while high-fidelity molecular recognition events have been installed to realize responsive reconfigurable assemblies. The emergence of anisotropic 'colloidal molecules', coupled with the ability to site-specifically decorate particle surfaces with supramolecular recognition motifs, has facilitated the formation of superstructures via directional interactions and shape recognition. In this Account, we describe supramolecular assembly routes to drive colloidal particles into precisely assembled architectures or crystalline lattices via directional noncovalent molecular interactions. The design principles are based upon the fabrication of colloidal particles bearing surface-exposed functional groups that can undergo programmable conjugation to install recognition motifs with high fidelity. Modular and versatile by design, our strategy allows for the introduction and integration of molecular recognition principles into the colloidal world. We define noncovalent molecular interactions as site-specific forces that are predictable (i.e., feature selective and controllable complementary bonding partners

Transient magnetic tunneling mediated by a molecular bridge

Czech Academy of Sciences Publication Activity Database

Kalvová, Anděla; Špička, Václav; Velický, B.

2015-01-01

Roč. 28, č. 3 (2015), 1087-1091 ISSN 1557-1939 R&D Projects: GA ČR GAP204/12/0897 Institutional support: RVO:68378271 Keywords : non-equilibrium * initial conditions * transient currents * molecular islands Subject RIV: BE - Theoretical Physics Impact factor: 1.100, year: 2015

[The molecular mechanisms of curcuma wenyujin extract-mediated inhibitory effects on human esophageal carcinoma cells in vitro].

Science.gov (United States)

Jing, Zhao; Zou, Hai-Zhou; Xu, Fang

2012-09-01

To study the molecular mechanisms of Curcuma Wenyujin extract-mediated inhibitory effects on human esophageal carcinoma cells. The Curcuma Wenyujin extract was obtained by supercritical carbon dioxide extraction. TE-1 cells were divided into 4 groups after adherence. 100 microL RMPI-1640 culture medium containing 0.1% DMSO was added in Group 1 as the control group. 100 microL 25, 50, and 100 mg/L Curcuma Wenyujin extract complete culture medium was respectively added in the rest 3 groups as the low, middle, and high dose Curcuma Wenyujin extract groups. The effects of different doses of Curcuma Wenyujin extract (25, 50, and 100 mg/L) on the proliferation of human esophageal carcinoma cell line TE-1 in vitro were analyzed by MTT assay. The gene expression profile was identified by cDNA microarrays in esophageal carcinoma TE-1 cells exposed to Curcuma Wenyujin extract for 48 h. The differential expression genes were further analyzed by Gene Ontology function analysis. Compared with the control group, MTT results showed that Curcuma Wenyujin extract significantly inhibited the proliferation of TE-1 cells in a dose-dependent manner (PCurcuma Wenyujin extract could inhibit the growth of human esophageal carcinoma cell line TE-1 in vitro. The molecular mechanisms might be associated with regulating genes expressions at multi-levels.

EAACI Molecular Allergology User's Guide

NARCIS (Netherlands)

Matricardi, P. M.; Kleine-Tebbe, J.; Hoffmann, H. J.; Valenta, R.; Hilger, C.; Hofmaier, S.; Aalberse, R. C.; Agache, I.; Asero, R.; Ballmer-Weber, B.; Barber, D.; Beyer, K.; Biedermann, T.; Bilò, M. B.; Blank, S.; Bohle, B.; Bosshard, P. P.; Breiteneder, H.; Brough, H. A.; Caraballo, L.; Caubet, J. C.; Crameri, R.; Davies, J. M.; Douladiris, N.; Ebisawa, M.; EIgenmann, P. A.; Fernandez-Rivas, M.; Ferreira, F.; Gadermaier, G.; Glatz, M.; Hamilton, R. G.; Hawranek, T.; Hellings, P.; Hoffmann-Sommergruber, K.; Jakob, T.; Jappe, U.; Jutel, M.; Kamath, S. D.; Knol, E. F.; Korosec, P.; Kuehn, A.; Lack, G.; Lopata, A. L.; Mäkelä, M.; Morisset, M.; Niederberger, V.; Nowak-Węgrzyn, A. H.; Papadopoulos, N. G.; Pastorello, E. A.; Pauli, G.; Platts-Mills, T.; Posa, D.; Poulsen, L. K.; Raulf, M.; Sastre, J.; Scala, E.; Schmid, J. M.; Schmid-Grendelmeier, P.; van Hage, M.; van Ree, R.; Vieths, S.; Weber, R.; Wickman, M.; Muraro, A.; Ollert, M.

2016-01-01

The availability of allergen molecules ('components') from several protein families has advanced our understanding of immunoglobulin E (IgE)-mediated responses and enabled 'component-resolved diagnosis' (CRD). The European Academy of Allergy and Clinical Immunology (EAACI) Molecular Allergology

Humor Use Moderates the Relation of Stressful Life Events With Psychological Distress.

Science.gov (United States)

Fritz, Heidi L; Russek, Leslie N; Dillon, Melissa M

2017-06-01

Three studies examined humor and adjustment to stressful events. In Study 1, patients with fibromyalgia syndrome ( N = 22) reported on mental and physical adjustment, social interaction, and reappraisal of their illness. Dispositional humor was associated with reduced distress and fewer physical symptoms. Study 2 ( N = 109) examined undergraduates' reports of stressful events. Dispositional, self-enhancing, affiliative, and self-defeating humor showed direct effects on distress, which were mediated by social interaction and reappraisal. Moreover, dispositional and aggressive humor showed stress-buffering effects. Study 3 ( N = 105) examined undergraduates' adjustment to the September 11, 2001, attacks at 1 and 3 months postattack. At T1, affiliative humor showed a stress-buffering effect on distress. Social interaction mediated the relation of self-enhancing humor with reduced T1 distress, and mediated relations of aggressive and self-defeating humor with greater distress. Relations of T1 dispositional and self-defeating humor to changes in T2 distress were mediated by reappraisal.

Fluorescence imaging with near-infrared light: new technological advances that enable in vivo molecular imaging

International Nuclear Information System (INIS)

Ntziachristos, Vasilis; Bremer, Christoph; Weissleder, Ralph

2003-01-01

A recent development in biomedical imaging is the non-invasive mapping of molecular events in intact tissues using fluorescence. Underpinning to this development is the discovery of bio-compatible, specific fluorescent probes and proteins and the development of highly sensitive imaging technologies for in vivo fluorescent detection. Of particular interest are fluorochromes that emit in the near infrared (NIR), a spectral window, whereas hemoglobin and water absorb minimally so as to allow photons to penetrate for several centimetres in tissue. In this review article we concentrate on optical imaging technologies used for non-invasive imaging of the distribution of such probes. We illuminate the advantages and limitations of simple photographic methods and turn our attention to fluorescence-mediated molecular tomography (FMT), a technique that can three-dimensionally image gene expression by resolving fluorescence activation in deep tissues. We describe theoretical specifics, and we provide insight into its in vivo capacity and the sensitivity achieved. Finally, we discuss its clinical feasibility. (orig.)

Translating and coordinating face in triadic speech events

DEFF Research Database (Denmark)

Jacobsen, Bente

participants, their specified role of either questioners or respondents, and the purpose of the event, i.e. the extraction of evidence. Thus, the results of a recent investigation by this author of the interpreter-mediated questioning of a defendant in a criminal trial in a Danish district court suggest......This paper reports on an on-going investigation of face in interpreter-mediated questionings in criminal proceedings in Danish district courts. The languages involved are Danish and English, and the mode of interpreting is the consecutive mode. The court interpreters are all state-authorized court...... interpreters and thus fully competent professionals. The concept of face employed in the present investigation is the one proposed by Brown & Levinson (1987) in their politeness theory. Various studies of triadic speech events have pointed to the significance of face within the framework of this theory...

EAACI Molecular Allergology User's Guide.

Science.gov (United States)

Matricardi, P M; Kleine-Tebbe, J; Hoffmann, H J; Valenta, R; Hilger, C; Hofmaier, S; Aalberse, R C; Agache, I; Asero, R; Ballmer-Weber, B; Barber, D; Beyer, K; Biedermann, T; Bilò, M B; Blank, S; Bohle, B; Bosshard, P P; Breiteneder, H; Brough, H A; Caraballo, L; Caubet, J C; Crameri, R; Davies, J M; Douladiris, N; Ebisawa, M; EIgenmann, P A; Fernandez-Rivas, M; Ferreira, F; Gadermaier, G; Glatz, M; Hamilton, R G; Hawranek, T; Hellings, P; Hoffmann-Sommergruber, K; Jakob, T; Jappe, U; Jutel, M; Kamath, S D; Knol, E F; Korosec, P; Kuehn, A; Lack, G; Lopata, A L; Mäkelä, M; Morisset, M; Niederberger, V; Nowak-Węgrzyn, A H; Papadopoulos, N G; Pastorello, E A; Pauli, G; Platts-Mills, T; Posa, D; Poulsen, L K; Raulf, M; Sastre, J; Scala, E; Schmid, J M; Schmid-Grendelmeier, P; van Hage, M; van Ree, R; Vieths, S; Weber, R; Wickman, M; Muraro, A; Ollert, M

2016-05-01

The availability of allergen molecules ('components') from several protein families has advanced our understanding of immunoglobulin E (IgE)-mediated responses and enabled 'component-resolved diagnosis' (CRD). The European Academy of Allergy and Clinical Immunology (EAACI) Molecular Allergology User's Guide (MAUG) provides comprehensive information on important allergens and describes the diagnostic options using CRD. Part A of the EAACI MAUG introduces allergen molecules, families, composition of extracts, databases, and diagnostic IgE, skin, and basophil tests. Singleplex and multiplex IgE assays with components improve both sensitivity for low-abundance allergens and analytical specificity; IgE to individual allergens can yield information on clinical risks and distinguish cross-reactivity from true primary sensitization. Part B discusses the clinical and molecular aspects of IgE-mediated allergies to foods (including nuts, seeds, legumes, fruits, vegetables, cereal grains, milk, egg, meat, fish, and shellfish), inhalants (pollen, mold spores, mites, and animal dander), and Hymenoptera venom. Diagnostic algorithms and short case histories provide useful information for the clinical workup of allergic individuals targeted for CRD. Part C covers protein families containing ubiquitous, highly cross-reactive panallergens from plant (lipid transfer proteins, polcalcins, PR-10, profilins) and animal sources (lipocalins, parvalbumins, serum albumins, tropomyosins) and explains their diagnostic and clinical utility. Part D lists 100 important allergen molecules. In conclusion, IgE-mediated reactions and allergic diseases, including allergic rhinoconjunctivitis, asthma, food reactions, and insect sting reactions, are discussed from a novel molecular perspective. The EAACI MAUG documents the rapid progression of molecular allergology from basic research to its integration into clinical practice, a quantum leap in the management of allergic patients. © 2016 John Wiley

Molecular mechanism and functional consequences of lansoprazole-mediated heme oxygenase-1 induction

Science.gov (United States)

Schulz-Geske, Stephanie; Erdmann, Kati; Wong, Ronald J; Stevenson, David K; Schröder, Henning; Grosser, Nina

2009-01-01

AIM: To investigate the molecular mechanism and functional consequences of heme oxygenase-1 (HO-1) activation by lansoprazole in endothelial cells and macrophages. METHODS: Expression of HO-1 mRNA was analyzed by Northern blotting. Western blotting was used to determine the HO-1 and ferritin protein levels. NADPH-dependent reactive oxygen species (ROS) formation was measured with lucigenin-enhanced chemiluminescence. HO-1 promoter activity in mouse fibroblasts, stably transfected with a 15-kb HO-1 gene that drives expression of the reporter gene luciferase, was assessed using in vivo bioluminescence imaging. RESULTS: Lansoprazole increased HO-1 mRNA levels in endothelial cells and HO-1 protein levels in macrophages. In addition, lansoprazole-induced ferritin protein levels in both cell systems. Moreover, induction of the antioxidant proteins HO-1 and ferritin by lansoprazole was followed by a decrease in NADPH-mediated ROS formation. The radical scavenging properties of lansoprazole were diminished in the presence of the HO inhibitor, chromium mesoporphyrin IX. Induction of HO-1 gene expression by lansoprazole was not related to oxidative stress or to the activation of the mitogen-activated protein kinase pathway. However, the phosphatidylinositol 3-kinase inhibitor LY294002 showed a concentration-dependent inhibition of HO-1 mRNA and promoter activity. CONCLUSION: Activation of HO-1 and ferritin may account for the gastric protection of lansoprazole and is dependent on a pathway blocked by LY294002. PMID:19764090

PyRETIS: A well-done, medium-sized python library for rare events.

Science.gov (United States)

Lervik, Anders; Riccardi, Enrico; van Erp, Titus S

2017-10-30

Transition path sampling techniques are becoming common approaches in the study of rare events at the molecular scale. More efficient methods, such as transition interface sampling (TIS) and replica exchange transition interface sampling (RETIS), allow the investigation of rare events, for example, chemical reactions and structural/morphological transitions, in a reasonable computational time. Here, we present PyRETIS, a Python library for performing TIS and RETIS simulations. PyRETIS directs molecular dynamics (MD) simulations in order to sample rare events with unbiased dynamics. PyRETIS is designed to be easily interfaced with any molecular simulation package and in the present release, it has been interfaced with GROMACS and CP2K, for classical and ab initio MD simulations, respectively. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

EAACI Molecular Allergology User's Guide

NARCIS (Netherlands)

Matricardi, P. M.; Kleine-Tebbe, J.; Hoffmann, H. J.; Valenta, R.; Hilger, C.; Hofmaier, S.; Aalberse, R. C.; Agache, I.; Asero, R.; Ballmer-Weber, B.; Barber, D.; Beyer, K.; Biedermann, T.; Bilò, M. B.; Blank, S.; Bohle, B.; Bosshard, P. P.; Breiteneder, H.; Brough, H. A.; Caraballo, L.; Caubet, J. C.; Crameri, R.; Davies, J. M.; Douladiris, N.; Ebisawa, M.; EIgenmann, P. A.; Fernandez-Rivas, M.; Ferreira, F.; Gadermaier, G.; Glatz, M.; Hamilton, R. G.; Hawranek, T.; Hellings, P.; Hoffmann-Sommergruber, K.; Jakob, T.; Jappe, U.; Jutel, M.; Kamath, S. D.; Knol, E. F.; Korosec, P.; Kuehn, A.; Lack, G.; Lopata, A. L.; Mäkelä, M.; Morisset, M.; Niederberger, V.; Nowak-Węgrzyn, A. H.; Papadopoulos, N. G.; Pastorello, E. A.; Pauli, G.; Platts-Mills, T.; Posa, D.; Poulsen, L. K.; Raulf, M.; Sastre, J.; Scala, E.; Schmid, J. M.; Schmid-Grendelmeier, P.; van Hage, M.; van Ree, R.; Vieths, S.; Weber, R.; Wickman, M.; Muraro, A.; Ollert, M.

2016-01-01

The availability of allergen molecules (‘components’) from several protein families has advanced our understanding of immunoglobulin E (IgE)-mediated responses and enabled ‘component-resolved diagnosis’ (CRD). The European Academy of Allergy and Clinical Immunology (EAACI) Molecular Allergology

Molecular determinants of dengue virus 2 envelope protein important for virus entry in FcγRIIA-mediated antibody-dependent enhancement of infection

International Nuclear Information System (INIS)

Chotiwan, Nunya; Roehrig, John T.; Schlesinger, Jacob J.; Blair, Carol D.; Huang, Claire Y.-H.

2014-01-01

Antibody-dependent enhancement (ADE) of infection may cause severe illness in patients suffering a secondary infection by a heterologous dengue virus (DENV) serotype. During ADE of infection, cross-reactive non- or poorly-neutralizing antibodies form infectious virus-Ab complexes with the newly infecting serotype and enhance virus infection by binding to the Fcγ receptors (FcγR) on FcγR-bearing cells. In this study, we determined that molecular determinants of DENV2 envelope protein critical for virus entry during non-ADE infection are also required for ADE infection mediated by FcγRIIA, and binding of virus-Ab complexes with FcγRIIA alone is not sufficient for ADE of infection. The FcγRIIA mainly plays an auxiliary role in concentrating the virus–Ab complex to the cell surface, and other primary cellular receptors are required for virus entry. Understanding the viral entry pathway in ADE of DENV infection will greatly facilitate rational designs of anti-viral therapeutics against severe dengue disease associated with ADE. - Highlights: • KKK305/307/310 in DENV2 E-DIII is critical for virus attachment in ADE and non-ADE infection. • Binding of DENV2–Ab complex with FcγRII alone is not sufficient for virus entry in ADE infection. • Other primary receptors were required for DENV2 internalization during FcγRII–mediated ADE. • G104 and L135 of DENV2 E are critical for virus-mediated membrane fusion. • DENV2 virus-mediated membrane fusion is required for both ADE and non-ADE infection

Molecular determinants of dengue virus 2 envelope protein important for virus entry in FcγRIIA-mediated antibody-dependent enhancement of infection

Energy Technology Data Exchange (ETDEWEB)

Chotiwan, Nunya; Roehrig, John T. [Arboviral Diseases Branch, Division of Vector-Borne Disease, Centers for Disease Control and Prevention, Fort Collins, CO 80521 (United States); Schlesinger, Jacob J. [Department of Medicine, University of Rochester, Rochester, NY 14642 (United States); Blair, Carol D. [Arthropod-borne and Infectious Diseases Laboratory, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523 (United States); Huang, Claire Y.-H., E-mail: yxh0@cdc.gov [Arboviral Diseases Branch, Division of Vector-Borne Disease, Centers for Disease Control and Prevention, Fort Collins, CO 80521 (United States)

2014-05-15

Antibody-dependent enhancement (ADE) of infection may cause severe illness in patients suffering a secondary infection by a heterologous dengue virus (DENV) serotype. During ADE of infection, cross-reactive non- or poorly-neutralizing antibodies form infectious virus-Ab complexes with the newly infecting serotype and enhance virus infection by binding to the Fcγ receptors (FcγR) on FcγR-bearing cells. In this study, we determined that molecular determinants of DENV2 envelope protein critical for virus entry during non-ADE infection are also required for ADE infection mediated by FcγRIIA, and binding of virus-Ab complexes with FcγRIIA alone is not sufficient for ADE of infection. The FcγRIIA mainly plays an auxiliary role in concentrating the virus–Ab complex to the cell surface, and other primary cellular receptors are required for virus entry. Understanding the viral entry pathway in ADE of DENV infection will greatly facilitate rational designs of anti-viral therapeutics against severe dengue disease associated with ADE. - Highlights: • KKK305/307/310 in DENV2 E-DIII is critical for virus attachment in ADE and non-ADE infection. • Binding of DENV2–Ab complex with FcγRII alone is not sufficient for virus entry in ADE infection. • Other primary receptors were required for DENV2 internalization during FcγRII–mediated ADE. • G104 and L135 of DENV2 E are critical for virus-mediated membrane fusion. • DENV2 virus-mediated membrane fusion is required for both ADE and non-ADE infection.

Direct evidence that FK506 inhibition of FcepsilonRI-mediated exocytosis from RBL mast cells involves calcineurin.

Science.gov (United States)

Hultsch, T; Brand, P; Lohmann, S; Saloga, J; Kincaid, R L; Knop, J

1998-05-01

FcepsilonRI-mediated exocytosis of preformed mediators from mast cells and basophils (e.g. histamine, serotonin, beta-hexosaminidase) is sensitive to the immunosuppressants cyclosporin A and FK506 (IC50 200 and 4 nM, respectively) but not rapamycin. The mechanism of inhibition does not appear to involve tyrosine phosphorylation, hydrolysis of inositol phosphates or calcium flux. Here we report experiments using a molecular approach to assess the role of calcineurin, a serine/threonine phosphatase thought to be the primary pharmacological target of these drugs. Calcineurin's activity requires association of its catalytic (A) subunit with an intrinsic regulatory (B) subunit. We hypothesized that calcineurin-sensitive signalling events should be affected by the depletion of calcineurin B subunits, thereby reducing the number of active A:B complexes. We therefore transfected rat basophilic leukemia (RBL) cells with an inhibitory (dominant negative) form of the calcineurin A subunit, which binds the calcineurin B subunit with high affinity but does not possess catalytic activity (B subunit knock-out, BKO). In these transfected cells, the dose-response curve for the inhibition of FcepsilonRI-mediated exocytosis by FK506 was shifted to the left, indicating an increased drug sensitivity of BKO-transfected cells. We conclude that FK506 inhibition of FcepsilonRI-mediated exocytosis in mast cells specifically targets calcineurin activity.

Deciphering the molecular events necessary for synergistic tumor cell apoptosis mediated by the histone deacetylase inhibitor vorinostat and the BH3 mimetic ABT-737

NARCIS (Netherlands)

Wiegmans, Adrian P.; Alsop, Amber E.; Bots, Michael; Cluse, Leonie A.; Williams, Steven P.; Banks, Kellie-Marie; Ralli, Rachael; Scott, Clare L.; Frenzel, Anna; Villunger, Andreas; Johnstone, Ricky W.

2011-01-01

The concept of personalized anticancer therapy is based on the use of targeted therapeutics through in-depth knowledge of the molecular mechanisms of action of these agents when used alone and in combination. We have identified the apoptotic proteins and pathways necessary for synergistic tumor cell

Molecular events associated with increased regenerative capacity of the goldfish retinal ganglion cells following X-irradiation: decreased level of axonal growth inhibitors

International Nuclear Information System (INIS)

Rachailovich, I.; Schwartz, M.

1984-01-01

In our previous work we established conditions to study the contribution of non-neuronal cells to the process of goldfish optic nerve regeneration. This issue has been studied successfully by adapting the use of X-irradiation to manipulate division of non-neuronal cells associated with the injured nerve. The regenerative capacity of the goldfish retinal ganglion cells was determined subsequent to the X-ray treatment. The authors present an analysis of the molecular events associated with regeneration and enhanced regenerative capacity which follows X-irradiation. (Auth.)

Molecular events associated with increased regenerative capacity of the goldfish retinal ganglion cells following X-irradiation: decreased level of axonal growth inhibitors

Energy Technology Data Exchange (ETDEWEB)

Rachailovich, I.; Schwartz, M. (Weizmann Inst. of Science, Rehovot (Israel). Dept. of Neurobiology)

1984-07-23

In our previous work we established conditions to study the contribution of non-neuronal cells to the process of goldfish optic nerve regeneration. This issue has been studied successfully by adapting the use of X-irradiation to manipulate division of non-neuronal cells associated with the injured nerve. The regenerative capacity of the goldfish retinal ganglion cells was determined subsequent to the X-ray treatment. The authors present an analysis of the molecular events associated with regeneration and enhanced regenerative capacity which follows X-irradiation.

Reliable Approximation of Long Relaxation Timescales in Molecular Dynamics

Directory of Open Access Journals (Sweden)

Wei Zhang

2017-07-01

Full Text Available Many interesting rare events in molecular systems, like ligand association, protein folding or conformational changes, occur on timescales that often are not accessible by direct numerical simulation. Therefore, rare event approximation approaches like interface sampling, Markov state model building, or advanced reaction coordinate-based free energy estimation have attracted huge attention recently. In this article we analyze the reliability of such approaches. How precise is an estimate of long relaxation timescales of molecular systems resulting from various forms of rare event approximation methods? Our results give a theoretical answer to this question by relating it with the transfer operator approach to molecular dynamics. By doing so we also allow for understanding deep connections between the different approaches.

Molecular Regulation of Histamine Synthesis

Directory of Open Access Journals (Sweden)

Hua Huang

2018-06-01

Full Text Available Histamine is a critical mediator of IgE/mast cell-mediated anaphylaxis, a neurotransmitter and a regulator of gastric acid secretion. Histamine is a monoamine synthesized from the amino acid histidine through a reaction catalyzed by the enzyme histidine decarboxylase (HDC, which removes carboxyl group from histidine. Despite the importance of histamine, transcriptional regulation of HDC gene expression in mammals is still poorly understood. In this review, we focus on discussing advances in the understanding of molecular regulation of mammalian histamine synthesis.

Molecular Buffers Permit Sensitivity Tuning and Inversion of Riboswitch Signals

DEFF Research Database (Denmark)

Rugbjerg, Peter; Genee, Hans Jasper; Jensen, Kristian

2016-01-01

transcription factor, while interacting DNA-binding domains mediate the transduction of signal and form an interacting molecular buffer. The molecular buffer system enables modular signal inversion through integration with repressor modules. Further, tuning of input sensitivity was achieved through perturbation...

Molecular-mediated crystal growth of PbTiO3 nanostructure on silicon substrate

International Nuclear Information System (INIS)

Chao Chunying; Ren Zhaohui; Liu Zhenya; Xiao Zhen; Xu Gang; Li Xiang; Wei Xiao; Shen Ge; Han Gaorong

2011-01-01

A simple approach based on an organically modified sol-gel process has been developed to fabricate PbTiO 3 (PT) nanocrystals on Si (1 0 0) substrate, where the amorphous powder modified by acetylacetone (acac) was used as precursor. After dropping the amorphous powder precursor prepared by freeze-drying process, PT nanocrystals on Si (1 0 0) substrate were obtained after heat treatment at 720 deg. C for 30 min in air. PT nanocrystals have been detected by XRD to be tetragonal perovskite structure. With the increase of acac/Pb molar ratio, the relative (1 0 0)/(0 0 1) diffraction peak intensity gradually increases, which probably suggested an oriented growth of PT nanocrystal along [1 0 0] on Si (1 0 0) substrates. In addition, Atomic force microscopy (AFM) results indicated that the height and the average lateral size of PT nanocrystal increased and then decreased as the acac/Pb molar ratio increased. Piezoelectric force microscopy (PFM) results demonstrated that all the samples show obvious piezoelectric activity. These results implied that the acetylacetone molecular mediated the growth of PT nanocrystals on Si (1 0 0) substrates possibly by the acac/Pb molar ratio. This simple method has been suggested to be attractive for tailoring an oriented growth of the nanostructures of perovskite oxide systems on Si substrates.

Role of Calcium and Mitochondria in MeHg-Mediated Cytotoxicity

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Daniel Roos

2012-01-01

Full Text Available Methylmercury (MeHg mediated cytotoxicity is associated with loss of intracellular calcium (Ca2+ homeostasis. The imbalance in Ca2+ physiology is believed to be associated with dysregulation of Ca2+ intracellular stores and/or increased permeability of the biomembranes to this ion. In this paper we summarize the contribution of glutamate dyshomeostasis in intracellular Ca2+ overload and highlight the mitochondrial dysfunctions induced by MeHg via Ca2+ overload. Mitochondrial disturbances elicited by Ca2+ may involve several molecular events (i.e., alterations in the activity of the mitochondrial electron transport chain complexes, mitochondrial proton gradient dissipation, mitochondrial permeability transition pore (MPTP opening, thiol depletion, failure of energy metabolism, reactive oxygen species overproduction that could culminate in cell death. Here we will focus on the role of oxidative stress in these phenomena. Additionally, possible antioxidant therapies that could be effective in the treatment of MeHg intoxication are briefly discussed.

NF-κB functions as a molecular link between tumor cells and Th1/Tc1 T cells in the tumor microenvironment to exert radiation-mediated tumor suppression

Science.gov (United States)

Simon, Priscilla S.; Bardhan, Kankana; Chen, May R.; Paschall, Amy V.; Lu, Chunwan; Bollag, Roni J.; Kong, Feng-Chong; Jin, JianYue; Kong, Feng-Ming; Waller, Jennifer L.; Pollock, Raphael E.; Liu, Kebin

2016-01-01

Radiation modulates both tumor cells and immune cells in the tumor microenvironment to exert its anti-tumor activity; however, the molecular connection between tumor cells and immune cells that mediates radiation-exerted tumor suppression activity in the tumor microenvironment is largely unknown. We report here that radiation induces rapid activation of the p65/p50 and p50/p50 NF-κB complexes in human soft tissue sarcoma (STS) cells. Radiation-activated p65/p50 and p50/p50 bind to the TNFα promoter to activate its transcription in STS cells. Radiation-induced TNFα induces tumor cell death in an autocrine manner. A sublethal dose of Smac mimetic BV6 induces cIAP1 and cIAP2 degradation to increase tumor cell sensitivity to radiation-induced cell death in vitro and to enhance radiation-mediated suppression of STS xenografts in vivo. Inhibition of caspases, RIP1, or RIP3 blocks radiation/TNFα-induced cell death, whereas inhibition of RIP1 blocks TNFα-induced caspase activation, suggesting that caspases and RIP1 act sequentially to mediate the non-compensatory cell death pathways. Furthermore, we determined in a syngeneic sarcoma mouse model that radiation up-regulates IRF3, IFNβ, and the T cell chemokines CCL2 and CCL5 in the tumor microenvironment, which are associated with activation and increased infiltration of Th1/Tc1 T cells in the tumor microenvironment. Moreover, tumor-infiltrating T cells are in their active form since both the perforin and FasL pathways are activated in irradiated tumor tissues. Consequently, combined BV6 and radiation completely suppressed tumor growth in vivo. Therefore, radiation-induced NF-κB functions as a molecular link between tumor cells and immune cells in the tumor microenvironment for radiation-mediated tumor suppression. PMID:27014915

Molecular mechanisms of lipoapoptosis and metformin protection in GLP-1 secreting cells

DEFF Research Database (Denmark)

Kappe, Camilla; Holst, Jens Juul; Zhang, Qimin

2012-01-01

Evidence is emerging that elevated serum free fatty acids (hyperlipidemia) contribute to the pathogenesis of type-2-diabetes, and lipotoxicity is observed in many cell types. We recently published data indicating lipotoxic effects of simulated hyperlipidemia also in GLP-1-secreting cells, where...... the antidiabetic drug metformin conferred protection from lipoapoptosis. The aim of the present study was to identify mechanisms involved in mediating lipotoxicity and metformin lipoprotection in GLP-1 secreting cells. These signaling events triggered by simulated hyperlipidemia may underlie reduced GLP-1...... secretion in diabetic subjects, and metformin lipoprotection by metformin could explain elevated plasma GLP-1 levels in diabetic patients on chronic metformin therapy. The present study may thus identify potential molecular targets for increasing endogenous GLP-1 secretion through enhanced viability of GLP...

Temporal expression profiling identifies pathways mediating effect of causal variant on phenotype.

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Saumya Gupta

2015-06-01

Full Text Available Even with identification of multiple causal genetic variants for common human diseases, understanding the molecular processes mediating the causal variants' effect on the disease remains a challenge. This understanding is crucial for the development of therapeutic strategies to prevent and treat disease. While static profiling of gene expression is primarily used to get insights into the biological bases of diseases, it makes differentiating the causative from the correlative effects difficult, as the dynamics of the underlying biological processes are not monitored. Using yeast as a model, we studied genome-wide gene expression dynamics in the presence of a causal variant as the sole genetic determinant, and performed allele-specific functional validation to delineate the causal effects of the genetic variant on the phenotype. Here, we characterized the precise genetic effects of a functional MKT1 allelic variant in sporulation efficiency variation. A mathematical model describing meiotic landmark events and conditional activation of MKT1 expression during sporulation specified an early meiotic role of this variant. By analyzing the early meiotic genome-wide transcriptional response, we demonstrate an MKT1-dependent role of novel modulators, namely, RTG1/3, regulators of mitochondrial retrograde signaling, and DAL82, regulator of nitrogen starvation, in additively effecting sporulation efficiency. In the presence of functional MKT1 allele, better respiration during early sporulation was observed, which was dependent on the mitochondrial retrograde regulator, RTG3. Furthermore, our approach showed that MKT1 contributes to sporulation independent of Puf3, an RNA-binding protein that steady-state transcription profiling studies have suggested to mediate MKT1-pleiotropic effects during mitotic growth. These results uncover interesting regulatory links between meiosis and mitochondrial retrograde signaling. In this study, we highlight the advantage

STRIDE: Species Tree Root Inference from Gene Duplication Events.

Science.gov (United States)

Emms, David M; Kelly, Steven

2017-12-01

The correct interpretation of any phylogenetic tree is dependent on that tree being correctly rooted. We present STRIDE, a fast, effective, and outgroup-free method for identification of gene duplication events and species tree root inference in large-scale molecular phylogenetic analyses. STRIDE identifies sets of well-supported in-group gene duplication events from a set of unrooted gene trees, and analyses these events to infer a probability distribution over an unrooted species tree for the location of its root. We show that STRIDE correctly identifies the root of the species tree in multiple large-scale molecular phylogenetic data sets spanning a wide range of timescales and taxonomic groups. We demonstrate that the novel probability model implemented in STRIDE can accurately represent the ambiguity in species tree root assignment for data sets where information is limited. Furthermore, application of STRIDE to outgroup-free inference of the origin of the eukaryotic tree resulted in a root probability distribution that provides additional support for leading hypotheses for the origin of the eukaryotes. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Journaling about stressful events: effects of cognitive processing and emotional expression.

Science.gov (United States)

Ullrich, Philip M; Lutgendorf, Susan K

2002-01-01

The effects of two journaling interventions, one focusing on emotional expression and the other on both cognitive processing and emotional expression, were compared during 1 month of journaling about a stressful or traumatic event. One hundred twenty-two students were randomly assigned to one of three writing conditions: (a) focusing on emotions related to a trauma or stressor, (b) focusing on cognitions and emotions related to a trauma or stressor, or (c) writing factually about media events. Writers focusing on cognitions and emotions developed greater awareness of the positive benefits of the stressful event than the other two groups. This effect was apparently mediated by greater cognitive processing during writing. Writers focusing on emotions alone reported more severe illness symptoms during the study than those in other conditions. This effect appeared to be mediated by a greater focus on negative emotional expression during writing.

The effect of childhood trauma and Five-Factor Model personality traits on exposure to adult life events in patients with psychotic disorders.

Science.gov (United States)

Pos, Karin; Boyette, Lindy Lou; Meijer, Carin J; Koeter, Maarten; Krabbendam, Lydia; de Haan, Lieuwe; For Group

2016-11-01

Recent life events are associated with transition to and outcome in psychosis. Childhood trauma and personality characteristics play a role in proneness to adult life events. However, little is known about the relative contribution and interrelatedness of these characteristics in psychotic disorders. Therefore, we investigated whether Five-Factor Model (FFM) personality traits and childhood trauma (abuse and neglect) predict adult life events, and whether the effect of childhood trauma on life events is mediated by personality traits. One hundred and sixty-three patients with psychotic disorders were assessed at baseline on history of childhood maltreatment and FFM personality traits, and on recent life events at 3-year follow-up. Childhood abuse is associated with negative life events, and part of the effect of childhood abuse on negative life events is mediated by openness to experience. Openness to experience and extraversion are associated with more positive and negative life events. Childhood neglect and lower extraversion are related to experiencing less positive events. The association between childhood trauma and recent life events is partly mediated by personality. Future research could focus on mechanisms leading to positive life events, as positive life events may buffer against development of mental health problems.

Mediated priming in the lexical decision task : Evidence from event-related potentials and reaction time

NARCIS (Netherlands)

Chwilla, DJ; Kolk, HHJ; Mulder, G

Mediated priming (e.g., from LION to STRIPES vis TIGER) is predicted by spreading activation models hut only by some integration model. The goal of the present research was to localize mediated priming by assessing two-step priming effects on N400 and reaction times (RT). We propose that the N400

Molecular anatomy of the recombination mediator function of Saccharomyces cerevisiae Rad52

DEFF Research Database (Denmark)

Seong, C.; Sehorn, M.G.; Plate, Iben

2008-01-01

A helical filament of Rad51 on single-strand DNA (ssDNA), called the presynaptic filament, catalyzes DNA joint formation during homologous recombination. Rad52 facilitates presynaptic filament assembly, and this recombination mediator activity is thought to rely on the interactions of Rad52...... with Rad51, the ssDNA-binding protein RPA, and ssDNA. The N-terminal region of Rad52, which has DNA binding activity and an oligomeric structure, is thought to be crucial for mediator activity and recombination. Unexpectedly, we find that the C-terminal region of Rad52 also harbors a DNA binding function....... Importantly, the Rad52 C-terminal portion alone can promote Rad51 presynaptic filament assembly. The middle portion of Rad52 associates with DNA-bound RPA and contributes to the recombination mediator activity. Accordingly, expression of a protein species that harbors the middle and C-terminal regions of Rad...

AFRICAN-STYLE MEDIATION AND WESTERN-STYLE DIVORCE AND FAMILY MEDIATION: REFLECTIONS FOR THE SOUTH AFRICAN CONTEXT

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AE Boniface

2012-12-01

Full Text Available Both Western-styled mediation and African-styled mediation are practised in South Africa. Each of these models is applied in specific social contexts. In this article a brief explanation of what is meant by the term divorce and family mediation is provided. Thereafter the principles and processes of both Western-styled divorce and family mediation and African-styled group mediation are explored. Attention is given to the roles of mediators in both of these models as well as the ubuntu-styled values found in African group mediation. In Africa, there is a tradition of family neighbourhood negotiation facilitated by elders and an attitude of togetherness in the spirit of humanhood. Both of these show a commitment to the community concerned and a comprehensive view of life. In Africa conflicts are viewed as non-isolated events and are viewed in their social contexts. Not only are consequences for the disputing parties taken into account but also consequences for others in their families. These methods can be found in present-day methods, which are either used independently of imported Western structures or used alternatively to such structures. In this article the concept of mediation circles, as currently found in Western-styled mediation are also covered. Additionally, the provisions of the Children’s Act 38 of 2005 referring to mediation as well as the provisions of the Child Justice Act 75 of 2008 and family group conferencing in the realm of restorative justice in South Africa are critiqued. It is suggested that divorce and family mediation can learn from the principles of restorative justice applied during family group conferencing as well as from African-styled group mediation.

Molecular mechanisms of NCAM function

DEFF Research Database (Denmark)

Hinsby, Anders M; Berezin, Vladimir; Bock, Elisabeth

2004-01-01

receptor that responds to both homophilic and heterophilic cues, as well as a mediator of cell-cell adhesion. This review describes NCAM function at the molecular level. We discuss recent models for extracellular ligand-interactions of NCAM, and the intracellular signaling cascade that follows to define...

Signal transduction by FcεRI: Analysis of the early molecular events

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Henry Metzger

1999-01-01

Full Text Available We are analysing the initial molecular events stimulated by the high-affinity receptor for IgE, FcεRI. Earlier studies have shown that the first response when the receptor-bound IgE interacts with a multivalent antigen is a transphosphorylation of receptor tyrosines, induced by the approximation of two or more receptors by a constitutively associated src-family kinase (Lyn. The amount of weakly associated kinase regulates the intensity of the response. Several aspects are being analyzed: (i the sites on Lyn and the receptor that account for the constitutive interaction; (ii how the intrinsic affinity of a ligand for the receptor-bound IgE influences the responses; and (iii the mechanism(s by which low-affinity ligands can act as antagonists. In the latter studies, mast cell responses were followed by monitoring the phosphorylation of tyrosines on several proteins and secretion. At equivalent levels of receptor phosphorylation, a ligand with high affinity stimulated vigorous phosphorylation of downstream components, whereas a low-affinity ligand was unable to stimulate phosphorylation of the same components effectively. Cells stimulated with a mixture of high- and low-affinity ligands, under a protocol where simple displacement of one by the other was prevented, remarkably showed that excess low-affinity ligand inhibited the phosphorylation as well as degranulation by the high-affinity ligand. This antagonism results from a competition for the limiting amount of the constitutive initiating kinase. Related receptors that depend on recruitment of initiating kinases may be subject to similar regulatory mechanisms.

Mediator independently orchestrates multiple steps of preinitiation complex assembly in vivo

OpenAIRE

Eyboulet, Fanny; Wydau-Dematteis, Sandra; Eychenne, Thomas; Alibert, Olivier; Neil, Helen; Boschiero, Claire; Nevers, Marie-Claire; Volland, Herv?; Cornu, David; Redeker, Virginie; Werner, Michel; Soutourina, Julie

2015-01-01

Mediator is a large multiprotein complex conserved in all eukaryotes, which has a crucial coregulator function in transcription by RNA polymerase II (Pol II). However, the molecular mechanisms of its action in vivo remain to be understood. Med17 is an essential and central component of the Mediator head module. In this work, we utilised our large collection of conditional temperature-sensitive med17 mutants to investigate Mediator's role in coordinating preinitiation complex (PIC) formation i...

A recombinase-mediated transcriptional induction system in transgenic plants

DEFF Research Database (Denmark)

Hoff, T; Schnorr, K M; Mundy, J

2001-01-01

We constructed and tested a Cre-loxP recombination-mediated vector system termed pCrox for use in transgenic plants. In this system, treatment of Arabidopsis under inducing conditions mediates an excision event that removes an intervening piece of DNA between a promoter and the gene to be expressed......-mediated GUS activation. Induction was shown to be possible at essentially any stage of plant growth. This single vector system circumvents the need for genetic crosses required by other, dual recombinase vector systems. The pCrox system may prove particularly useful in instances where transgene over...

Agrobacterium rhizogenes-Mediated Transformation – a Non-GMO Platform For Developing Compact Ornamentals

DEFF Research Database (Denmark)

Lütken, Henrik Vlk; Hegelund, Josefine Nymark; Lauridsen, Uffe Bjerre

of these compounds are potentially harmful to both the environment and human health. A new non-GMO molecular breeding strategy, as opposed to both the application of chemical growth retardants and conventional molecular breeding is Agrobacterium rhizogenes-mediated transformation. In this method, the soil borne...... for transformations, plants produced via this approach are not considered as GMOs in the European Union and Japan. We have developed an optimised Agrobacterium rhizogenes-mediated transformation platform useful for a wide range of ornamentals. Kalanchoë was the starting point and the effect of the rol-genes has now...

Mediator, SWI/SNF and SAGA complexes regulate Yap8-dependent transcriptional activation of ACR2 in response to arsenate.

Science.gov (United States)

Menezes, Regina Andrade; Pimentel, Catarina; Silva, Ana Rita Courelas; Amaral, Catarina; Merhej, Jawad; Devaux, Frédéric; Rodrigues-Pousada, Claudina

2017-04-01

Response to arsenic stress in Saccharomyces cerevisiae is orchestrated by the regulatory protein Yap8, which mediates transcriptional activation of ACR2 and ACR3. This study contributes to the state of art knowledge of the molecular mechanisms underlying yeast stress response to arsenate as it provides the genetic and biochemical evidences that Yap8, through cysteine residues 132, 137, and 274, is the sensor of presence of arsenate in the cytosol. Moreover, it is here reported for the first time the essential role of the Mediator complex in the transcriptional activation of ACR2 by Yap8. Based on our data, we propose an order-of-function map to recapitulate the sequence of events taking place in cells injured with arsenate. Modification of the sulfhydryl state of these cysteines converts Yap8 in its activated form, triggering the recruitment of the Mediator complex to the ACR2/ACR3 promoter, through the interaction with the tail subunit Med2. The Mediator complex then transfers the regulatory signals conveyed by Yap8 to the core transcriptional machinery, which culminates with TBP occupancy, ACR2 upregulation and cell adaptation to arsenate stress. Additional co-factors are required for the transcriptional activation of ACR2 by Yap8, particularly the nucleosome remodeling activity of SWI/SNF and SAGA complexes. Copyright © 2017. Published by Elsevier B.V.

Modeling and validation of autoinducer-mediated bacterial gene expression in microfluidic environments

Science.gov (United States)

Austin, Caitlin M.; Stoy, William; Su, Peter; Harber, Marie C.; Bardill, J. Patrick; Hammer, Brian K.; Forest, Craig R.

2014-01-01

Biosensors exploiting communication within genetically engineered bacteria are becoming increasingly important for monitoring environmental changes. Currently, there are a variety of mathematical models for understanding and predicting how genetically engineered bacteria respond to molecular stimuli in these environments, but as sensors have miniaturized towards microfluidics and are subjected to complex time-varying inputs, the shortcomings of these models have become apparent. The effects of microfluidic environments such as low oxygen concentration, increased biofilm encapsulation, diffusion limited molecular distribution, and higher population densities strongly affect rate constants for gene expression not accounted for in previous models. We report a mathematical model that accurately predicts the biological response of the autoinducer N-acyl homoserine lactone-mediated green fluorescent protein expression in reporter bacteria in microfluidic environments by accommodating these rate constants. This generalized mass action model considers a chain of biomolecular events from input autoinducer chemical to fluorescent protein expression through a series of six chemical species. We have validated this model against experimental data from our own apparatus as well as prior published experimental results. Results indicate accurate prediction of dynamics (e.g., 14% peak time error from a pulse input) and with reduced mean-squared error with pulse or step inputs for a range of concentrations (10 μM–30 μM). This model can help advance the design of genetically engineered bacteria sensors and molecular communication devices. PMID:25379076

Abundant genetic overlap between blood lipids and immune-mediated diseases indicates shared molecular genetic mechanisms.

Directory of Open Access Journals (Sweden)

Ole A Andreassen

Full Text Available Epidemiological studies suggest a relationship between blood lipids and immune-mediated diseases, but the nature of these associations is not well understood. We used genome-wide association studies (GWAS to investigate shared single nucleotide polymorphisms (SNPs between blood lipids and immune-mediated diseases. We analyzed data from GWAS (n~200,000 individuals, applying new False Discovery Rate (FDR methods, to investigate genetic overlap between blood lipid levels [triglycerides (TG, low density lipoproteins (LDL, high density lipoproteins (HDL] and a selection of archetypal immune-mediated diseases (Crohn's disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, celiac disease, psoriasis and sarcoidosis. We found significant polygenic pleiotropy between the blood lipids and all the investigated immune-mediated diseases. We discovered several shared risk loci between the immune-mediated diseases and TG (n = 88, LDL (n = 87 and HDL (n = 52. Three-way analyses differentiated the pattern of pleiotropy among the immune-mediated diseases. The new pleiotropic loci increased the number of functional gene network nodes representing blood lipid loci by 40%. Pathway analyses implicated several novel shared mechanisms for immune pathogenesis and lipid biology, including glycosphingolipid synthesis (e.g. FUT2 and intestinal host-microbe interactions (e.g. ATG16L1. We demonstrate a shared genetic basis for blood lipids and immune-mediated diseases independent of environmental factors. Our findings provide novel mechanistic insights into dyslipidemia and immune-mediated diseases and may have implications for therapeutic trials involving lipid-lowering and anti-inflammatory agents.

IgE-mediated reaction to local anaesthetics

International Nuclear Information System (INIS)

Kartal, O.; Gulec, M.; Sener, O.; Caliskaner, A.Z.

2013-01-01

Local anaesthetics (LAs) are essential agents in daily practices of dentistry, minor surgery and dermatology. Although they have an impressive history of safety and efficacy, LAs also have the potential to produce adverse events, which are mainly of non-immune nature. The true IgE-mediated allergies are quite rare, but are more considerable in terms of ability to cause life-threatening outcomes. In this report, we present a case of IgE-mediated systemic reaction to LAs occurring during epidural anaesthesia for Cesarean section. (author)

Role of Inflammation and Oxidative Stress Mediators in Gliomas

Directory of Open Access Journals (Sweden)

Alfredo Conti

2010-04-01

Full Text Available Gliomas are the most common primary brain tumors of the central nervous system. Despite relevant progress in conventional treatments, the prognosis of such tumors remains almost invariably dismal. The genesis of gliomas is a complex, multistep process that includes cellular neoplastic transformation, resistance to apoptosis, loss of control of the cell cycle, angiogenesis, and the acquisition of invasive properties. Among a number of different biomolecular events, the existence of molecular connections between inflammation and oxidative stress pathways and the development of this cancer has been demonstrated. In particular, the tumor microenvironment, which is largely orchestrated by inflammatory molecules, is an indispensable participant in the neoplastic process, promoting proliferation, survival and migration of such tumors. Proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma, as well as chemokines and prostaglandins, are synthesized by resident brain cells and lymphocytes invading the affected brain tissue. Key mediators of cancer progression include nuclear factor-kappaB, reactive oxygen and nitrogen species, and specific microRNAs. The collective activity of these mediators is largely responsible for a pro-tumorigenic response through changes in cell proliferation, cell death, cellular senescence, DNA mutation rates, DNA methylation and angiogenesis. We provide a general overview of the connection between specific inflammation and oxidative stress pathway molecules and gliomas. The elucidation of specific effects and interactions of these factors may provide the opportunity for the identification of new target molecules leading to improved diagnosis and treatment.

Role of Inflammation and Oxidative Stress Mediators in Gliomas

Energy Technology Data Exchange (ETDEWEB)

Conti, Alfredo, E-mail: alfredo.conti@unime.it; Gulì, Carlo; La Torre, Domenico; Tomasello, Chiara; Angileri, Filippo F.; Aguennouz, M’Hammed [Department of Neuroscience and Department of Oncology, University of Messina, Policlinico Universitario, Via Consolare Valeria 1, 98125, Messina (Italy)

2010-04-26

Gliomas are the most common primary brain tumors of the central nervous system. Despite relevant progress in conventional treatments, the prognosis of such tumors remains almost invariably dismal. The genesis of gliomas is a complex, multistep process that includes cellular neoplastic transformation, resistance to apoptosis, loss of control of the cell cycle, angiogenesis, and the acquisition of invasive properties. Among a number of different biomolecular events, the existence of molecular connections between inflammation and oxidative stress pathways and the development of this cancer has been demonstrated. In particular, the tumor microenvironment, which is largely orchestrated by inflammatory molecules, is an indispensable participant in the neoplastic process, promoting proliferation, survival and migration of such tumors. Proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma, as well as chemokines and prostaglandins, are synthesized by resident brain cells and lymphocytes invading the affected brain tissue. Key mediators of cancer progression include nuclear factor-kappaB, reactive oxygen and nitrogen species, and specific microRNAs. The collective activity of these mediators is largely responsible for a pro-tumorigenic response through changes in cell proliferation, cell death, cellular senescence, DNA mutation rates, DNA methylation and angiogenesis. We provide a general overview of the connection between specific inflammation and oxidative stress pathway molecules and gliomas. The elucidation of specific effects and interactions of these factors may provide the opportunity for the identification of new target molecules leading to improved diagnosis and treatment.

Role of Inflammation and Oxidative Stress Mediators in Gliomas

International Nuclear Information System (INIS)

Conti, Alfredo; Gulì, Carlo; La Torre, Domenico; Tomasello, Chiara; Angileri, Filippo F.; Aguennouz, M’Hammed

2010-01-01

Gliomas are the most common primary brain tumors of the central nervous system. Despite relevant progress in conventional treatments, the prognosis of such tumors remains almost invariably dismal. The genesis of gliomas is a complex, multistep process that includes cellular neoplastic transformation, resistance to apoptosis, loss of control of the cell cycle, angiogenesis, and the acquisition of invasive properties. Among a number of different biomolecular events, the existence of molecular connections between inflammation and oxidative stress pathways and the development of this cancer has been demonstrated. In particular, the tumor microenvironment, which is largely orchestrated by inflammatory molecules, is an indispensable participant in the neoplastic process, promoting proliferation, survival and migration of such tumors. Proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma, as well as chemokines and prostaglandins, are synthesized by resident brain cells and lymphocytes invading the affected brain tissue. Key mediators of cancer progression include nuclear factor-kappaB, reactive oxygen and nitrogen species, and specific microRNAs. The collective activity of these mediators is largely responsible for a pro-tumorigenic response through changes in cell proliferation, cell death, cellular senescence, DNA mutation rates, DNA methylation and angiogenesis. We provide a general overview of the connection between specific inflammation and oxidative stress pathway molecules and gliomas. The elucidation of specific effects and interactions of these factors may provide the opportunity for the identification of new target molecules leading to improved diagnosis and treatment

Early events triggering delayed vasoconstrictor receptor upregulation and cerebral ischemia after subarachnoid hemorrhage

DEFF Research Database (Denmark)

Povlsen, Gro Klitgaard; Johansson, Sara Ellinor; Larsen, Carl Christian

2013-01-01

shown to be mediated by intracellular signalling via the mitogen activated protein kinase kinase (MEK1/2)--extracellular regulated kinase 1/2 (ERK1/2) pathway. However, it is not known what event(s) that trigger MEK-ERK1/2 activation and vasoconstrictor receptor upregulation after SAH.We hypothesise...

Revisiting R-invariant direct gauge mediation

Energy Technology Data Exchange (ETDEWEB)

Chiang, Cheng-Wei [Center for Mathematics and Theoretical Physics andDepartment of Physics, National Central University,Taoyuan, Taiwan 32001, R.O.C. (China); Institute of Physics, Academia Sinica,Taipei, Taiwan 11529, R.O.C. (China); Physics Division, National Center for Theoretical Sciences,Hsinchu, Taiwan 30013, R.O.C. (China); Kavli IPMU (WPI), UTIAS, University of Tokyo,Kashiwa, Chiba 277-8583 (Japan); Harigaya, Keisuke [Department of Physics, University of California,Berkeley, California 94720 (United States); Theoretical Physics Group, Lawrence Berkeley National Laboratory,Berkeley, California 94720 (United States); ICRR, University of Tokyo,Kashiwa, Chiba 277-8582 (Japan); Ibe, Masahiro [Kavli IPMU (WPI), UTIAS, University of Tokyo,Kashiwa, Chiba 277-8583 (Japan); ICRR, University of Tokyo,Kashiwa, Chiba 277-8582 (Japan); Yanagida, Tsutomu T. [Kavli IPMU (WPI), UTIAS, University of Tokyo,Kashiwa, Chiba 277-8583 (Japan)

2016-03-21

We revisit a special model of gauge mediated supersymmetry breaking, the “R-invariant direct gauge mediation.” We pay particular attention to whether the model is consistent with the minimal model of the μ-term, i.e., a simple mass term of the Higgs doublets in the superpotential. Although the incompatibility is highlighted in view of the current experimental constraints on the superparticle masses and the observed Higgs boson mass, the minimal μ-term can be consistent with the R-invariant gauge mediation model via a careful choice of model parameters. We derive an upper limit on the gluino mass from the observed Higgs boson mass. We also discuss whether the model can explain the 3σ excess of the Z+jets+E{sub T}{sup miss} events reported by the ATLAS collaboration.

Say it with flowers! An fMRI study of object mediated communication

DEFF Research Database (Denmark)

Tylén, Kristian; Wallentin, Mikkel; Roepstorff, Andreas

2009-01-01

Human communicational interaction can be mediated by a host of expressive means from words in a natural language to gestures and material symbols. Given the proper contextual setting even an everyday object can gain a mediating function in a communicational situation. In this study we used event...

Teaching Responsibly with Technology-Mediated Communication

Science.gov (United States)

Veltsos, Jennifer R.; Veltsos, Christophe

2010-01-01

Technology-mediated communication, or "new media," such as blogs, Twitter, wikis, and social network sites, can be an endless source of ideas for activities or inspiration for classroom discussion. Many instructors ask students to monitor current events by following keywords and industry leaders on Twitter and reading both corporate and…

NOS-mediated morphological and molecular modifications in rats infused with Aβ (1-40), as a model of Alzheimer's disease, in response to a new lipophilic molecular combination codrug-1.

Science.gov (United States)

Zara, Susi; Di Stefano, Antonio; Nasuti, Cinzia; Rapino, Monica; Patruno, Antonia; Pesce, Mirko; Sozio, Piera; Cerasa, Laura S; Cataldi, Amelia

2011-04-01

Alzheimer's disease is a neurodegenerative pathology due to the presence of β-amyloid plaques at brain level and hippocampus level and associated with the loss of memory speech and learning. At the basis of these effects lie molecular mechanisms which include nitric oxide metabolic pathway, whose involvement in the occurrence of morphological modifications related to such neurodegenerative process is suggested. Current evidences show that the non-steroidal anti-inflammatory drug ibuprofen posses a protective effect against the development of the disease, substantially delaying its onset; furthermore (R)-α-lipoic acid seems to have an antioxidant ameliorating effect on disease progression. Starting from these data, a new lipophilic codrug 1, obtained by joining an antioxidant molecule with an NSAID, has been previously synthesized. Our aim has been to investigate the possible therapeutical effects of codrug 1, compared to ibuprofen, on the molecular events at the basis of behavioural and morphological modifications occurring in Aβ (1-40) infused rat brains. Ibuprofen and codrug 1 seem to protect the subject against memory performance impairment and against behavioural detriment, induced by administration of Aβ (1-40) peptide. Such evidences are supported by morphological and biochemical findings showing Aβ (1-40) to determine cell disorganization, increased number of β-amyloid plaques and capillary vessels dilatation in parallel to increased total and specific NOS activity and to apoptosis occurrence, partly prevented by ibuprofen, more broadly by codrug 1. Such results underline the involvement of nitric oxide metabolic pathway in the events related to the onset of this pathology and suggest codrug 1 as a useful tool to protect the brain against cognitive and behavioural dysfunction, by reducing β-amyloid plaques formation and by inhibiting NOS signalling pathway and apoptosis occurrence. Copyright © 2010 Elsevier Inc. All rights reserved.

Ecological momentary assessment of stressful events and negative affect in bulimia nervosa.

Science.gov (United States)

Goldschmidt, Andrea B; Wonderlich, Stephen A; Crosby, Ross D; Engel, Scott G; Lavender, Jason M; Peterson, Carol B; Crow, Scott J; Cao, Li; Mitchell, James E

2014-02-01

Negative affect precedes binge eating and purging in bulimia nervosa (BN), but little is known about factors that precipitate negative affect in relation to these behaviors. We aimed to assess the temporal relation among stressful events, negative affect, and bulimic events in the natural environment using ecological momentary assessment. A total of 133 women with current BN recorded their mood, eating behavior, and the occurrence of stressful events every day for 2 weeks. Multilevel structural equation mediation models evaluated the relations among Time 1 stress measures (i.e., interpersonal stressors, work/environment stressors, general daily hassles, and stress appraisal), Time 2 negative affect, and Time 2 binge eating and purging, controlling for Time 1 negative affect. Increases in negative affect from Time 1 to Time 2 significantly mediated the relations between Time 1 interpersonal stressors, work/environment stressors, general daily hassles, and stress appraisal and Time 2 binge eating and purging. When modeled simultaneously, confidence intervals for interpersonal stressors, general daily hassles, and stress appraisal did not overlap, suggesting that each had a distinct impact on negative affect in relation to binge eating and purging. Our findings indicate that stress precedes the occurrence of bulimic behaviors and that increases in negative affect following stressful events mediate this relation. Results suggest that stress and subsequent negative affect may function as maintenance factors for bulimic behaviors and should be targeted in treatment. PsycINFO Database Record (c) 2014 APA, all rights reserved.

PET-based molecular imaging in neuroscience

International Nuclear Information System (INIS)

Jacobs, A.H.; Heiss, W.D.; Li, H.; Knoess, C.; Schaller, B.; Kracht, L.; Monfared, P.; Vollmar, S.; Bauer, B.; Wagner, R.; Graf, R.; Wienhard, K.; Winkeler, A.; Rueger, A.; Klein, M.; Hilker, R.; Galldiks, N.; Herholz, K.; Sobesky, J.

2003-01-01

Positron emission tomography (PET) allows non-invasive assessment of physiological, metabolic and molecular processes in humans and animals in vivo. Advances in detector technology have led to a considerable improvement in the spatial resolution of PET (1-2 mm), enabling for the first time investigations in small experimental animals such as mice. With the developments in radiochemistry and tracer technology, a variety of endogenously expressed and exogenously introduced genes can be analysed by PET. This opens up the exciting and rapidly evolving field of molecular imaging, aiming at the non-invasive localisation of a biological process of interest in normal and diseased cells in animal models and humans in vivo. The main and most intriguing advantage of molecular imaging is the kinetic analysis of a given molecular event in the same experimental subject over time. This will allow non-invasive characterisation and ''phenotyping'' of animal models of human disease at various disease stages, under certain pathophysiological stimuli and after therapeutic intervention. The potential broad applications of imaging molecular events in vivo lie in the study of cell biology, biochemistry, gene/protein function and regulation, signal transduction, transcriptional regulation and characterisation of transgenic animals. Most importantly, molecular imaging will have great implications for the identification of potential molecular therapeutic targets, in the development of new treatment strategies, and in their successful implementation into clinical application. Here, the potential impact of molecular imaging by PET in applications in neuroscience research with a special focus on neurodegeneration and neuro-oncology is reviewed. (orig.)

RACK1-mediated translation control promotes liver fibrogenesis

Energy Technology Data Exchange (ETDEWEB)

Liu, Min; Peng, Peike; Wang, Jiajun [Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032 (China); Wang, Lan; Duan, Fangfang [Institute of Biomedical Science, Fudan University, Shanghai 200032 (China); Jia, Dongwei, E-mail: jiadongwei@fudan.edu.cn [Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032 (China); Ruan, Yuanyuan, E-mail: yuanyuanruan@fudan.edu.cn [Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032 (China); Gu, Jianxin [Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032 (China); Institute of Biomedical Science, Fudan University, Shanghai 200032 (China)

2015-07-31

Activation of quiescent hepatic stellate cells (HSCs) is the central event of liver fibrosis. The translational machinery is an optimized molecular network that affects cellular homoeostasis and diseases, whereas the role of protein translation in HSCs activation and liver fibrosis is little defined. Our previous report suggests that up-regulation of receptor for activated C-kinase 1(RACK1) in HSCs is critical for liver fibrogenesis. In this study, we found that RACK1 promoted macrophage conditioned medium (MCM)-induced assembly of eIF4F and phosphorylation of eIF4E in primary HSCs. RACK1 enhanced the translation and expression of pro-fibrogenic factors collagen 1α1, snail and cyclin E1 induced by MCM. Administration of PP242 or knock-down of eIF4E suppressed RACK1-stimulated collagen 1α1 production, proliferation and migration in primary HSCs. In addition, depletion of eIF4E attenuated thioacetamide (TAA)-induced liver fibrosis in vivo. Our data suggest that RACK1-mediated stimulation of cap-dependent translation plays crucial roles in HSCs activation and liver fibrogenesis, and targeting translation initiation could be a promising strategy for the treatment of liver fibrosis. - Highlights: • RACK1 induces the assembly of eIF4F and phosphorylation of eIF4E in primary HSCs. • RACK1 stimulates the translation of collagen 1α1, snail and cyclin E1 in HSCs. • RACK1 promotes HSCs activation via cap-mediated translation. • Depletion of eIF4E suppresses liver fibrogenesis in vivo.

RACK1-mediated translation control promotes liver fibrogenesis

International Nuclear Information System (INIS)

Liu, Min; Peng, Peike; Wang, Jiajun; Wang, Lan; Duan, Fangfang; Jia, Dongwei; Ruan, Yuanyuan; Gu, Jianxin

2015-01-01

Activation of quiescent hepatic stellate cells (HSCs) is the central event of liver fibrosis. The translational machinery is an optimized molecular network that affects cellular homoeostasis and diseases, whereas the role of protein translation in HSCs activation and liver fibrosis is little defined. Our previous report suggests that up-regulation of receptor for activated C-kinase 1(RACK1) in HSCs is critical for liver fibrogenesis. In this study, we found that RACK1 promoted macrophage conditioned medium (MCM)-induced assembly of eIF4F and phosphorylation of eIF4E in primary HSCs. RACK1 enhanced the translation and expression of pro-fibrogenic factors collagen 1α1, snail and cyclin E1 induced by MCM. Administration of PP242 or knock-down of eIF4E suppressed RACK1-stimulated collagen 1α1 production, proliferation and migration in primary HSCs. In addition, depletion of eIF4E attenuated thioacetamide (TAA)-induced liver fibrosis in vivo. Our data suggest that RACK1-mediated stimulation of cap-dependent translation plays crucial roles in HSCs activation and liver fibrogenesis, and targeting translation initiation could be a promising strategy for the treatment of liver fibrosis. - Highlights: • RACK1 induces the assembly of eIF4F and phosphorylation of eIF4E in primary HSCs. • RACK1 stimulates the translation of collagen 1α1, snail and cyclin E1 in HSCs. • RACK1 promotes HSCs activation via cap-mediated translation. • Depletion of eIF4E suppresses liver fibrogenesis in vivo

Pathways from assaultive violence to post-traumatic stress, depression, and generalized anxiety symptoms through stressful life events: longitudinal mediation models.

Science.gov (United States)

Lowe, S R; Joshi, S; Galea, S; Aiello, A E; Uddin, M; Koenen, K C; Cerdá, M

2017-10-01

Assaultive violence events are associated with increased risk for adverse psychiatric outcomes, including post-traumatic stress (PTS), depression, and generalized anxiety. Prior research has indicated that economic, legal, and social stressors that could follow assaultive events may explain the increased risk for adverse psychiatric outcomes, yet longitudinal studies have not adequately examined this pathway. In the current study, we aimed to address this limitation. Participants (N = 1360) were part of a longitudinal population-based study of adults living in Detroit. At three waves, participants indicated their exposure to assaultive violence and economic, legal, and social stressors, and completed inventories of PTS, depression, and generalized anxiety. Longitudinal mediation models were used to test the hypothesized pathway from assaultive violence to each psychiatric outcome. The hypothesized models evidenced good fit with the data and, in each, the paths from Wave 1 (W1) assaultive violence to W2 stressors, and from W2 stressors to W3 symptoms were significant (range of Standardized Estimates: 0.09-0.15, all p violence to W3 symptoms were significant (range of Standardized Estimates: 0.01-0.02, all p violence increase risk for a range of psychiatric symptoms. Although future research is needed, the results suggest that investment in interventions that prevent and mitigate assaultive violence survivors' exposure to such stressors may be an effective way to prevent mental illness in the aftermath of violent assaults.

Immune mediated liver failure.

Science.gov (United States)

Wang, Xiaojing; Ning, Qin

2014-01-01

Liver failure is a clinical syndrome of various etiologies, manifesting as jaundice, encephalopathy, coagulopathy and circulatory dysfunction, which result in subsequent multiorgan failure. Clinically, liver failure is classified into four categories: acute, subacute, acute-on-chronic and chronic liver failure. Massive hepatocyte death is considered to be the core event in the development of liver failure, which occurs when the extent of hepatocyte death is beyond the liver regenerative capacity. Direct damage and immune-mediated liver injury are two major factors involved in this process. Increasing evidence has suggested the essential role of immune-mediated liver injury in the pathogenesis of liver failure. Here, we review the evolved concepts concerning the mechanisms of immune-mediated liver injury in liver failure from human and animal studies. Both innate and adaptive immunity, especially the interaction of various immune cells and molecules as well as death receptor signaling system are discussed. In addition, we highlight the concept of "immune coagulation", which has been shown to be related to the disease progression and liver injury exacerbation in HBV related acute-on-chronic liver failure.

CDX1 is an important molecular mediator of Barrett's metaplasia

DEFF Research Database (Denmark)

Wong, N A C S; Wilding, J; Bartlett, S

2005-01-01

and the inflammatory cytokines TNF-alpha and IL-1beta were all found to increase CDX1 mRNA expression in vitro. These effects were primarily mediated by NF-kappaB signaling but only occurred when the CDX1 promoter was unmethylated or partially methylated. The data suggest that CDX1 is a key molecule linking...

Gratitude and suicidal ideation and suicide attempts among Chinese adolescents: direct, mediated, and moderated effects.

Science.gov (United States)

Li, Dongping; Zhang, Wei; Li, Xian; Li, Nini; Ye, Baojuan

2012-02-01

In a sample of 1252 Chinese adolescents (mean age = 15.00 years), this study examined the direct relations between gratitude and adolescents' suicidal ideation and suicide attempts. This study also examined indirect relations between gratitude and suicidal ideation and suicide attempts via two self-system beliefs--coping efficacy and self-esteem. Finally, this study examined the extent to which stressful life events moderated the direct and indirect relations between gratitude and suicidal ideation and suicide attempts. The odds of suicidal ideation and suicide attempts were lower among adolescents who scored higher on gratitude, after controlling for demographic variables. Self-esteem mediated the relations between gratitude and suicidal ideation and suicide attempts, while the mediating role of coping efficacy was not significant. Moreover, stressful life events moderated the mediated path through self-esteem. This indirect effect was stronger for adolescents low on stressful life events than that for those high on stressful life events. This study discusses the theoretical and practical implications of these findings. Copyright © 2011 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.

Predictive value of reactive hyperemia for cardiovascular events in patients with peripheral arterial disease undergoing vascular surgery.

Science.gov (United States)

Huang, Alex L; Silver, Annemarie E; Shvenke, Elena; Schopfer, David W; Jahangir, Eiman; Titas, Megan A; Shpilman, Alex; Menzoian, James O; Watkins, Michael T; Raffetto, Joseph D; Gibbons, Gary; Woodson, Jonathan; Shaw, Palma M; Dhadly, Mandeep; Eberhardt, Robert T; Keaney, John F; Gokce, Noyan; Vita, Joseph A

2007-10-01

Reactive hyperemia is the compensatory increase in blood flow that occurs after a period of tissue ischemia, and this response is blunted in patients with cardiovascular risk factors. The predictive value of reactive hyperemia for cardiovascular events in patients with atherosclerosis and the relative importance of reactive hyperemia compared with other measures of vascular function have not been previously studied. We prospectively measured reactive hyperemia and brachial artery flow-mediated dilation by ultrasound in 267 patients with peripheral arterial disease referred for vascular surgery (age 66+/-11 years, 26% female). Median follow-up was 309 days (range 1 to 730 days). Fifty patients (19%) had an event, including cardiac death (15), myocardial infarction (18), unstable angina (8), congestive heart failure (6), and nonhemorrhagic stroke (3). Patients with an event were older and had lower hyperemic flow velocity (75+/-39 versus 95+/-50 cm/s, P=0.009). Patients with an event also had lower flow-mediated dilation (4.5+/-3.0 versus 6.9+/-4.6%, P<0.001), and when these 2 measures of vascular function were included in the same Cox proportional hazards model, lower hyperemic flow (OR 2.7, 95% CI 1.2 to 5.9, P=0.018) and lower flow-mediated dilation (OR 4.2, 95% CI: 1.8 to 9.8, P=0.001) both predicted cardiovascular events while adjusting for other risk factors. Thus, lower reactive hyperemia is associated with increased cardiovascular risk in patients with peripheral arterial disease. Furthermore, flow-mediated dilation and reactive hyperemia incrementally relate to cardiovascular risk, although impaired flow-mediated dilation was the stronger predictor in this population. These findings further support the clinical relevance of vascular function measured in the microvasculature and conduit arteries in the upper extremity.

Molecular Characterization of Macrophage-Biomaterial Interactions.

Science.gov (United States)

Moore, Laura Beth; Kyriakides, Themis R

2015-01-01

Implantation of biomaterials in vascularized tissues elicits the sequential engagement of molecular and cellular elements that constitute the foreign body response. Initial events include the non-specific adsorption of proteins to the biomaterial surface that render it adhesive for cells such as neutrophils and macrophages. The latter undergo unique activation and in some cases undergo cell-cell fusion to form foreign body giant cells that contribute to implant damage and fibrotic encapsulation. In this review, we discuss the molecular events that contribute to macrophage activation and fusion with a focus on the role of the inflammasome, signaling pathways such as JAK/STAT and NF-κB, and the putative involvement of micro RNAs in the regulation of these processes.

Cardiovascular Molecular Imaging

International Nuclear Information System (INIS)

Lee, Kyung Han

2009-01-01

Molecular imaging strives to visualize processes in living subjects at the molecular level. Monitoring biochemical processes at this level will allow us to directly track biological processes and signaling events that lead to pathophysiological abnormalities, and help make personalized medicine a reality by allowing evaluation of therapeutic efficacies on an individual basis. Although most molecular imaging techniques emerged from the field of oncology, they have now gradually gained acceptance by the cardiovascular community. Hence, the availability of dedicated high-resolution small animal imaging systems and specific targeting imaging probes is now enhancing our understanding of cardiovascular diseases and expediting the development of newer therapies. Examples include imaging approaches to evaluate and track the progress of recent genetic and cellular therapies for treatment of myocardial ischemia. Other areas include in vivo monitoring of such key molecular processes as angiogenesis and apoptosis. Cardiovascular molecular imaging is already an important research tool in preclinical experiments. The challenge that lies ahead is to implement these techniques into the clinics so that they may help fulfill the promise of molecular therapies and personalized medicine, as well as to resolve disappointments and controversies surrounding the field

Alternative splicing and nonsense-mediated decay of circadian clock genes under environmental stress conditions in Arabidopsis.

Science.gov (United States)

Kwon, Young-Ju; Park, Mi-Jeong; Kim, Sang-Gyu; Baldwin, Ian T; Park, Chung-Mo

2014-05-19

The circadian clock enables living organisms to anticipate recurring daily and seasonal fluctuations in their growth habitats and synchronize their biology to the environmental cycle. The plant circadian clock consists of multiple transcription-translation feedback loops that are entrained by environmental signals, such as light and temperature. In recent years, alternative splicing emerges as an important molecular mechanism that modulates the clock function in plants. Several clock genes are known to undergo alternative splicing in response to changes in environmental conditions, suggesting that the clock function is intimately associated with environmental responses via the alternative splicing of the clock genes. However, the alternative splicing events of the clock genes have not been studied at the molecular level. We systematically examined whether major clock genes undergo alternative splicing under various environmental conditions in Arabidopsis. We also investigated the fates of the RNA splice variants of the clock genes. It was found that the clock genes, including EARLY FLOWERING 3 (ELF3) and ZEITLUPE (ZTL) that have not been studied in terms of alternative splicing, undergo extensive alternative splicing through diverse modes of splicing events, such as intron retention, exon skipping, and selection of alternative 5' splice site. Their alternative splicing patterns were differentially influenced by changes in photoperiod, temperature extremes, and salt stress. Notably, the RNA splice variants of TIMING OF CAB EXPRESSION 1 (TOC1) and ELF3 were degraded through the nonsense-mediated decay (NMD) pathway, whereas those of other clock genes were insensitive to NMD. Taken together, our observations demonstrate that the major clock genes examined undergo extensive alternative splicing under various environmental conditions, suggesting that alternative splicing is a molecular scheme that underlies the linkage between the clock and environmental stress

Alternative splicing and nonsense-mediated decay of circadian clock genes under environmental stress conditions in Arabidopsis

Science.gov (United States)

2014-01-01

Background The circadian clock enables living organisms to anticipate recurring daily and seasonal fluctuations in their growth habitats and synchronize their biology to the environmental cycle. The plant circadian clock consists of multiple transcription-translation feedback loops that are entrained by environmental signals, such as light and temperature. In recent years, alternative splicing emerges as an important molecular mechanism that modulates the clock function in plants. Several clock genes are known to undergo alternative splicing in response to changes in environmental conditions, suggesting that the clock function is intimately associated with environmental responses via the alternative splicing of the clock genes. However, the alternative splicing events of the clock genes have not been studied at the molecular level. Results We systematically examined whether major clock genes undergo alternative splicing under various environmental conditions in Arabidopsis. We also investigated the fates of the RNA splice variants of the clock genes. It was found that the clock genes, including EARLY FLOWERING 3 (ELF3) and ZEITLUPE (ZTL) that have not been studied in terms of alternative splicing, undergo extensive alternative splicing through diverse modes of splicing events, such as intron retention, exon skipping, and selection of alternative 5′ splice site. Their alternative splicing patterns were differentially influenced by changes in photoperiod, temperature extremes, and salt stress. Notably, the RNA splice variants of TIMING OF CAB EXPRESSION 1 (TOC1) and ELF3 were degraded through the nonsense-mediated decay (NMD) pathway, whereas those of other clock genes were insensitive to NMD. Conclusion Taken together, our observations demonstrate that the major clock genes examined undergo extensive alternative splicing under various environmental conditions, suggesting that alternative splicing is a molecular scheme that underlies the linkage between the clock

Acute Social Stress Engages Synergistic Activity of Stress Mediators in the VTA to Promote Pavlovian Reward Learning

OpenAIRE

Kan, Russell; Pomrenze, Matthew; Tovar-Diaz, Jorge; Morikawa, Hitoshi; Drew, Michael; Pahlavan, Bahram

2017-01-01

Stressful events rapidly trigger activity-dependent synaptic plasticity in certain brain areas, driving the formation of aversive memories. However, it remains unclear how stressful experience affects plasticity mechanisms to regulate learning of appetitive events, such as intake of addictive drugs or palatable foods. Using rats, we show that two acute stress mediators, corticotropin-releasing factor (CRF) and norepinephrine (NE), enhance plasticity of NMDA receptor-mediated glutamatergic tra...

Characterization of Mediator Complex and its Associated Proteins from Rice.

Science.gov (United States)

Samanta, Subhasis; Thakur, Jitendra Kumar

2017-01-01

The Mediator complex is a multi-protein complex that acts as a molecular bridge conveying transcriptional messages from the cis element-bound transcription factor to the RNA Polymerase II machinery. It is found in all eukaryotes including members of the plant kingdom. Increasing number of reports from plants regarding different Mediator subunits involved in a multitude of processes spanning from plant development to environmental interactions have firmly established it as a central hub of plant regulatory networks. Routine isolation of Mediator complex in a particular species is a necessity because of many reasons. First, composition of the Mediator complex varies from species to species. Second, the composition of the Mediator complex in a particular species is not static under all developmental and environmental conditions. Besides this, at times, Mediator complex is used in in vitro transcription systems. Rice, a staple food crop of the world, is used as a model monocot crop. Realizing the need of a reliable protocol for the isolation of Mediator complex from plants, we describe here the isolation of Mediator complex from rice.

Agrobacterium-mediated transformation: state of the art and future prospect

Institute of Scientific and Technical Information of China (English)

无

2000-01-01

Great progress has been made in recent years in studies on the mechanism of Agrobacterium-mediated transformation and its application. Many details of the key molecular events within the bacterial cells involved in T-DNA transfer have been elucidated, and it is notable that some plant factors which were elusive before are purified and characterized. Vast kinds of species, which were either recalcitrant to or not included in the host range of Agrobacterium, can now be transformed by this bacterium, and they include the very important cereal species, gymnosperms, yeast and many filamentous fungi. The simple in vivo transformation of tissue in intact plants and the "agrolistic" methods to transform recalcitrant plants are the two novel technical achievements. Combined with other powerful techniques such as bacterial artificial chromosome, very large DNA fragment can be transformed into the plant genome by Agrobacterium. Further studies will elucidate more plant-encoded factors involved in T-DNA transformation and there is a need to develop more powerful Agrobacterium-based transformation systems to meet different needs in basic research and crop improvement practice.

Molecular stopwatches, cogwheels and ``spinflakes'': studying the dynamics of molecular superrotors

Science.gov (United States)

Korobenko, Aleksey; Milner, Alexander; Hepburn, John; Milner, Valery

2015-05-01

Using the technique of an optical centrifuge, we excite diatomic molecules to ultrafast synchronous rotation. Femtosecond velocity-map imaging allows us to visualize and study the coherent dynamics of molecular superrotors under field free conditions and in external magnetic field. We demonstrate that when the created rotational wave packet is narrow, its free evolution is nondispersing and follows the motion of a classically rotating dumbbell or a hand of the smallest natural stopwatch. For wider rotational distributions, we observe the breakdown of classical rotation, when a dumbbell shape changes to that of a ``quantum cogwheel'' - a molecular state simultaneously aligned along multiple direction. Our measurements in external magnetic field reveal other peculiar aspects of the rich dynamics of molecular superrotors. The rotation of a non-magnetic molecule interacts with the applied field only weakly, giving rise to slow precession of the molecular angular momentum around the field direction. In contrast, the electronic spin of a paramagnetic superrotor mediates this interaction, causing the initial disk-like angular distribution to split into several spatial components, each precessing with its own frequency determined by the spin projection.

Diet, lifestyle, and molecular alterations that drive colorectal carcinogenesis

NARCIS (Netherlands)

Diergaarde, B.

2004-01-01

Environmental factors have been repeatedly implicated in the etiology of colorectal cancer, and much is known about the molecular events involved in colorectal carcinogenesis. The relationships between environmental risk factors and the molecular alterations that drive colorectal carcinogenesis are

Immune-mediated bone marrow failure syndromes of progenitor and stem cells: molecular analysis of cytotoxic T cell clones.

Directory of Open Access Journals (Sweden)

Ramon Tiu

2007-03-01

Full Text Available The unique structure of the T cell receptor (TCR enables molecular identification of individual T cell clones and provides an unique opportunity for the design of molecular diagnostic tests based on the structure of the rearranged TCR chain e.g., using the TCR CDR3 region. Initially, clonal T cell malignancies, including T cell large granular lymphocyte leukemia (T-LGL, mucosis fungoides and peripheral T cell lymphoma were targets for the TCR-based analytic assays such as detection of clonality by T-gamma rearrangement using y-chain-specific PCR or Southern Blotting. Study of these disorders facilitated further analytic concepts and application of rational methods of TCR analysis to investigations of polyclonal T cell-mediated diseases. In hematology, such conditions include graft versus host disease (GvHD and immune-mediated bone marrow failure syndromes. In aplastic anemia (AA, myelodysplastic syndrome (MDS or paroxysmal nocturnal hemoglobinuria (PNH, cytotoxic T cell responses may be directed against certain antigens located on stem or more lineage-restricted progenitor cells in single lineage cytopenias. The nature of the antigenic targets driving polyclonal CTL responses remains unclear. Novel methods of TCR repertoire analysis, include VB flow cytometry, peptide-specific tetramer staining, in vitro stimulation assays and TCR CDR3-specific PCR. Such PCR assay can be either VB family-specific or multiplexed for all VB families. Amplified products can be characterized and quantitated to facilitate detection of the most immunodominant clonotypes. Such clonotypes may serve as markers for the global polyclonal T cell response. Identification of these clonotypes can be performed in blood and tissue biopsy material by various methods. Once immunodominant clonotypes corresponding to pathogenic CTL clones are identified they can serve as surrogate markers for the activity of the pathophysiologic process or even indicate the presence of specific

Environmental conditions synchronize waterbird mortality events in the Great Lakes

Science.gov (United States)

Prince, Karine; Chipault, Jennifer G.; White, C. LeAnn; Zuckerberg, Benjamin

2018-01-01

Since the 1960s, periodic outbreaks of avian botulism type E have contributed to large-scale die-offs of thousands of waterbirds throughout the Great Lakes of the United States. In recent years, these events have become more common and widespread. Occurring during the summer and autumn months, the prevalence of these die-offs varies across years and is often associated with years of warmer lake temperatures and lower water levels. Little information exists on how environmental conditions mediate the spatial and temporal characteristics of mortality events.In 2010, a citizen science programme, Avian Monitoring for Botulism Lakeshore Events (AMBLE), was launched to enhance surveillance efforts and detect the appearance of beached waterbird carcasses associated with avian botulism type E outbreaks in northern Lake Michigan. Using these data, our goal was to quantify the within-year characteristics of mortality events for multiple species, and to test whether the synchrony of these events corresponded to fluctuations in two environmental factors suspected to be important in the spread of avian botulism: water temperature and the prevalence of green macroalgae.During two separate events of mass waterbird mortality, we found that the detection of bird carcasses was spatially synchronized at scales of c. 40 km. Notably, the extent of this spatial synchrony in avian mortality matched that of fluctuations in lake surface water temperatures and the prevalence of green macroalgae.Synthesis and applications. Our findings are suggestive of a synchronizing effect where warmer lake temperatures and the appearance of macroalgae mediate the characteristics of avian mortality. In future years, rising lake temperatures and a higher propensity of algal masses could lead to increases in the magnitude and synchronization of avian mortality due to botulism. We advocate that citizen-based monitoring efforts are critical for identifying the potential environmental conditions associated

Molecular communications and nanonetworks from nature to practical systems

CERN Document Server

Atakan, Barış

2014-01-01

In this book, the concepts of molecular communications and nanonetworks are introduced. Throughout the book, the existing molecular communication paradigms are categorized into two main groups. The first group includes the Passive Molecular Communication (PMC) paradigms in which molecules freely diffuse to transfer information from a transmitter to a receiver. The second group includes the Active Molecular Communication (AMC) paradigms in which molecules are carried or guided by some mediators such as molecular motors, gap junction channels and bacteria. In the book, after briefly discussing why molecular communication is needed for the sophisticated nano and biotechnology applications, the existing molecular communication systems are first presented. Then, the principles of diffusion phenomena and molecular reception with absorbers and the ligand-receptor binding mechanism are introduced. Based on these principles, the communication theories and techniques are given for the PMC. Then, the physical dynamics o...

Clinical effects of low-molecular-weight heparin combined with ...

African Journals Online (AJOL)

Tropical Journal of Pharmaceutical Research August 2016; 15 (8): 1787-1792 ... Keywords: Acute pancreatitis, Low-molecular-weight heparin, Multiple organ function syndrome,. APACHE II score ... mediators by lowering the expression of.

Human iPSC-Derived Neuronal Model of Tau-A152T Frontotemporal Dementia Reveals Tau-Mediated Mechanisms of Neuronal Vulnerability

Directory of Open Access Journals (Sweden)

M. Catarina Silva

2016-09-01

Full Text Available Frontotemporal dementia (FTD and other tauopathies characterized by focal brain neurodegeneration and pathological accumulation of proteins are commonly associated with tau mutations. However, the mechanism of neuronal loss is not fully understood. To identify molecular events associated with tauopathy, we studied induced pluripotent stem cell (iPSC-derived neurons from individuals carrying the tau-A152T variant. We highlight the potential of in-depth phenotyping of human neuronal cell models for pre-clinical studies and identification of modulators of endogenous tau toxicity. Through a panel of biochemical and cellular assays, A152T neurons showed accumulation, redistribution, and decreased solubility of tau. Upregulation of tau was coupled to enhanced stress-inducible markers and cell vulnerability to proteotoxic, excitotoxic, and mitochondrial stressors, which was rescued upon CRISPR/Cas9-mediated targeting of tau or by pharmacological activation of autophagy. Our findings unmask tau-mediated perturbations of specific pathways associated with neuronal vulnerability, revealing potential early disease biomarkers and therapeutic targets for FTD and other tauopathies.

A new signature for gauge mediated supersymmetry breaking

International Nuclear Information System (INIS)

Dicus, D.A.; Dutta, B.; Nandi, S.; Oklahoma State Univ., Stillwater, OK

1997-01-01

In theories with gauge mediated supersymmetry breaking, the scalar tau, (τ 1 ) is the lightest superpartner for a large range of the parameter space. At the large electron positron collider (LEP 2) this scenario can give rise to events with four τ leptons and large missing energy. Two of the τ's (coming from the decays of τ 1 's) will have large energy and transverse momentum, and can have similar sign electrical charges. Such events are very different from the usual photonic events that have been widely studied, and could be a very distinct signal for the discovery of supersymmetry. 20 refs., 2 figs., 3 tabs

An UPF3-based nonsense-mediated decay in Paramecium.

Science.gov (United States)

Contreras, Julia; Begley, Victoria; Macias, Sandra; Villalobo, Eduardo

2014-12-01

Nonsense-mediated decay recognises mRNAs containing premature termination codons. One of its components, UPF3, is a molecular link bridging through its binding to the exon junction complex nonsense-mediated decay and splicing. In protists UPF3 has not been identified yet. We report that Paramecium tetraurelia bears an UPF3 gene and that it has a role in nonsense-mediated decay. Interestingly, the identified UPF3 has not conserved the essential amino acids required to bind the exon junction complex. Though, our data indicates that this ciliate bears genes coding for core proteins of the exon junction complex. Copyright © 2014 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Negative Life Events and Antenatal Depression among Pregnant Women in Rural China: The Role of Negative Automatic Thoughts.

Science.gov (United States)

Wang, Yang; Wang, Xiaohua; Liu, Fangnan; Jiang, Xiaoning; Xiao, Yun; Dong, Xuehan; Kong, Xianglei; Yang, Xuemei; Tian, Donghua; Qu, Zhiyong

2016-01-01

Few studies have looked at the relationship between psychological and the mental health status of pregnant women in rural China. The current study aims to explore the potential mediating effect of negative automatic thoughts between negative life events and antenatal depression. Data were collected in June 2012 and October 2012. 495 rural pregnant women were interviewed. Depressive symptoms were measured by the Edinburgh postnatal depression scale, stresses of pregnancy were measured by the pregnancy pressure scale, negative automatic thoughts were measured by the automatic thoughts questionnaire, and negative life events were measured by the life events scale for pregnant women. We used logistic regression and path analysis to test the mediating effect. The prevalence of antenatal depression was 13.7%. In the logistic regression, the only socio-demographic and health behavior factor significantly related to antenatal depression was sleep quality. Negative life events were not associated with depression in the fully adjusted model. Path analysis showed that the eventual direct and general effects of negative automatic thoughts were 0.39 and 0.51, which were larger than the effects of negative life events. This study suggested that there was a potentially significant mediating effect of negative automatic thoughts. Pregnant women who had lower scores of negative automatic thoughts were more likely to suffer less from negative life events which might lead to antenatal depression.

The Mediator Complex: At the Nexus of RNA Polymerase II Transcription.

Science.gov (United States)

Jeronimo, Célia; Robert, François

2017-10-01

Mediator is an essential, large, multisubunit, transcriptional co-activator highly conserved across eukaryotes. Mediator interacts with gene-specific transcription factors at enhancers as well as with the RNA polymerase II (RNAPII) transcription machinery bound at promoters. It also interacts with several other factors involved in various aspects of transcription, chromatin regulation, and mRNA processing. Hence, Mediator is at the nexus of RNAPII transcription, regulating its many steps and connecting transcription with co-transcriptional events. To achieve this flexible role, Mediator, which is divided into several functional modules, reorganizes its conformation and composition while making transient contacts with other components. Here, we review the mechanisms of action of Mediator and propose a unifying model for its function. Copyright © 2017 Elsevier Ltd. All rights reserved.

Learning and Memory, Part II: Molecular Mechanisms of Synaptic Plasticity

Science.gov (United States)

Lombroso, Paul; Ogren, Marilee

2009-01-01

The molecular events that are responsible for strengthening synaptic connections and how these are linked to memory and learning are discussed. The laboratory preparations that allow the investigation of these events are also described.

AGROBEST: an efficient Agrobacterium-mediated transient expression method for versatile gene function analyses in Arabidopsis seedlings

Science.gov (United States)

2014-01-01

Background Transient gene expression via Agrobacterium-mediated DNA transfer offers a simple and fast method to analyze transgene functions. Although Arabidopsis is the most-studied model plant with powerful genetic and genomic resources, achieving highly efficient and consistent transient expression for gene function analysis in Arabidopsis remains challenging. Results We developed a highly efficient and robust Agrobacterium-mediated transient expression system, named AGROBEST (Agrobacterium-mediated enhanced seedling transformation), which achieves versatile analysis of diverse gene functions in intact Arabidopsis seedlings. Using β-glucuronidase (GUS) as a reporter for Agrobacterium-mediated transformation assay, we show that the use of a specific disarmed Agrobacterium strain with vir gene pre-induction resulted in homogenous GUS staining in cotyledons of young Arabidopsis seedlings. Optimization with AB salts in plant culture medium buffered with acidic pH 5.5 during Agrobacterium infection greatly enhanced the transient expression levels, which were significantly higher than with two existing methods. Importantly, the optimized method conferred 100% infected seedlings with highly increased transient expression in shoots and also transformation events in roots of ~70% infected seedlings in both the immune receptor mutant efr-1 and wild-type Col-0 seedlings. Finally, we demonstrated the versatile applicability of the method for examining transcription factor action and circadian reporter-gene regulation as well as protein subcellular localization and protein–protein interactions in physiological contexts. Conclusions AGROBEST is a simple, fast, reliable, and robust transient expression system enabling high transient expression and transformation efficiency in Arabidopsis seedlings. Demonstration of the proof-of-concept experiments elevates the transient expression technology to the level of functional studies in Arabidopsis seedlings in addition to previous

A mediation skills model to manage disclosure of errors and adverse events to patients.

Science.gov (United States)

Liebman, Carol B; Hyman, Chris Stern

2004-01-01

In 2002 Pennsylvania became the first state to impose on hospitals a statutory duty to notify patients in writing of a serious event. If the disclosure conversations are carefully planned, properly executed, and responsive to patients' needs, this new requirement creates possible benefits for both patient safety and litigation risk management. This paper describes a model for accomplishing these goals that encourages health care providers to communicate more effectively with patients following an adverse event or medical error, learn from mistakes, respond to the concerns of patients and families after an adverse event, and arrive at a fair and cost-effective resolution of valid claims.

Evolution of Soybean mosaic virus-G7 molecularly cloned genome in Rsv1-genotype soybean results in emergence of a mutant capable of evading Rsv1-mediated recognition

International Nuclear Information System (INIS)

Hajimorad, M.R.; Eggenberger, A.L.; Hill, J.H.

2003-01-01

Plant resistance (R) genes direct recognition of pathogens harboring matching avirluent signals leading to activation of defense responses. It has long been hypothesized that under selection pressure the infidelity of RNA virus replication together with large population size and short generation times results in emergence of mutants capable of evading R-mediated recognition. In this study, the Rsv1/Soybean mosaic virus (SMV) pathosystem was used to investigate this hypothesis. In soybean line PI 96983 (Rsv1), the progeny of molecularly cloned SMV strain G7 (pSMV-G7) provokes a lethal systemic hypersensitive response (LSHR) with up regulation of a defense-associated gene transcript (PR-1). Serial passages of a large population of the progeny in PI 96983 resulted in emergence of a mutant population (vSMV-G7d), incapable of provoking either Rsv1-mediated LSHR or PR-1 protein gene transcript up regulation. An infectious clone of the mutant (pSMV-G7d) was synthesized whose sequences were very similar but not identical to the vSMV-G7d population; however, it displayed a similar phenotype. The genome of pSMV-G7d differs from parental pSMV-G7 by 17 substitutions, of which 10 are translationally silent. The seven amino acid substitutions in deduced sequences of pSMV-G7d differ from that of pSMV-G7 by one each in P1 proteinase, helper component-proteinase, and coat protein, respectively, and by four in P3. To the best of our knowledge, this is the first demonstration in which experimental evolution of a molecularly cloned plant RNA virus resulted in emergence of a mutant capable of evading an R-mediated recognition

Detection of enterotoxigenic Clostridium perfringens in meat samples by using molecular methods.

Science.gov (United States)

Kaneko, Ikuko; Miyamoto, Kazuaki; Mimura, Kanako; Yumine, Natsuko; Utsunomiya, Hirotoshi; Akimoto, Shigeru; McClane, Bruce A

2011-11-01

To prevent food-borne bacterial diseases and to trace bacterial contamination events to foods, microbial source tracking (MST) methods provide important epidemiological information. To apply molecular methods to MST, it is necessary not only to amplify bacterial cells to detection limit levels but also to prepare DNA with reduced inhibitory compounds and contamination. Isolates carrying the Clostridium perfringens enterotoxin gene (cpe) on the chromosome or a plasmid rank among the most important food-borne pathogens. Previous surveys indicated that cpe-positive C. perfringens isolates are present in only ∼5% of nonoutbreak food samples and then only at low numbers, usually less than 3 cells/g. In this study, four molecular assays for the detection of cpe-positive C. perfringens isolates, i.e., ordinary PCR, nested PCR, real-time PCR, and loop-mediated isothermal amplification (LAMP), were developed and evaluated for their reliability using purified DNA. For use in the artificial contamination of meat samples, DNA templates were prepared by three different commercial DNA preparation kits. The four molecular assays always detected cpe when >10³ cells/g of cpe-positive C. perfringens were present, using any kit. Of three tested commercial DNA preparation kits, the InstaGene matrix kit appeared to be most suitable for the testing of a large number of samples. By using the InstaGene matrix kit, the four molecular assays efficiently detected cpe using DNA prepared from enrichment culture specimens of meat samples contaminated with low numbers of cpe-positive C. perfringens vegetative cells or spores. Overall, the current study developed molecular assay protocols for MST to detect the contamination of foods with low numbers of cells, and at a low frequency, of cpe-positive C. perfringens isolates.

Detection of Enterotoxigenic Clostridium perfringens in Meat Samples by Using Molecular Methods▿

Science.gov (United States)

Kaneko, Ikuko; Miyamoto, Kazuaki; Mimura, Kanako; Yumine, Natsuko; Utsunomiya, Hirotoshi; Akimoto, Shigeru; McClane, Bruce A.

2011-01-01

To prevent food-borne bacterial diseases and to trace bacterial contamination events to foods, microbial source tracking (MST) methods provide important epidemiological information. To apply molecular methods to MST, it is necessary not only to amplify bacterial cells to detection limit levels but also to prepare DNA with reduced inhibitory compounds and contamination. Isolates carrying the Clostridium perfringens enterotoxin gene (cpe) on the chromosome or a plasmid rank among the most important food-borne pathogens. Previous surveys indicated that cpe-positive C. perfringens isolates are present in only ∼5% of nonoutbreak food samples and then only at low numbers, usually less than 3 cells/g. In this study, four molecular assays for the detection of cpe-positive C. perfringens isolates, i.e., ordinary PCR, nested PCR, real-time PCR, and loop-mediated isothermal amplification (LAMP), were developed and evaluated for their reliability using purified DNA. For use in the artificial contamination of meat samples, DNA templates were prepared by three different commercial DNA preparation kits. The four molecular assays always detected cpe when >103 cells/g of cpe-positive C. perfringens were present, using any kit. Of three tested commercial DNA preparation kits, the InstaGene matrix kit appeared to be most suitable for the testing of a large number of samples. By using the InstaGene matrix kit, the four molecular assays efficiently detected cpe using DNA prepared from enrichment culture specimens of meat samples contaminated with low numbers of cpe-positive C. perfringens vegetative cells or spores. Overall, the current study developed molecular assay protocols for MST to detect the contamination of foods with low numbers of cells, and at a low frequency, of cpe-positive C. perfringens isolates. PMID:21890671

Uncovering molecular processes in crystal nucleation and growth by using molecular simulation.

Science.gov (United States)

Anwar, Jamshed; Zahn, Dirk

2011-02-25

Exploring nucleation processes by molecular simulation provides a mechanistic understanding at the atomic level and also enables kinetic and thermodynamic quantities to be estimated. However, whilst the potential for modeling crystal nucleation and growth processes is immense, there are specific technical challenges to modeling. In general, rare events, such as nucleation cannot be simulated using a direct "brute force" molecular dynamics approach. The limited time and length scales that are accessible by conventional molecular dynamics simulations have inspired a number of advances to tackle problems that were considered outside the scope of molecular simulation. While general insights and features could be explored from efficient generic models, new methods paved the way to realistic crystal nucleation scenarios. The association of single ions in solvent environments, the mechanisms of motif formation, ripening reactions, and the self-organization of nanocrystals can now be investigated at the molecular level. The analysis of interactions with growth-controlling additives gives a new understanding of functionalized nanocrystals and the precipitation of composite materials. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

New molecular probes of vascular inflammation

International Nuclear Information System (INIS)

Molecular Cardiovascular Imaging, Westfälische Wilhelms University Münster, Münster, (Germany))" data-affiliation=" (Department of Nuclear Medicine, University Hospital Münster, Münster, and DFG CRC 656 Molecular Cardiovascular Imaging, Westfälische Wilhelms University Münster, Münster, (Germany))" >VRACHIMIS, Alexis; HONOLD, Lisa; Cells in Motion Cluster of Excellence, Westfälische Wilhelms University Münster, Münster, (Germany))" data-affiliation=" (European Institute of Molecular Imaging, Westfälische Wilhelms University Münster, Münster, and DFG EXC 1003 Cells in Motion Cluster of Excellence, Westfälische Wilhelms University Münster, Münster, (Germany))" >FAUST, Andreas; Cells in Motion Cluster of Excellence, Westfälische Wilhelms University Münster, Münster, (Germany))" data-affiliation=" (European Institute of Molecular Imaging, Westfälische Wilhelms University Münster, Münster, and DFG EXC 1003 Cells in Motion Cluster of Excellence, Westfälische Wilhelms University Münster, Münster, (Germany))" >HERMANN, Sven; SCHÄFERS, Michael

2016-01-01

New molecular imaging approaches featuring the assessment of inflammatory processes in the vascular wall on top of existing anatomic and functional vessel imaging procedures could emerge as decisive tools for the understanding and prevention of cardiovascular events. In this respect imaging approaches addressing specific molecular and cellular targets in atherosclerosis are of high interest. This review summarizes the rationale and current status of nuclear imaging probes which possess high translational potential.

Elucidation of molecular kinetic schemes from macroscopic traces using system identification.

Directory of Open Access Journals (Sweden)

Miguel Fribourg

2017-02-01

Full Text Available Overall cellular responses to biologically-relevant stimuli are mediated by networks of simpler lower-level processes. Although information about some of these processes can now be obtained by visualizing and recording events at the molecular level, this is still possible only in especially favorable cases. Therefore the development of methods to extract the dynamics and relationships between the different lower-level (microscopic processes from the overall (macroscopic response remains a crucial challenge in the understanding of many aspects of physiology. Here we have devised a hybrid computational-analytical method to accomplish this task, the SYStems-based MOLecular kinetic scheme Extractor (SYSMOLE. SYSMOLE utilizes system-identification input-output analysis to obtain a transfer function between the stimulus and the overall cellular response in the Laplace-transformed domain. It then derives a Markov-chain state molecular kinetic scheme uniquely associated with the transfer function by means of a classification procedure and an analytical step that imposes general biological constraints. We first tested SYSMOLE with synthetic data and evaluated its performance in terms of its rate of convergence to the correct molecular kinetic scheme and its robustness to noise. We then examined its performance on real experimental traces by analyzing macroscopic calcium-current traces elicited by membrane depolarization. SYSMOLE derived the correct, previously known molecular kinetic scheme describing the activation and inactivation of the underlying calcium channels and correctly identified the accepted mechanism of action of nifedipine, a calcium-channel blocker clinically used in patients with cardiovascular disease. Finally, we applied SYSMOLE to study the pharmacology of a new class of glutamate antipsychotic drugs and their crosstalk mechanism through a heteromeric complex of G protein-coupled receptors. Our results indicate that our methodology

Emotion-induced myoclonic absence-like seizures in a patient with inv-dup(15) syndrome: a clinical, EEG, and molecular genetic study.

Science.gov (United States)

Aguglia, U; Le Piane, E; Gambardella, A; Messina, D; Russo, C; Sirchia, S M; Porta, G; Quattrone, A

1999-09-01

We have described a clinical EEG and molecular genetic study of a 9-year-old boy with inv-dup(15) syndrome in whom seizures were induced by emotionally gratifying stimuli. The reflex seizures began 5-20 s after the onset of repeated cheek-kissing from his mother or after viewing of pleasant or funny events. They were characterized by bilateral discharges involving mainly the temporal regions and evolving into myoclonic absence-like seizures. Nonemotional stimuli, such as a pinch, sucking or rubbing his cheeks, or the sound of the kiss alone, failed to provoke seizures. The seizures were resistant to antiepileptic (AED) treatments. Molecular genetic investigations revealed a correct methylation pattern of the chromosomes 15, and three copies (two maternal and one paternal) of the segment 15q11-q13, including the GABRb3 gene. We hypothesize that an overexpression of cerebral gamma-aminobutyric acid (GABA)-mediated inhibition accounts for the severe epilepsy that we observed in this patient.

Attributional style as a mediator between parental abuse risk and child internalizing symptomatology.

Science.gov (United States)

Rodriguez, Christina M

2006-05-01

This study examined a model wherein children's attributional style mediates the relationship between parental physical child-abuse risk and children's internalizing problems. Using structural equation modeling, three indices of abuse risk were selected (child abuse potential, physical discipline use, and dysfunctional parenting style) and two indices of children's internalizing problems (depression and anxiety). The sample included 75 parent-child dyads, in which parents reported on their abuse risk and children independently completed measures of depressive and anxious symptomatology and a measure on their attributional style. Findings supported the model that children's attributional style for positive events (but not negative events) partially mediated the relationship between abuse risk and internalizing symptoms, with significant direct and indirect effects of abuse risk on internalizing symptomatology. Future directions to continue evaluating additional mediators and other possible contextual variables are discussed.

Molecular ion photofragment spectroscopy

International Nuclear Information System (INIS)

Bustamente, S.W.

1983-11-01

A new molecular ion photofragment spectrometer is described which features a supersonic molecular beam ion source and a radio frequency octapole ion trap interaction region. This unique combination allows several techniques to be applied to the problem of detecting a photon absorption event of a molecular ion. In particular, it may be possible to obtain low resolution survey spectra of exotic molecular ions by using a direct vibrational predissociation process, or by using other more indirect detection methods. The use of the spectrometer is demonstrated by measuring the lifetime of the O 2 + ( 4 π/sub u/) metastable state which is found to consist of two main components: the 4 π/sub 5/2/ and 4 π/sub -1/2/ spin components having a long lifetime (approx. 129 ms) and the 4 π/sub 3/2/ and 4 π/sub 1/2/ spin components having a short lifetime (approx. 6 ms)

Molecular Cell Biology of Apoptosis and Necroptosis in Cancer.

Science.gov (United States)

Dillon, Christopher P; Green, Douglas R

Cell death is a major mechanism to eliminate cells in which DNA is damaged, organelles are stressed, or oncogenes are overexpressed, all events that would otherwise predispose cells to oncogenic transformation. The pathways that initiate and execute cell death are complex, genetically encoded, and subject to significant regulation. Consequently, while these pathways are often mutated in malignancy, there is considerable interest in inducing cell death in tumor cells as therapy. This chapter addresses our current understanding of molecular mechanisms contributing to two cell death pathways, apoptotic cell death and necroptosis, a regulated form of necrotic cell death. Apoptosis can be induced by a wide variety of signals, leading to protease activation that dismantles the cell. We discuss the physiological importance of each apoptosis pathway and summarize their known roles in cancer suppression and the current efforts at targeting each pathway therapeutically. The intricate mechanistic link between death receptor-mediated apoptosis and necroptosis is described, as well as the potential opportunities for utilizing necroptosis in the treatment of malignancy.

The practice of mediation to resolve clinical, bioethical, and medical malpractice disputes.

Science.gov (United States)

Lee, Danny W H; Lai, Paul B S

2015-12-01

Mediation is a voluntary process whereby a neutral and impartial third party-t-he mediator--is present to facilitate communication and negotiation between the disputing parties so that amicable settlements can be agreed. Being confidential and non-adversarial in nature, the mediation process and skills are particularly applicable in clinical practice to facilitate challenging communications following adverse events, to assist bioethical decision making and to resolve disputes. Mediation is also a more effective and efficient means of dispute resolution in medical malpractice claims when compared with civil litigation. Health care mediation teams should be set up at individual facilities to provide education and consultation services to frontline staff and patients. At a community level, the Government, the mediation community, and the health care professionals should join forces to promote mediation as a means to settle medical malpractice claims outside of the courtroom.

Event centrality in trauma and PTSD: relations between event relevance and posttraumatic symptoms

Directory of Open Access Journals (Sweden)

Thiago Loreto Garcia da Silva

2016-01-01

Full Text Available Abstract Recent investigations propose that cognitive characteristics of autobiographical memory significantly interact with Posttraumatic Stress Disorder (PTSD. A traumatic event becoming more or less central in a person’s identity and life story might influence development of the disorder. Studies show high correlations between event centrality (EC and PTSD. Participated in this study 68 treatment-seeking individuals referred to a specialized service for suspected trauma-related disorder: 39 matched criteria for PTSD and 29 were exposed to trauma without PTSD. Our aims were to explore how the groups differ regarding EC, depression, anxiety, posttraumatic cognitions, PTSD symptom severity, and peritraumatic dissociative experience; and how distinctively EC interacts with the measures in each group. The PTSD group had higher scores in all variables but dissociation. EC correlated with overall PTSD symptoms only in the PTSD group and with dissociation only in the no-PTSD group. Findings support a model emphasizing the role of memory processes in PTSD. People exposed to trauma who developed PTSD had the memory of the traumatic experience more intensively governing their sense of self and thus eliciting more negative cognitive reactions. As EC facilitates recollection of the traumatic event, it could also mediate a semantization process that reinforces and increases posttraumatic symptoms.

Computational challenges in modeling gene regulatory events.

Science.gov (United States)

Pataskar, Abhijeet; Tiwari, Vijay K

2016-10-19

Cellular transcriptional programs driven by genetic and epigenetic mechanisms could be better understood by integrating "omics" data and subsequently modeling the gene-regulatory events. Toward this end, computational biology should keep pace with evolving experimental procedures and data availability. This article gives an exemplified account of the current computational challenges in molecular biology.

An overview of techniques for linking high-dimensional molecular data to time-to-event endpoints by risk prediction models.

Science.gov (United States)

Binder, Harald; Porzelius, Christine; Schumacher, Martin

2011-03-01

Analysis of molecular data promises identification of biomarkers for improving prognostic models, thus potentially enabling better patient management. For identifying such biomarkers, risk prediction models can be employed that link high-dimensional molecular covariate data to a clinical endpoint. In low-dimensional settings, a multitude of statistical techniques already exists for building such models, e.g. allowing for variable selection or for quantifying the added value of a new biomarker. We provide an overview of techniques for regularized estimation that transfer this toward high-dimensional settings, with a focus on models for time-to-event endpoints. Techniques for incorporating specific covariate structure are discussed, as well as techniques for dealing with more complex endpoints. Employing gene expression data from patients with diffuse large B-cell lymphoma, some typical modeling issues from low-dimensional settings are illustrated in a high-dimensional application. First, the performance of classical stepwise regression is compared to stage-wise regression, as implemented by a component-wise likelihood-based boosting approach. A second issues arises, when artificially transforming the response into a binary variable. The effects of the resulting loss of efficiency and potential bias in a high-dimensional setting are illustrated, and a link to competing risks models is provided. Finally, we discuss conditions for adequately quantifying the added value of high-dimensional gene expression measurements, both at the stage of model fitting and when performing evaluation. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The Voltage-dependent Anion Channel 1 Mediates Amyloid β Toxicity and Represents a Potential Target for Alzheimer Disease Therapy.

Science.gov (United States)

Smilansky, Angela; Dangoor, Liron; Nakdimon, Itay; Ben-Hail, Danya; Mizrachi, Dario; Shoshan-Barmatz, Varda

2015-12-25

The voltage-dependent anion channel 1 (VDAC1), found in the mitochondrial outer membrane, forms the main interface between mitochondrial and cellular metabolisms, mediates the passage of a variety of molecules across the mitochondrial outer membrane, and is central to mitochondria-mediated apoptosis. VDAC1 is overexpressed in post-mortem brains of Alzheimer disease (AD) patients. The development and progress of AD are associated with mitochondrial dysfunction resulting from the cytotoxic effects of accumulated amyloid β (Aβ). In this study we demonstrate the involvement of VDAC1 and a VDAC1 N-terminal peptide (VDAC1-N-Ter) in Aβ cell penetration and cell death induction. Aβ directly interacted with VDAC1 and VDAC1-N-Ter, as monitored by VDAC1 channel conductance, surface plasmon resonance, and microscale thermophoresis. Preincubated Aβ interacted with bilayer-reconstituted VDAC1 and increased its conductance ∼ 2-fold. Incubation of cells with Aβ resulted in mitochondria-mediated apoptotic cell death. However, the presence of non-cell-penetrating VDAC1-N-Ter peptide prevented Aβ cellular entry and Aβ-induced mitochondria-mediated apoptosis. Likewise, silencing VDAC1 expression by specific siRNA prevented Aβ entry into the cytosol as well as Aβ-induced toxicity. Finally, the mode of Aβ-mediated action involves detachment of mitochondria-bound hexokinase, induction of VDAC1 oligomerization, and cytochrome c release, a sequence of events leading to apoptosis. As such, we suggest that Aβ-mediated toxicity involves mitochondrial and plasma membrane VDAC1, leading to mitochondrial dysfunction and apoptosis induction. The VDAC1-N-Ter peptide targeting Aβ cytotoxicity is thus a potential new therapeutic strategy for AD treatment. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Remembering the past and imagining the future: common and distinct neural substrates during event construction and elaboration

OpenAIRE

Addis, Donna Rose; Wong, Alana T.; Schacter, Daniel L.

2006-01-01

People can consciously re-experience past events and pre-experience possible future events. This fMRI study examined the neural regions mediating the construction and elaboration of past and future events. Participants were cued with a noun for 20 seconds and instructed to construct a past or future event within a specified time period (week, year, 5–20 years). Once participants had the event in mind, they made a button press and for the remainder of the 20 seconds elaborated on the event. Im...

Shear Stress Induces Phenotypic Modulation of Vascular Smooth Muscle Cells via AMPK/mTOR/ULK1-Mediated Autophagy.

Science.gov (United States)

Sun, Liqian; Zhao, Manman; Liu, Aihua; Lv, Ming; Zhang, Jingbo; Li, Youxiang; Yang, Xinjian; Wu, Zhongxue

2018-03-01

Phenotypic modulation of vascular smooth muscle cells (VSMCs) is involved in the pathophysiological processes of the intracranial aneurysms (IAs). Although shear stress has been implicated in the proliferation, migration, and phenotypic conversion of VSMCs, the molecular mechanisms underlying these events are currently unknown. In this study, we investigated whether shear stress(SS)-induced VSMC phenotypic modulation was mediated by autophagy involved in adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/Unc-51-like kinase 1 (ULK1) pathway. The results show that shear stress could inhibit the expression of key VSMC contractile genes and induce pro-inflammatory/matrix-remodeling genes levels, contributing to VSMCs phenotypic switching from a contractile to a synthetic phenotype. More importantly, Shear stress also markedly increased the levels of the autophagy marker microtubule-associated protein light chain 3-II (LC3II), Beclin-1, and p62 degradation. The autophagy inhibitor 3-methyladenine (3-MA) significantly blocked shear-induced phenotypic modulation of VSMCs. To further explore the molecular mechanism involved in shear-induced autophagy, we found that shear stress could activate AMPK/mTOR/ULK1 signaling pathway in VSMCs. Compound C, a pharmacological inhibitor of AMPK, significantly reduced the levels of p-AMPK and p-ULK, enhanced p-mTOR level, and finally decreased LC3II and Beclin-1 level, which suggested that activated AMPK/mTOR/ULK1 signaling was related to shear-mediated autophagy. These results indicate that shear stress promotes VSMC phenotypic modulation through the induction of autophagy involved in activating the AMPK/mTOR/ULK1 pathway.

Mediation Analysis with Multiple Mediators.

Science.gov (United States)

VanderWeele, T J; Vansteelandt, S

2014-01-01

Recent advances in the causal inference literature on mediation have extended traditional approaches to direct and indirect effects to settings that allow for interactions and non-linearities. In this paper, these approaches from causal inference are further extended to settings in which multiple mediators may be of interest. Two analytic approaches, one based on regression and one based on weighting are proposed to estimate the effect mediated through multiple mediators and the effects through other pathways. The approaches proposed here accommodate exposure-mediator interactions and, to a certain extent, mediator-mediator interactions as well. The methods handle binary or continuous mediators and binary, continuous or count outcomes. When the mediators affect one another, the strategy of trying to assess direct and indirect effects one mediator at a time will in general fail; the approach given in this paper can still be used. A characterization is moreover given as to when the sum of the mediated effects for multiple mediators considered separately will be equal to the mediated effect of all of the mediators considered jointly. The approach proposed in this paper is robust to unmeasured common causes of two or more mediators.

WeChat Addiction Suppresses the Impact of Stressful Life Events on Life Satisfaction.

Science.gov (United States)

Li, Bi; Wu, Yan; Jiang, Shengyi; Zhai, Huizhen

2018-03-01

The current study examined the influences of stressful life events and WeChat addiction on life satisfaction, and investigated the mediating role of WeChat addiction on the relationship between the two research variables. A total of 463 undergraduates completed self-reported scales for stressful life events, WeChat addiction, and life satisfaction. Structural equation modeling was used to analyze the questionnaire data. The results showed the suppressing effect of WeChat addiction on the negative impact of stressful life events on life satisfaction. Stressful life events affect life satisfaction both directly and indirectly. Stressful life events are positively associated with WeChat addiction, which exerts positive impact on life satisfaction. The contributions of the findings are discussed.

Male-mediated developmental toxicity

Directory of Open Access Journals (Sweden)

Diana Anderson

2014-02-01

Full Text Available Male-mediated developmental toxicity has been of concern for many years. The public became aware of male-mediated developmental toxicity in the early 1990s when it was reported that men working at Sellafield might be causing leukemia in their children. Human and animal studies have contributed to our current understanding of male-mediated effects. Animal studies in the 1980s and 1990s suggested that genetic damage after radiation and chemical exposure might be transmitted to offspring. With the increasing understanding that there is histone retention and modification, protamine incorporation into the chromatin and DNA methylation in mature sperm and that spermatozoal RNA transcripts can play important roles in the epigenetic state of sperm, heritable studies began to be viewed differently. Recent reports using molecular approaches have demonstrated that DNA damage can be transmitted to babies from smoking fathers, and expanded simple tandem repeats minisatellite mutations were found in the germline of fathers who were exposed to radiation from the Chernobyl nuclear power plant disaster. In epidemiological studies, it is possible to clarify whether damage is transmitted to the sons after exposure of the fathers. Paternally transmitted damage to the offspring is now recognized as a complex issue with genetic as well as epigenetic components.

Proteomic Analysis of the Mediator Complex Interactome in Saccharomyces cerevisiae.

Science.gov (United States)

Uthe, Henriette; Vanselow, Jens T; Schlosser, Andreas

2017-02-27

Here we present the most comprehensive analysis of the yeast Mediator complex interactome to date. Particularly gentle cell lysis and co-immunopurification conditions allowed us to preserve even transient protein-protein interactions and to comprehensively probe the molecular environment of the Mediator complex in the cell. Metabolic 15 N-labeling thereby enabled stringent discrimination between bona fide interaction partners and nonspecifically captured proteins. Our data indicates a functional role for Mediator beyond transcription initiation. We identified a large number of Mediator-interacting proteins and protein complexes, such as RNA polymerase II, general transcription factors, a large number of transcriptional activators, the SAGA complex, chromatin remodeling complexes, histone chaperones, highly acetylated histones, as well as proteins playing a role in co-transcriptional processes, such as splicing, mRNA decapping and mRNA decay. Moreover, our data provides clear evidence, that the Mediator complex interacts not only with RNA polymerase II, but also with RNA polymerases I and III, and indicates a functional role of the Mediator complex in rRNA processing and ribosome biogenesis.

Single-cell force spectroscopy of pili-mediated adhesion

Science.gov (United States)

Sullan, Ruby May A.; Beaussart, Audrey; Tripathi, Prachi; Derclaye, Sylvie; El-Kirat-Chatel, Sofiane; Li, James K.; Schneider, Yves-Jacques; Vanderleyden, Jos; Lebeer, Sarah; Dufrêne, Yves F.

2013-12-01

Although bacterial pili are known to mediate cell adhesion to a variety of substrates, the molecular interactions behind this process are poorly understood. We report the direct measurement of the forces guiding pili-mediated adhesion, focusing on the medically important probiotic bacterium Lactobacillus rhamnosus GG (LGG). Using non-invasive single-cell force spectroscopy (SCFS), we quantify the adhesion forces between individual bacteria and biotic (mucin, intestinal cells) or abiotic (hydrophobic monolayers) surfaces. On hydrophobic surfaces, bacterial pili strengthen adhesion through remarkable nanospring properties, which - presumably - enable the bacteria to resist high shear forces under physiological conditions. On mucin, nanosprings are more frequent and adhesion forces larger, reflecting the influence of specific pili-mucin bonds. Interestingly, these mechanical responses are no longer observed on human intestinal Caco-2 cells. Rather, force curves exhibit constant force plateaus with extended ruptures reflecting the extraction of membrane nanotethers. These single-cell analyses provide novel insights into the molecular mechanisms by which piliated bacteria colonize surfaces (nanosprings, nanotethers), and offer exciting avenues in nanomedicine for understanding and controlling the adhesion of microbial cells (probiotics, pathogens).

HLA DNA sequence variation among human populations: molecular signatures of demographic and selective events.

Directory of Open Access Journals (Sweden)

Stéphane Buhler

2011-02-01

Full Text Available Molecular differences between HLA alleles vary up to 57 nucleotides within the peptide binding coding region of human Major Histocompatibility Complex (MHC genes, but it is still unclear whether this variation results from a stochastic process or from selective constraints related to functional differences among HLA molecules. Although HLA alleles are generally treated as equidistant molecular units in population genetic studies, DNA sequence diversity among populations is also crucial to interpret the observed HLA polymorphism. In this study, we used a large dataset of 2,062 DNA sequences defined for the different HLA alleles to analyze nucleotide diversity of seven HLA genes in 23,500 individuals of about 200 populations spread worldwide. We first analyzed the HLA molecular structure and diversity of these populations in relation to geographic variation and we further investigated possible departures from selective neutrality through Tajima's tests and mismatch distributions. All results were compared to those obtained by classical approaches applied to HLA allele frequencies.Our study shows that the global patterns of HLA nucleotide diversity among populations are significantly correlated to geography, although in some specific cases the molecular information reveals unexpected genetic relationships. At all loci except HLA-DPB1, populations have accumulated a high proportion of very divergent alleles, suggesting an advantage of heterozygotes expressing molecularly distant HLA molecules (asymmetric overdominant selection model. However, both different intensities of selection and unequal levels of gene conversion may explain the heterogeneous mismatch distributions observed among the loci. Also, distinctive patterns of sequence divergence observed at the HLA-DPB1 locus suggest current neutrality but old selective pressures on this gene. We conclude that HLA DNA sequences advantageously complement HLA allele frequencies as a source of data used

Molecular simulations in electrochemistry : Electron and proton transfer reactions mediated by flavins in different molecular environments

NARCIS (Netherlands)

Kılıç, M.

2014-01-01

The aim of this thesis is to address specific questions about the role of solvent reorganization on electron transfer in different environments and about the calculation of acidity constant, as well. Particularly, we focus on molecular simulation of flavin in water and different protein (BLUF and

Introduction to Molecular Dynamics and Accelerated Molecular Dynamics

International Nuclear Information System (INIS)

Perez, Danny

2012-01-01

We first introduce classical molecular dynamics (MD) simulations. We discuss their main constituents - the interatomic potentials, the boundary conditions, and the integrators - and the discuss the various ensembles that can be sampled. We discuss the strengths and weaknesses of MD, specifically in terms of time and length-scales. We then move on to discuss accelerated MD (AMD) methods, techniques that were designed to circumvent the timescale limitations of MD for rare event systems. The different methods are introduced and examples of use given.

Transformation of Botrytis cinerea by direct hyphal blasting or by wound-mediated transformation of sclerotia

Directory of Open Access Journals (Sweden)

Ish - Shalom Shahar

2011-12-01

Full Text Available Abstract Background Botrytis cinerea is a haploid necrotrophic ascomycete which is responsible for 'grey mold' disease in more than 200 plant species. Broad molecular research has been conducted on this pathogen in recent years, resulting in the sequencing of two strains, which has generated a wealth of information toward developing additional tools for molecular transcriptome, proteome and secretome investigations. Nonetheless, transformation protocols have remained a significant bottleneck for this pathogen, hindering functional analysis research in many labs. Results In this study, we tested three different transformation methods for B. cinerea: electroporation, air-pressure-mediated and sclerotium-mediated transformation. We demonstrate successful transformation with three different DNA constructs using both air-pressure- and sclerotium-mediated transformation. Conclusions These transformation methods, which are fast, simple and reproducible, can expedite functional gene analysis of B. cinerea.

Monitoring intracellular oxidative events using dynamic spectral unmixing microscopy

Science.gov (United States)

There is increasing interest in using live-cell imaging to monitor not just individual intracellular endpoints, but to investigate the interplay between multiple molecular events as they unfold in real time within the cell. A major impediment to simultaneous acquisition of multip...

The Impact of Negative Life Events on Attempted Suicide in Rural China.

Science.gov (United States)

Liu, Yanzheng; Zhang, Jie

2018-03-01

This study aims to explore the impact of negative life events (NLEs) on attempted suicide in a Chinese cultural setting. The sample comprised 791 suicide attempters and an equal number of controls matched on age, sex, and location from selected rural counties in China. Conditional logistic regression model was used to examine the association between NLEs and suicide risk. The impact of NLEs on attempted suicide was further examined using regression-based method to explore its mediation effect. The types of NLEs that were most likely to precede a suicide attempt in rural sample included the events in marriage/love, family/home, and friend/relationship. Rural women were more likely to experience more interpersonal conflicts than rural men. Approximately 75.6% of suicide attempters had experienced at least one NLE, and NLEs were strongly associated with attempted suicide. Total effect (0.676), direct effect (0.501), and the total indirect effect (0.301) of NLEs on suicide attempts were significantly mediated by hopelessness and depression. NLEs play a crucial role in predicting suicidal attempt in rural China, and they are mediated by depression and hopelessness.

Molecular confirmation of Bacillus Calmette Guerin vaccine related adverse events among Saudi Arabian children.

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Sahal Al-Hajoj

Full Text Available Bacillus Calmette Guerin (BCG is the only available vaccine for tuberculosis (TB. Low grade complications in healthy recipients and disseminated vaccine associated complications among immuno-suppressed individuals were noticed globally after administration. Recently a series of clinically suspected BCG associated suppurative and non-suppurative lymphadenitis cases were reported from different regions of Saudi Arabia. However a molecular confirmative analysis was lacking to prove these claims.During 2009-2010, 42 Mycobacterium bovis BCG suspected clinical isolates from children diagnosed with suppurative lymphadenitis from different provinces of the country were collected and subjected to 24 loci based MIRU-VNTR typing, spoligotyping and first line anti-TB drugs susceptibility testing.Of the total 42 cases, 41 (97.6% were Saudi nationals and particularly male (64.3%. Majority of the cases were aged below 6 months (83.3% with a median of age 4 months. All the enrolled subjects showed left axillary mass which suppurated in a median of 4 months after vaccination. Among the study subjects, 1 (2.4% case was reactive to HIV antigen and 2 (4.8% case had severe combined immunodeficiency. Genotyping results showed that, 41 (97.6% isolates were identical to the vaccine strain Danish 1331 and one to Tokyo 172-1. Phylogenetic analysis revealed all the Danish 1331 isolates in a single cluster.Elevated proportion of suppurative lymphadenitis caused by M. bovis BCG reported in the country recently is majorly related to the vaccine strain Danish 1331. However lack of nationwide data on real magnitude of BCG related adverse events warrants population centric, long term future studies.

Use of electroporation for high-molecular-weight DNA-mediated gene transfer.

Science.gov (United States)

Jastreboff, M M; Ito, E; Bertino, J R; Narayanan, R

1987-08-01

Electroporation was used to introduce high-molecular-weight DNA into murine hematopoietic cells and NIH3T3 cells. CCRF-CEM cells were stably transfected with SV2NEO plasmid and the genomic DNA from G-418-resistant clones (greater than 65 kb) was introduced into mouse bone marrow and NIH3T3 cells by electroporation. NEO sequences and expression were detected in the hematopoietic tissues of lethally irradiated mice, with 24% of individual spleen colonies expressing NEO. The frequency of genomic DNA transfer into NIH3T3 cells was 0.25 X 10(-3). Electroporation thus offers a powerful mode of gene transfer not only of cloned genes but also of high-molecular-weight DNA into cells.

The stressed eyewitness: The interaction of thematic arousal and post-event stress in memory for central and peripheral event information

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Gerald eEchterhoff

2012-08-01

Full Text Available Both arousal during the encoding of stimuli and subsequent stress can affect memory, often by increasing memory for important or central information. We explored whether event-based (thematic arousal and post-event stress interact to selectively enhance eyewitnesses’ memory for the central aspects of an observed incident. Specifically, we argue that memory for stimuli should be enhanced when (a the stimuli are encoded under arousal (vs. non-arousal, and (b stress is experienced soon after the encoding episode.We designed an experiment that extended previous research by manipulating arousal without changing the stimulus material, distinguishing between central and peripheral event information, and using a dynamic, life-like event instead of static pictures. After watching a video depicting a burglary under high or low thematic arousal, psychosocial stress was induced or not induced by the Trier Social Stress Test. Salivary cortisol was measured at standard intervals. Consistent with our prediction, we found a significant thematic arousal x post-event stress x centrality interaction, indicating that the recognition advantage for central event items over peripheral event items was most pronounced under both high thematic arousal and post-event stress. Because stress was induced after encoding this interaction cannot be explained by possible differences at encoding, such as narrowed attention. The centrality effect of post-event stress under high thematic arousal was statistically mediated by the cortisol increase, which suggests a key role of the stress hormone. We discuss implications of our findings for psychological and neuroscientific theories of emotional memory formation.

Bad news: The influence of news coverage and Google searches on Gardasil adverse event reporting.

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Faasse, Kate; Porsius, Jarry T; Faasse, Jonathan; Martin, Leslie R

2017-12-14

Human papilloma virus vaccines are a safe and effective tool for reducing HPV infections that can cause cervical cancer. However, uptake of these vaccines has been suboptimal, with many people holding negative beliefs and misconceptions. Such beliefs have been linked with the experience of unpleasant side effects following medical treatment, and media coverage may heighten such concerns. The present study sought to assess the influence of news coverage (number of news articles per month) on adverse event reporting in response to Gardasil vaccination in New Zealand over a 7.5-year period, and whether the influence of news coverage was mediated by internet search activity (Google search volumes). Multiple linear regression analyses and simple mediation analyses were used, controlling for year and number of vaccinations delivered. News coverage in the previous month, and Google search volumes in the same month, were significant predictors of adverse event reporting, after accounting for vaccination rates and year. Concurrent Google search volumes partially mediated the effect of prior news coverage. The results suggest that some of the adverse events reported were not related to the vaccination itself, but to news coverage and internet search volumes, which may have contributed to public concerns about potentially unpleasant or harmful outcomes. These findings have implications for the importance of psychological and social factors in adverse event reporting, and the role of the news media in disseminating health information. Copyright © 2017 Elsevier Ltd. All rights reserved.

Lignin Biodegradation with Laccase-Mediator Systems

International Nuclear Information System (INIS)

Christopher, Lew Paul; Yao, Bin; Ji, Yun

2014-01-01

Lignin has a significant and largely unrealized potential as a source for the sustainable production of fuels and bulk high-value chemicals. It can replace fossil-based oil as a renewable feedstock that would bring about socio-economic and environmental benefits in our transition to a biobased economy. The efficient utilization of lignin however requires its depolymerization to low-molecular weight phenolics and aromatics that can then serve as the building blocks for chemical syntheses of high-value products. The ability of laccase to attack and degrade lignin in conjunction with laccase mediators is currently viewed as one of the potential “breakthrough” applications for lignin valorization. Here, we review the recent progress in lignin biodegradation with laccase-mediator systems, and research needs that need to be addressed in this field.

Lignin Biodegradation with Laccase-Mediator Systems

Energy Technology Data Exchange (ETDEWEB)

Christopher, Lew Paul, E-mail: lew.christopher@sdsmt.edu [Center for Bioprocessing Research and Development, South Dakota School of Mines & Technology, Rapid City, SD (United States); Department of Civil and Environmental Engineering, South Dakota School of Mines & Technology, Rapid City, SD (United States); Yao, Bin [Center for Bioprocessing Research and Development, South Dakota School of Mines & Technology, Rapid City, SD (United States); Ji, Yun [Department of Chemical Engineering, University of North Dakota, Grand Forks, ND (United States)

2014-03-31

Lignin has a significant and largely unrealized potential as a source for the sustainable production of fuels and bulk high-value chemicals. It can replace fossil-based oil as a renewable feedstock that would bring about socio-economic and environmental benefits in our transition to a biobased economy. The efficient utilization of lignin however requires its depolymerization to low-molecular weight phenolics and aromatics that can then serve as the building blocks for chemical syntheses of high-value products. The ability of laccase to attack and degrade lignin in conjunction with laccase mediators is currently viewed as one of the potential “breakthrough” applications for lignin valorization. Here, we review the recent progress in lignin biodegradation with laccase-mediator systems, and research needs that need to be addressed in this field.

Phospho-Caveolin-1 Mediates Integrin-Regulated Membrane Domain Internalisation

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del Pozo, Miguel A.; Alderson, Nazilla B.; Grande-García, Araceli; Balasubramanian, Nagaraj; Schwartz, Martin A.; Kiosses, William B.; Anderson, Richard G.W.

2005-01-01

Growth of normal cells is anchorage-dependent because signalling through multiple pathways including Erk, PI 3-kinase and Rac requires integrin-mediated cell adhesion 1. Components of these pathways localize to low density, cholesterol-rich domains in the plasma membrane named “lipid rafts” 2,3 or “cholesterol enriched membrane microdomains” (CEMM) 4. We previously reported that integrin-mediated adhesion regulates CEMM trafficking such that cell detachment from the extracellular matrix (ECM) triggers CEMM internalisation and clearance from the plasma membrane 5. We now report that this internalisation is mediated by dynamin-2 and caveolin-1. Internalisation requires phosphorylation of caveolin-1 on tyrosine 14. A shift in localisation of phospho-caveolin-1 from focal adhesions to caveolae induces CEMM internalisation upon cell detachment, which mediates inhibition of Erk, PI 3-kinase and Rac. These data define a novel molecular mechanism for growth and tumour suppression by caveolin-1. PMID:16113676

Development and evaluation of a computerbased instrument supporting event analysis in NPP. Final report

International Nuclear Information System (INIS)

Szameitat, S.

2002-11-01

Information technologies (IT) in safety management are seen as opportunity to control and reduce risks. The processing of safety-critical event information, a central function of safety management, could be more efficient using computers. But organization structures are different, the processes of experience transfer are complex and the opportunities of IT are broad. To implement a support system is to question about design criteria of computer support for an event-based safety management system (eSMS). Two studies were conducted. Study 1 compares the organizational, technical and legal conditions for Safety Management in the German Nuclear Industry and the Norwegian Offshore Industry. It could identify design criteria, which independent from the operator influence the eSMS. Study 2 compares the eSMS of different nuclear power plants analyzing the organization structures and processes. Those internal and external criteria have a significant influence on a efficient design of a system support for eSMS. The third study makes the options and impact of computer support on experience transfer in eSMS as subject of discussion. For this purpose a simulation environment has been created. Groups investigated typical event scenarios from a nuclear power plant for contributing factors. The communication medium has been manipulated (face-to-face versus computer-mediated). Results of 15 groups indicate, that the collection of event information was promoted by computer-mediated communication. This is the foundation of the identification of contributing factors. The depth of analysis has not been influenced. Computer mediation hampers the learning of facts. IT can support safety management effectively. (orig.) [de

Light mediators in dark matter direct detections

International Nuclear Information System (INIS)

Li, Tai; Miao, Sen; Zhou, Yu-Feng

2015-01-01

In an extended effective operator framework, we investigate in detail the effects of light mediators on the event spectra of dark matter (DM)-nucleus scatterings. The presence of light mediators changes the interpretation of the current experimental data, especially the determination of DM particle mass. We show by analytic and numerical illustrations that in general for all the operators relevant to spin-independent scatterings, the DM particle mass allowed by a given set of experimental data increases significantly when the mediator particle becomes lighter. For instance, in the case of CDMS-II-Si experiment, the allowed DM particle mass can reach ∼50 (100) GeV at 68% (90%) confidence level, which is much larger than ∼10 GeV in the case with contact interactions. The increase of DM particle mass saturates when the mediator mass is below O(10) MeV. The upper limits from other experiments such as SuperCDMS, CDMSlite, CDEX, XENON10/100, LUX, PandaX etc. all tend to be weaker toward high DM mass regions. In a combined analysis, we show that the presence of light mediators can partially relax the tension in the current results of CDMS-II-Si, SuperCDMS and LUX

Genetics of immune-mediated disorders : from genome-wide association to molecular mechanism

NARCIS (Netherlands)

Kumar, Vinod; Wijmenga, Cisca; Xavier, Ramnik J.

2014-01-01

Genetic association studies have identified not only hundreds of susceptibility loci to immune-mediated diseases but also pinpointed causal amino-acid variants of HLA genes that contribute to many autoimmune reactions. Majority of non-HLA genetic variants are located within non-coding regulatory

EpiGeNet: A Graph Database of Interdependencies Between Genetic and Epigenetic Events in Colorectal Cancer.

Science.gov (United States)

Balaur, Irina; Saqi, Mansoor; Barat, Ana; Lysenko, Artem; Mazein, Alexander; Rawlings, Christopher J; Ruskin, Heather J; Auffray, Charles

2017-10-01

The development of colorectal cancer (CRC)-the third most common cancer type-has been associated with deregulations of cellular mechanisms stimulated by both genetic and epigenetic events. StatEpigen is a manually curated and annotated database, containing information on interdependencies between genetic and epigenetic signals, and specialized currently for CRC research. Although StatEpigen provides a well-developed graphical user interface for information retrieval, advanced queries involving associations between multiple concepts can benefit from more detailed graph representation of the integrated data. This can be achieved by using a graph database (NoSQL) approach. Data were extracted from StatEpigen and imported to our newly developed EpiGeNet, a graph database for storage and querying of conditional relationships between molecular (genetic and epigenetic) events observed at different stages of colorectal oncogenesis. We illustrate the enhanced capability of EpiGeNet for exploration of different queries related to colorectal tumor progression; specifically, we demonstrate the query process for (i) stage-specific molecular events, (ii) most frequently observed genetic and epigenetic interdependencies in colon adenoma, and (iii) paths connecting key genes reported in CRC and associated events. The EpiGeNet framework offers improved capability for management and visualization of data on molecular events specific to CRC initiation and progression.

The impact of students with left-behind experiences on childhood: The relationship between negative life events and depression among college students in China.

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Han, Li; Zhao, Sheng-Yu; Pan, Xuan-Ying; Liao, Chuan-Jing

2018-02-01

The number of left-behind children in rural China has increased dramatically over the last decade. It is reported that about 21.88% of child population with an estimated number of 61 million are left-behind children whose parents leave them to work in cities. We conducted a cross-sectional study to explore the impacts of left-behind experience (LBE) on college students' depression and other influencing factors. This study discusses the mediation effect of self-esteem together with psychological resilience on college students with depression and negative life events of left-behind. The study also discusses the regulation effect of LBE. A total of 788 college students were selected from three universities in Sichuan and Chongqing (367 with LBEs, 421 without LBEs). Adolescent Self-Rating Life Events Check List (ASLEC), Self-Esteem Scale (SES), Resilience Scale of Chinese Adolescent (RSCA) and Self-Rating Depression Scale (SDS) were used to measure the negative life events, self-esteem, psychological resilience and depression, respectively. Bootstrap program was used to test the mediation effect, and multiple-group analysis was used to examine the regulation effect for LBE. Scores of ASLEC for the college students with LBEs were higher than those without LBEs (8.59 ± 3.57) vs (7.06 ± 3.38), p ASLEC and SDS were positively correlated with the college students with LBEs ( r = .21 to .29, p < .01), while the scores of RSCA and SES were negatively correlated ( r = -.30 to -.59, p < .01). The mediation effect of college students' self-esteem and psychological resilience between negative life events and depression was significant (mediating effect = .08, .13, .07; p < .01). Thus, the college students' self-esteem and psychological resilience on negative life events had strong mediation effect on depression. The test of Bootstrap showed that the mediation effect of self-esteem and psychological resilience was significant (95% confidence

Metabolic and Molecular Events Occurring during Chromoplast Biogenesis

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Wanping Bian

2011-01-01

Full Text Available Chromoplasts are nonphotosynthetic plastids that accumulate carotenoids. They derive from other plastid forms, mostly chloroplasts. The biochemical events responsible for the interconversion of one plastid form into another are poorly documented. However, thanks to transcriptomics and proteomics approaches, novel information is now available. Data of proteomic and biochemical analysis revealed the importance of lipid metabolism and carotenoids biosynthetic activities. The loss of photosynthetic activity was associated with the absence of the chlorophyll biosynthesis branch and the presence of proteins involved in chlorophyll degradation. Surprisingly, the entire set of Calvin cycle and of the oxidative pentose phosphate pathway persisted after the transition from chloroplast to chromoplast. The role of plastoglobules in the formation and organisation of carotenoid-containing structures and that of the Or gene in the control of chromoplastogenesis are reviewed. Finally, using transcriptomic data, an overview is given the expression pattern of a number of genes encoding plastid-located proteins during tomato fruit ripening.

Heat Shock Proteins in Tendinopathy: Novel Molecular Regulators

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Neal L. Millar

2012-01-01

Full Text Available Tendon disorders—tendinopathies—are the primary reason for musculoskeletal consultation in primary care and account for up to 30% of rheumatological consultations. Whilst the molecular pathophysiology of tendinopathy remains difficult to interpret the disease process involving repetitive stress, and cellular load provides important mechanistic insight into the area of heat shock proteins which spans many disease processes in the autoimmune community. Heat shock proteins, also called damage-associated molecular patterns (DAMPs, are rapidly released following nonprogrammed cell death, are key effectors of the innate immune system, and critically restore homeostasis by promoting the reconstruction of the effected tissue. Our investigations have highlighted a key role for HSPs in tendion disease which may ultimately affect tissue rescue mechanisms in tendon pathology. This paper aims to provide an overview of the biology of heat shock proteins in soft tissue and how these mediators may be important regulators of inflammatory mediators and matrix regulation in tendinopathy.

Trajectories of late-life change in God-mediated control.

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Hayward, R David; Krause, Neal

2013-01-01

To track within-individual change during late life in the sense of personal control and God-mediated control (the belief that one can work collaboratively with God to achieve one's goals and exercise control over life events) and to evaluate the hypothesis that this element of religion is related to declining personal control. A longitudinal survey representative of older White and Black adults in the United States tracked changes in personal and God-mediated control in four waves over the course of 7 years. Growth curve analysis found that the pattern of change differed by race. White adults had less sense of God-mediated control at younger ages, which increased among those who were highly religious but decreased among those who were less religious. Black adults had higher God-mediated control, which increased over time among those with low personal control. These results indicate that God-mediated control generally increases during older adulthood, but that its relationships with personal control and religious commitment are complex and differ between Black and White adults.

Mood as a mediator of the link between child sexual abuse and psychosis.

Science.gov (United States)

Marwaha, S; Bebbington, P

2015-04-01

The significance of affective changes in psychosis is increasingly acknowledged, as is the role of early traumatic events. In a previous paper, using data from the English Adult Psychiatric Morbidity Survey 2007 (APMS2007), strong associations between child sexual abuse (CSA) and psychosis were demonstrated, with some evidence of mediation by affect. In the current paper, we subjected the same dataset to formal tests of mediation. For CSA involving sexual intercourse, 38.5% of the link was mediated, 30.0% by depression and 8.5% by anxiety. For all forms of contact abuse, 38.2% was mediated, 29.1% by depression and 9.1% by anxiety.

Molecular imaging of cancer using PET and SPECT

DEFF Research Database (Denmark)

Kjaer, Andreas

2006-01-01

for molecular imaging of cancer. Especially the possibility of a quick transfer of methods developed in animals to patients (translational research) is an important strength. This article will briefly discuss the newest applications and their importance and perspective in relation to the shift in paradigm......Molecular imaging allows for the study of molecular and cellular events in the living intact organism. The nuclear medicine methodologies of positron emission tomography (PET) and single photon emission computer tomography (SPECT) posses several advantages, which make them particularly suited...

Simplified Real-Time Multiplex Detection of Loop-Mediated Isothermal Amplification Using Novel Mediator Displacement Probes with Universal Reporters.

Science.gov (United States)

Becherer, Lisa; Bakheit, Mohammed; Frischmann, Sieghard; Stinco, Silvina; Borst, Nadine; Zengerle, Roland; von Stetten, Felix

2018-04-03

A variety of real-time detection techniques for loop-mediated isothermal amplification (LAMP) based on the change in fluorescence intensity during DNA amplification enable simultaneous detection of multiple targets. However, these techniques depend on fluorogenic probes containing target-specific sequences. That complicates the adaption to different targets leading to time-consuming assay optimization. Here, we present the first universal real-time detection technique for multiplex LAMP. The novel approach allows simple assay design and is easy to implement for various targets. The innovation features a mediator displacement probe and a universal reporter. During amplification of target DNA the mediator is displaced from the mediator displacement probe. Then it hybridizes to the reporter generating a fluorescence signal. The novel mediator displacement (MD) detection was validated against state-of-the-art molecular beacon (MB) detection by means of a HIV-1 RT-LAMP: MD surpassed MB detection by accelerated probe design (MD: 10 min, MB: 3-4 h), shorter times to positive (MD 4.1 ± 0.1 min shorter than MB, n = 36), improved signal-to-noise fluorescence ratio (MD: 5.9 ± 0.4, MB: 2.7 ± 0.4; n = 15), and showed equally good or better analytical performance parameters. The usability of one universal mediator-reporter set in different multiplex assays was successfully demonstrated for a biplex RT-LAMP of HIV-1 and HTLV-1 and a biplex LAMP of Haemophilus ducreyi and Treponema pallidum, both showing good correlation between target concentration and time to positive. Due to its simple implementation it is suggested to extend the use of the universal mediator-reporter sets to the detection of various other diagnostic panels.

A simple and rapid molecular method for Leptospira species identification

NARCIS (Netherlands)

Ahmed, Ahmed; Anthony, Richard M.; Hartskeerl, Rudy A.

2010-01-01

Serological and DNA-based classification systems only have little correlation. Currently serological and molecular methods for characterizing Leptospira are complex and costly restricting their world-wide distribution and use. Ligation mediated amplification combined with microarray analysis

Revisiting Mediation in the Social and Behavioral Sciences

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Aurelio José Figueredo

2013-11-01

Full Text Available The process of mediation is of critical importance to the social and behavioral sciences and to evolutionary social psychology in particular. As with the concept of evolutionary adaptation, however, one can argue that causal mediation is in need of explicit theoretical justification and empirical support. Mainstream evolutionary social psychology proposes, for example, that organisms are “adaptation executers”, and not “fitness maximizers”. The execution of adaptations is triggered by fitness-relevant ecological contingencies at both ultimate and proximate levels of analysis. This logic is essentially equivalent to what methodologists refer to as the process of mediation; the adaptations to be executed (or not, depending upon the prevailing environmental circumstances causally mediate the effects of the ecological contingencies upon the fitness outcomes. Thus, the process of mediation can be generally conceptualized as a causal chain of events leading to a given outcome or set of outcomes. If a predictor variable operates through an intervening variable to affect a criterion variable, then mediation is said to exist. Nevertheless, it does not appear that some psychologists (particularly evolutionary-social psychologists are sufficiently well-versed in the fundamental logic and quantitative methodology of establishing causal mediation to support such claims. In the current paper, we set out to review the ways researchers support their use of mediation statements and also propose critical considerations on this front. We start with more conventional methods for testing mediation, discuss variants of the conventional approach, discuss the limitations of such methods as we see them, and end with our preferred mediation approach. DOI: 10.2458/azu_jmmss.v4i1.17761

Emerging functions of multi-protein complex Mediator with special emphasis on plants.

Science.gov (United States)

Malik, Naveen; Agarwal, Pinky; Tyagi, Akhilesh

2017-10-01

Mediator is a multi-subunit protein complex which is involved in transcriptional regulation in yeast and other eukaryotes. As a co-activator, it connects information from transcriptional activators/repressors to transcriptional machinery including RNA polymerase II and general transcription factors. It is not only involved in transcription initiation but also has important roles to play in transcription elongation and termination. Functional attributes of different Mediator subunits have been largely defined in yeast and mammalian systems earlier, while such studies in plants have gained momentum recently. Mediator regulates various processes related to plant development and is also involved in biotic and abiotic stress response. Thus, plant Mediator, like yeast and mammalian Mediator complex, is indispensable for plant growth and survival. Interaction of its multiple subunits with other regulatory proteins and their ectopic expression or knockdown in model plant like Arabidopsis and certain crop plants are paving the way to biochemical analysis and unravel molecular mechanisms of action of Mediator in plants.

[Ru(bpy){sub 3}]{sup 2+}-mediated photoelectrochemical detection of bisphenol A on a molecularly imprinted polypyrrole modified SnO{sub 2} electrode

Energy Technology Data Exchange (ETDEWEB)

Zhang, Bintian [State Key Laboratory of Structures, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, 350002 (China); Lu, Lili; Huang, Feng [Key Laboratory of Optoelectronic Materials Chemistry and Physics, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, 350002 (China); Lin, Zhang, E-mail: zlin@fjirsm.ac.cn [State Key Laboratory of Structures, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, 350002 (China)

2015-08-05

A ruthenium-mediated photoelectrochemical sensor was developed for the detection of BPA, using molecularly imprinted polymers (MIPs) as the recognition element, a tin oxide (SnO{sub 2}) nanoparticle-modified ITO as the electrode, and a blue 473-nm LED as the excitation light source. Photoelectrochemical oxidation of BPA on SnO{sub 2} electrode was achieved by [Ru(bpy){sub 3}]{sup 2+} under the irradiation of light. It was found that BPA was oxidized by Ru{sup 3+} species produced in the photoelectrochemical reaction, resulting in the regeneration of Ru{sup 2+} and the concomitant photocurrent enhancement. MIPs film was prepared by electropolymerization of pyrrole on SnO{sub 2} electrode using BPA as the template. Surface morphology and properties of the as-prepared electrode were characterized by SEM, electrochemical impedance spectroscopy, and photocurrent measurement. In the presence of BPA, an enhanced photocurrent was observed, which was dependent on the amount of BPA captured on the electrode. A detection limit of 1.2 nM was obtained under the optimized conditions, with a linear range of 2–500 nM. Selectivity of the sensor was demonstrated by measuring five BPA analogs. To verify its practicality, this sensor was applied to analyze BPA spiked tap water and river water. With advantages of high sensitivity and selectivity, low-cost instrument, and facile sensor preparation procedure, this sensor is potentially suitable for the rapid monitoring of BPA in real environmental samples. Moreover, the configuration of this sensor is universal and can be extended to organic molecules that can be photoelectrochemically oxidized by Ru{sup 3+}. - Highlights: • [Ru(bpy){sub 3}]{sup 2+}-mediated photoelectrochemical sensor was developed for BPA detection. • Molecularly imprinted polypyrrole was modified on a SnO{sub 2} electrode as the recognition element. • The measurement was realized using a visible light source. • This sensor was highly sensitive and

Agrobacterium-Mediated Transformation of Leaf Base Segments.

Science.gov (United States)

Gasparis, Sebastian

2017-01-01

Agrobacterium-mediated transformation has become a routine method of genetic engineering of cereals, gradually replacing the biolistic protocols. Simple integration patterns of transgenic loci, decent transformation efficiency, and technical simplicity are the main advantages offered by this method. Here we present a detailed protocol for the production of transgenic oat plants by Agrobacterium-mediated transformation of leaf base segments. The use of leaf explants as target tissues for transformation and in vitro regeneration of transgenic plants may be a good alternative for genotypes which are not susceptible to regeneration from immature or mature embryos. We also describe the biochemical and molecular analysis procedures of the transgenic plants including a GUS histochemical assay, and Southern blot, both of which are optimized for application in oat.

The costly burden of an inauthentic self: insecure self-esteem predisposes to emotional exhaustion by increasing reactivity to negative events.

Science.gov (United States)

Alessandri, Guido; Perinelli, Enrico; De Longis, Evelina; Rosa, Valentina; Theodorou, Annalisa; Borgogni, Laura

2017-11-01

A long research tradition has investigated the impact of stress on university students by assuming that individuals have a limited reservoir of resources, and that negative events and circumstances progressively drain resources thereby producing exhaustion. A recent research tradition, instead, has focused on the detrimental consequences of discrepant levels of implicit (ISE) and explicit (ESE) self-esteem on the development of stress-related symptoms. The present research attempted to merge the aforementioned approaches, with the aim of explaining significant predictors of stress. Within the framework of a Longitudinal Structural Equation Model, we followed a moderated-mediated approach. A sample of university students (N = 209; 66% females) completed a questionnaire battery including measures of ISE, ESE, perceptions of negative events, and emotional exhaustion. Participants were assessed once a week for eight consecutive weeks. ISE significantly moderated the relationship between ESE and negative events; in turn, the latter significantly predicted emotional exhaustion. Monte Carlo method for assessing mediation showed that negative events significantly mediated the relationship between incongruent self-esteem and emotional exhaustion. The detrimental role of incongruent self-esteem has been corroborated. Practical implications and suggestions for future research dealing with stress in a university setting were provided.

The incremental value of brachial flow-mediated dilation measurements in risk stratification for incident cardiovascular events: a systematic review.

Science.gov (United States)

Peters, Sanne A E; den Ruijter, Hester M; Bots, Michiel L

2012-06-01

Abstract Adequate risk assessment for cardiovascular disease (CVD) is essential as a guide to initiate drug treatment. Current methods based on traditional risk factors could be improved considerably. Although brachial flow-mediated dilation (FMD) predicts subsequent cardiovascular events, its predictive value on top of traditional risk factors is unknown. We performed a systematic review to evaluate the incremental predictive value of FMD on top of traditional risk factors in asymptomatic individuals. Using PubMed and reference tracking, three studies were identified that reported on the incremental value of FMD using change in the area under the curve (AUC). Two large cohort studies found no improvement in AUC when FMD was added to traditional risk prediction models, whereas one small case-control study found an improvement. One study used the net reclassification improvement (NRI) to assess whether FMD measurement leads to correct risk stratification in risk categories. Although this study did not find an improvement in AUC, the NRI was statistically significant. Based on the reclassification results of this study, FMD measurement might be helpful in risk prediction. Evidence supporting the use of FMD measurement in clinical practice for risk stratification for CVD on top of traditional risk factors is limited, and future studies are needed.

A Cultural Psychological Analysis of Collective Memory as Mediated Action: Constructions of Indian History

Directory of Open Access Journals (Sweden)

Sahana Mukherjee

2018-01-01

Full Text Available The present research applies a cultural psychological perspective on collective memory as mediated action to examine how constructions of a national past serve as tools that both reflect and shape national identity concerns. We employ a situation-sampling method to investigate collective memory in a series of studies concerning intergroup relations in the Indian context. In Study 1, participants (N = 55 generated three historical events that they considered important/relevant for Indian history. In Study 2, participants (N = 95 rated the importance and relevance of these events in a within-participant design. Illuminating the psychological constitution of cultural reality, frequency of recall (Study 1 and ratings of importance/relevance (Study 2 were greater for nation-glorifying events celebrating ingroup triumph than for typically silenced, critical events acknowledging ingroup wrongdoing. Moreover, these patterns were stronger among participants who scored higher in national identification. In Studies 3 (N = 65 and 4 (N = 160, we exposed participants to different categories of events in a between-participants design. Illuminating the cultural constitution of psychological experience, participants exposed to typically silenced, critical events reported lower national identification and greater perception of injustice against marginalized groups than did participants exposed to nation-glorifying events. Together, results illuminate a conception of collective memory as mediated action. Producers invest memory products with an identity-interested charge that directs subsequent intergroup relations toward identity-consistent ends.

Molecular diagnostics for human leptospirosis.

Science.gov (United States)

Waggoner, Jesse J; Pinsky, Benjamin A

2016-10-01

The definitive diagnosis of leptospirosis, which results from infection with spirochetes of the genus Leptospira, currently relies on the use of culture, serological testing (microscopic agglutination testing), and molecular detection. The purpose of this review is to describe new molecular diagnostics for Leptospira and discuss advancements in the use of available methods. Efforts have been focused on improving the clinical sensitivity of Leptospira detection using molecular methods. In this review, we describe a reoptimized pathogenic species-specific real-time PCR (targeting lipL32) that has demonstrated improved sensitivity, findings by two groups that real-time reverse-transcription PCR assays targeting the 16S rrs gene can improve detection, and two new loop-mediated amplification techniques. Quantitation of leptospiremia, detection in different specimen types, and the complementary roles played by molecular detection and microscopic agglutination testing will be discussed. Finally, a protocol for Leptospira strain subtyping using variable number tandem repeat targets and high-resolution melting will be described. Molecular diagnostics have an established role for the diagnosis of leptospirosis and provide an actionable diagnosis in the acute setting. The use of real-time reverse-transcription PCR for testing serum/plasma and cerebrospinal fluid, when available, may improve the detection of Leptospira without decreasing clinical specificity.

MECHANISMS IN ENDOCRINOLOGY: Nutrition as a mediator of oxidative stress in metabolic and reproductive disorders in women.

Science.gov (United States)

Diamanti-Kandarakis, Evanthia; Papalou, Olga; Kandaraki, Eleni A; Kassi, Georgia

2017-02-01

Nutrition can generate oxidative stress and trigger a cascade of molecular events that can disrupt oxidative and hormonal balance. Nutrient ingestion promotes a major inflammatory and oxidative response at the cellular level in the postprandial state, altering the metabolic state of tissues. A domino of unfavorable metabolic changes is orchestrated in the main metabolic organs, including adipose tissue, skeletal muscle, liver and pancreas, where subclinical inflammation, endothelial dysfunction, mitochondrial deregulation and impaired insulin response and secretion take place. Simultaneously, in reproductive tissues, nutrition-induced oxidative stress can potentially violate delicate oxidative balance that is mandatory to secure normal reproductive function. Taken all the above into account, nutrition and its accompanying postprandial oxidative stress, in the unique context of female hormonal background, can potentially compromise normal metabolic and reproductive functions in women and may act as an active mediator of various metabolic and reproductive disorders. © 2017 European Society of Endocrinology.

I-mediated signaling events by Lyn kinase C-terminal tyrosine phosphorylation

Czech Academy of Sciences Publication Activity Database

Tolar, Pavel; Dráberová, Lubica; Tolarová, Helena; Dráber, Petr

2004-01-01

Roč. 34, č. 4 (2004), s. 1136-1145 ISSN 0014-2980 R&D Projects: GA MŠk LN00A026; GA ČR GA204/00/0204; GA ČR GA310/00/0205; GA ČR GA204/03/0594; GA ČR GA301/03/0596; GA AV ČR IAA5052005; GA AV ČR IAA7052006; GA AV ČR IAA5052310 Institutional research plan: CEZ:AV0Z5052915 Keywords : mast cell * Fc receptor * signal transduction Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.005, year: 2004

Two conserved modules of Schizosaccharomyces pombe Mediator regulate distinct cellular pathways

DEFF Research Database (Denmark)

Linder, Tomas; Rasmussen, Nina; Samuelsen, Camilla O

2008-01-01

Mediator is an evolutionary conserved coregulator complex required for transcription of almost all RNA polymerase II-dependent genes. The Schizosaccharomyces pombe Mediator consists of two dissociable components-a core complex organized into a head and middle domain as well as the Cdk8 regulatory...... subcomplex. In this work we describe a functional characterization of the S. pombe Mediator. We report the identification of the S. pombe Med20 head subunit and the isolation of ts alleles of the core head subunit encoding med17+. Biochemical analysis of med8(ts), med17(ts), Deltamed18, Deltamed20...... and Deltamed27 alleles revealed a stepwise head domain molecular architecture. Phenotypical analysis of Cdk8 and head module alleles including expression profiling classified the Mediator mutant alleles into one of two groups. Cdk8 module mutants flocculate due to overexpression of adhesive cell...

TLR-mediated albuminuria needs TNFα-mediated cooperativity between TLRs present in hematopoietic tissues and CD80 present on non-hematopoietic tissues in mice

Directory of Open Access Journals (Sweden)

Nidhi Jain

2016-06-01

Full Text Available Transient albuminuria induced by pathogen-associated molecular patterns (PAMPs in mice through engagement of Toll-like receptors (TLRs is widely studied as a partial model for some forms of human nephrotic syndrome (NS. In addition to TLRs, CD80 has been shown to be essential for PAMP-mediated albuminuria. However, the mechanistic relationships between TLRs, CD80 and albuminuria remain unclear. Here, we show that albuminuria and CD80-uria induced in mice by many TLR ligands are dependent on the expression of TLRs and their downstream signalling intermediate MyD88 exclusively in hematopoietic cells and, conversely, on CD80 expression exclusively in non-hematopoietic cells. TNFα is crucial for TLR-mediated albuminuria and CD80-uria, and induces CD80 expression in cultured renal podocytes. IL-10 from hematopoietic cells ameliorates TNFα production, albuminuria and CD80-uria but does not prevent TNFα-mediated induction of podocyte CD80 expression. Chitohexaose, a small molecule originally of parasite origin, mediates TLR4-dependent anti-inflammatory responses, and blocks TLR-mediated albuminuria and CD80-uria through IL-10. Thus, TNFα is a prominent mediator of renal CD80 induction and resultant albuminuria in this model, and small molecules modulating TLR-mediated inflammatory activation might have contributory or adjunct therapeutic potential in some contexts of NS development.

Molecular photoionization studies of nucleobases and correlated systems

Energy Technology Data Exchange (ETDEWEB)

Poliakoff, Erwin D. [Louisiana State Univ., Baton Rouge, LA (United States)

2015-03-11

We proposed molecular photoionization studies in order to probe correlated events in fundamental scattering phenomena. In particular, we suggested that joint theoretical-experimental studies would provide a window into the microscopic aspects that are of central importance in AMO and chemical physics generally, and would generate useful data for wide array of important DOE topics, such as ultrafast dynamics, high harmonic generation, and probes of nonadiabatic processes. The unifying theme is that correlations between electron scattering dynamics and molecular geometry highlight inherently molecular aspects of the photoelectron behavior.

Inferring phylogenetic trees from the knowledge of rare evolutionary events.

Science.gov (United States)

Hellmuth, Marc; Hernandez-Rosales, Maribel; Long, Yangjing; Stadler, Peter F

2018-06-01

Rare events have played an increasing role in molecular phylogenetics as potentially homoplasy-poor characters. In this contribution we analyze the phylogenetic information content from a combinatorial point of view by considering the binary relation on the set of taxa defined by the existence of a single event separating two taxa. We show that the graph-representation of this relation must be a tree. Moreover, we characterize completely the relationship between the tree of such relations and the underlying phylogenetic tree. With directed operations such as tandem-duplication-random-loss events in mind we demonstrate how non-symmetric information constrains the position of the root in the partially reconstructed phylogeny.

Search for gauge-mediated supersymmetry in events with at least one photon and missing transverse momentum in pp collisions at √{ s } = 13TeV

Science.gov (United States)

Sirunyan, A. M.; Tumasyan, A.; Adam, W.; Ambrogi, F.; Asilar, E.; Bergauer, T.; Brandstetter, J.; Brondolin, E.; Dragicevic, M.; Erö, J.; Flechl, M.; Friedl, M.; Frühwirth, R.; Ghete, V. M.; Grossmann, J.; Hrubec, J.; Jeitler, M.; König, A.; Krammer, N.; Krätschmer, I.; Liko, D.; Madlener, T.; Mikulec, I.; Pree, E.; Rad, N.; Rohringer, H.; Schieck, J.; Schöfbeck, R.; Spanring, M.; Spitzbart, D.; Waltenberger, W.; Wittmann, J.; Wulz, C.-E.; Zarucki, M.; Chekhovsky, V.; Mossolov, V.; Suarez Gonzalez, J.; De Wolf, E. A.; Di Croce, D.; Janssen, X.; Lauwers, J.; Van De Klundert, M.; Van Haevermaet, H.; Van Mechelen, P.; Van Remortel, N.; Abu Zeid, S.; Blekman, F.; D'Hondt, J.; De Bruyn, I.; De Clercq, J.; Deroover, K.; Flouris, G.; Lontkovskyi, D.; Lowette, S.; Marchesini, I.; Moortgat, S.; Moreels, L.; Python, Q.; Skovpen, K.; Tavernier, S.; Van Doninck, W.; Van Mulders, P.; Van Parijs, I.; Beghin, D.; Brun, H.; Clerbaux, B.; De Lentdecker, G.; Delannoy, H.; Dorney, B.; Fasanella, G.; Favart, L.; Goldouzian, R.; Grebenyuk, A.; Lenzi, T.; Luetic, J.; Maerschalk, T.; Marinov, A.; Seva, T.; Starling, E.; Vander Velde, C.; Vanlaer, P.; Vannerom, D.; Yonamine, R.; Zenoni, F.; Zhang, F.; Cimmino, A.; Cornelis, T.; Dobur, D.; Fagot, A.; Gul, M.; Khvastunov, I.; Poyraz, D.; Roskas, C.; Salva, S.; Tytgat, M.; Verbeke, W.; Zaganidis, N.; Bakhshiansohi, H.; Bondu, O.; Brochet, S.; Bruno, G.; Caputo, C.; Caudron, A.; David, P.; De Visscher, S.; Delaere, C.; Delcourt, M.; Francois, B.; Giammanco, A.; Komm, M.; Krintiras, G.; Lemaitre, V.; Magitteri, A.; Mertens, A.; Musich, M.; Piotrzkowski, K.; Quertenmont, L.; Saggio, A.; Vidal Marono, M.; Wertz, S.; Zobec, J.; Aldá Júnior, W. L.; Alves, F. L.; Alves, G. A.; Brito, L.; Correa Martins Junior, M.; Hensel, C.; Moraes, A.; Pol, M. E.; Rebello Teles, P.; Belchior Batista Das Chagas, E.; Carvalho, W.; Chinellato, J.; Coelho, E.; Da Costa, E. M.; Da Silveira, G. G.; De Jesus Damiao, D.; Fonseca De Souza, S.; Huertas Guativa, L. M.; Malbouisson, H.; Melo De Almeida, M.; Mora Herrera, C.; Mundim, L.; Nogima, H.; Sanchez Rosas, L. J.; Santoro, A.; Sznajder, A.; Thiel, M.; Tonelli Manganote, E. J.; Torres Da Silva De Araujo, F.; Vilela Pereira, A.; Ahuja, S.; Bernardes, C. A.; Fernandez Perez Tomei, T. R.; Gregores, E. M.; Mercadante, P. G.; Novaes, S. F.; Padula, Sandra S.; Romero Abad, D.; Ruiz Vargas, J. C.; Aleksandrov, A.; Hadjiiska, R.; Iaydjiev, P.; Misheva, M.; Rodozov, M.; Shopova, M.; Sultanov, G.; Dimitrov, A.; Litov, L.; Pavlov, B.; Petkov, P.; Fang, W.; Gao, X.; Yuan, L.; Ahmad, M.; Bian, J. G.; Chen, G. M.; Chen, H. S.; Chen, M.; Chen, Y.; Jiang, C. H.; Leggat, D.; Liao, H.; Liu, Z.; Romeo, F.; Shaheen, S. M.; Spiezia, A.; Tao, J.; Wang, C.; Wang, Z.; Yazgan, E.; Zhang, H.; Zhang, S.; Zhao, J.; Ban, Y.; Chen, G.; Li, J.; Li, Q.; Liu, S.; Mao, Y.; Qian, S. J.; Wang, D.; Xu, Z.; Wang, Y.; Avila, C.; Cabrera, A.; Chaparro Sierra, L. F.; Florez, C.; González Hernández, C. F.; Ruiz Alvarez, J. D.; Segura Delgado, M. A.; Courbon, B.; Godinovic, N.; Lelas, D.; Puljak, I.; Ribeiro Cipriano, P. M.; Sculac, T.; Antunovic, Z.; Kovac, M.; Brigljevic, V.; Ferencek, D.; Kadija, K.; Mesic, B.; Starodumov, A.; Susa, T.; Ather, M. W.; Attikis, A.; Mavromanolakis, G.; Mousa, J.; Nicolaou, C.; Ptochos, F.; Razis, P. A.; Rykaczewski, H.; Finger, M.; Finger, M.; Carrera Jarrin, E.; Ellithi Kamel, A.; Khalil, S.; Mohamed, A.; Dewanjee, R. K.; Kadastik, M.; Perrini, L.; Raidal, M.; Tiko, A.; Veelken, C.; Eerola, P.; Kirschenmann, H.; Pekkanen, J.; Voutilainen, M.; Havukainen, J.; Heikkilä, J. K.; Järvinen, T.; Karimäki, V.; Kinnunen, R.; Lampén, T.; Lassila-Perini, K.; Laurila, S.; Lehti, S.; Lindén, T.; Luukka, P.; Siikonen, H.; Tuominen, E.; Tuominiemi, J.; Tuuva, T.; Besancon, M.; Couderc, F.; Dejardin, M.; Denegri, D.; Faure, J. L.; Ferri, F.; Ganjour, S.; Ghosh, S.; Gras, P.; Hamel de Monchenault, G.; Jarry, P.; Kucher, I.; Leloup, C.; Locci, E.; Machet, M.; Malcles, J.; Negro, G.; Rander, J.; Rosowsky, A.; Sahin, M. Ö.; Titov, M.; Abdulsalam, A.; Amendola, C.; Antropov, I.; Baffioni, S.; Beaudette, F.; Busson, P.; Cadamuro, L.; Charlot, C.; Granier de Cassagnac, R.; Jo, M.; Lisniak, S.; Lobanov, A.; Martin Blanco, J.; Nguyen, M.; Ochando, C.; Ortona, G.; Paganini, P.; Pigard, P.; Salerno, R.; Sauvan, J. B.; Sirois, Y.; Stahl Leiton, A. G.; Strebler, T.; Yilmaz, Y.; Zabi, A.; Zghiche, A.; Agram, J.-L.; Andrea, J.; Bloch, D.; Brom, J.-M.; Buttignol, M.; Chabert, E. C.; Chanon, N.; Collard, C.; Conte, E.; Coubez, X.; Fontaine, J.-C.; Gelé, D.; Goerlach, U.; Jansová, M.; Le Bihan, A.-C.; Tonon, N.; Van Hove, P.; Gadrat, S.; Beauceron, S.; Bernet, C.; Boudoul, G.; Chierici, R.; Contardo, D.; Depasse, P.; El Mamouni, H.; Fay, J.; Finco, L.; Gascon, S.; Gouzevitch, M.; Grenier, G.; Ille, B.; Lagarde, F.; Laktineh, I. B.; Lethuillier, M.; Mirabito, L.; Pequegnot, A. L.; Perries, S.; Popov, A.; Sordini, V.; Vander Donckt, M.; Viret, S.; Khvedelidze, A.; Tsamalaidze, Z.; Autermann, C.; Feld, L.; Kiesel, M. K.; Klein, K.; Lipinski, M.; Preuten, M.; Schomakers, C.; Schulz, J.; Teroerde, M.; Zhukov, V.; Albert, A.; Dietz-Laursonn, E.; Duchardt, D.; Endres, M.; Erdmann, M.; Erdweg, S.; Esch, T.; Fischer, R.; Güth, A.; Hamer, M.; Hebbeker, T.; Heidemann, C.; Hoepfner, K.; Knutzen, S.; Merschmeyer, M.; Meyer, A.; Millet, P.; Mukherjee, S.; Pook, T.; Radziej, M.; Reithler, H.; Rieger, M.; Scheuch, F.; Teyssier, D.; Thüer, S.; Flügge, G.; Kargoll, B.; Kress, T.; Künsken, A.; Müller, T.; Nehrkorn, A.; Nowack, A.; Pistone, C.; Pooth, O.; Stahl, A.; Aldaya Martin, M.; Arndt, T.; Asawatangtrakuldee, C.; Beernaert, K.; Behnke, O.; Behrens, U.; Bermúdez Martínez, A.; Bin Anuar, A. A.; Borras, K.; Botta, V.; Campbell, A.; Connor, P.; Contreras-Campana, C.; Costanza, F.; Diez Pardos, C.; Eckerlin, G.; Eckstein, D.; Eichhorn, T.; Eren, E.; Gallo, E.; Garay Garcia, J.; Geiser, A.; Grados Luyando, J. M.; Grohsjean, A.; Gunnellini, P.; Guthoff, M.; Harb, A.; Hauk, J.; Hempel, M.; Jung, H.; Kasemann, M.; Keaveney, J.; Kleinwort, C.; Korol, I.; Krücker, D.; Lange, W.; Lelek, A.; Lenz, T.; Leonard, J.; Lipka, K.; Lohmann, W.; Mankel, R.; Melzer-Pellmann, I.-A.; Meyer, A. B.; Mittag, G.; Mnich, J.; Mussgiller, A.; Ntomari, E.; Pitzl, D.; Raspereza, A.; Savitskyi, M.; Saxena, P.; Shevchenko, R.; Spannagel, S.; Stefaniuk, N.; Van Onsem, G. P.; Walsh, R.; Wen, Y.; Wichmann, K.; Wissing, C.; Zenaiev, O.; Aggleton, R.; Bein, S.; Blobel, V.; Centis Vignali, M.; Dreyer, T.; Garutti, E.; Gonzalez, D.; Haller, J.; Hinzmann, A.; Hoffmann, M.; Karavdina, A.; Klanner, R.; Kogler, R.; Kovalchuk, N.; Kurz, S.; Lapsien, T.; Marconi, D.; Meyer, M.; Niedziela, M.; Nowatschin, D.; Pantaleo, F.; Peiffer, T.; Perieanu, A.; Scharf, C.; Schleper, P.; Schmidt, A.; Schumann, S.; Schwandt, J.; Sonneveld, J.; Stadie, H.; Steinbrück, G.; Stober, F. M.; Stöver, M.; Tholen, H.; Troendle, D.; Usai, E.; Vanhoefer, A.; Vormwald, B.; Akbiyik, M.; Barth, C.; Baselga, M.; Baur, S.; Butz, E.; Caspart, R.; Chwalek, T.; Colombo, F.; De Boer, W.; Dierlamm, A.; Faltermann, N.; Freund, B.; Friese, R.; Giffels, M.; Harrendorf, M. A.; Hartmann, F.; Heindl, S. M.; Husemann, U.; Kassel, F.; Kudella, S.; Mildner, H.; Mozer, M. U.; Müller, Th.; Plagge, M.; Quast, G.; Rabbertz, K.; Schröder, M.; Shvetsov, I.; Sieber, G.; Simonis, H. J.; Ulrich, R.; Wayand, S.; Weber, M.; Weiler, T.; Williamson, S.; Wöhrmann, C.; Wolf, R.; Anagnostou, G.; Daskalakis, G.; Geralis, T.; Kyriakis, A.; Loukas, D.; Topsis-Giotis, I.; Karathanasis, G.; Kesisoglou, S.; Panagiotou, A.; Saoulidou, N.; Kousouris, K.; Evangelou, I.; Foudas, C.; Gianneios, P.; Katsoulis, P.; Kokkas, P.; Mallios, S.; Manthos, N.; Papadopoulos, I.; Paradas, E.; Strologas, J.; Triantis, F. A.; Tsitsonis, D.; Csanad, M.; Filipovic, N.; Pasztor, G.; Surányi, O.; Veres, G. I.; Bencze, G.; Hajdu, C.; Horvath, D.; Hunyadi, Á.; Sikler, F.; Veszpremi, V.; Beni, N.; Czellar, S.; Karancsi, J.; Makovec, A.; Molnar, J.; Szillasi, Z.; Bartók, M.; Raics, P.; Trocsanyi, Z. L.; Ujvari, B.; Choudhury, S.; Komaragiri, J. R.; Bahinipati, S.; Bhowmik, S.; Mal, P.; Mandal, K.; Nayak, A.; Sahoo, D. K.; Sahoo, N.; Swain, S. K.; Bansal, S.; Beri, S. B.; Bhatnagar, V.; Chawla, R.; Dhingra, N.; Kalsi, A. K.; Kaur, A.; Kaur, M.; Kaur, S.; Kumar, R.; Kumari, P.; Mehta, A.; Singh, J. B.; Walia, G.; Kumar, Ashok; Shah, Aashaq; Bhardwaj, A.; Chauhan, S.; Choudhary, B. C.; Garg, R. B.; Keshri, S.; Kumar, A.; Malhotra, S.; Naimuddin, M.; Ranjan, K.; Sharma, R.; Bhardwaj, R.; Bhattacharya, R.; Bhattacharya, S.; Bhawandeep, U.; Dey, S.; Dutt, S.; Dutta, S.; Ghosh, S.; Majumdar, N.; Modak, A.; Mondal, K.; Mukhopadhyay, S.; Nandan, S.; Purohit, A.; Roy, A.; Roy Chowdhury, S.; Sarkar, S.; Sharan, M.; Thakur, S.; Behera, P. K.; Chudasama, R.; Dutta, D.; Jha, V.; Kumar, V.; Mohanty, A. K.; Netrakanti, P. K.; Pant, L. M.; Shukla, P.; Topkar, A.; Aziz, T.; Dugad, S.; Mahakud, B.; Mitra, S.; Mohanty, G. B.; Sur, N.; Sutar, B.; Banerjee, S.; Bhattacharya, S.; Chatterjee, S.; Das, P.; Guchait, M.; Jain, Sa.; Kumar, S.; Maity, M.; Majumder, G.; Mazumdar, K.; Sarkar, T.; Wickramage, N.; Chauhan, S.; Dube, S.; Hegde, V.; Kapoor, A.; Kothekar, K.; Pandey, S.; Rane, A.; Sharma, S.; Chenarani, S.; Eskandari Tadavani, E.; Etesami, S. M.; Khakzad, M.; Mohammadi Najafabadi, M.; Naseri, M.; Paktinat Mehdiabadi, S.; Rezaei Hosseinabadi, F.; Safarzadeh, B.; Zeinali, M.; Felcini, M.; Grunewald, M.; Abbrescia, M.; Calabria, C.; Colaleo, A.; Creanza, D.; Cristella, L.; De Filippis, N.; De Palma, M.; Errico, F.; Fiore, L.; Iaselli, G.; Lezki, S.; Maggi, G.; Maggi, M.; Miniello, G.; My, S.; Nuzzo, S.; Pompili, A.; Pugliese, G.; Radogna, R.; Ranieri, A.; Selvaggi, G.; Sharma, A.; Silvestris, L.; Venditti, R.; Verwilligen, P.; Abbiendi, G.; Battilana, C.; Bonacorsi, D.; Borgonovi, L.; Braibant-Giacomelli, S.; Campanini, R.; Capiluppi, P.; Castro, A.; Cavallo, F. R.; Chhibra, S. S.; Codispoti, G.; Cuffiani, M.; Dallavalle, G. M.; Fabbri, F.; Fanfani, A.; Fasanella, D.; Giacomelli, P.; Grandi, C.; Guiducci, L.; Marcellini, S.; Masetti, G.; Montanari, A.; Navarria, F. L.; Perrotta, A.; Rossi, A. M.; Rovelli, T.; Siroli, G. P.; Tosi, N.; Albergo, S.; Costa, S.; Di Mattia, A.; Giordano, F.; Potenza, R.; Tricomi, A.; Tuve, C.; Barbagli, G.; Chatterjee, K.; Ciulli, V.; Civinini, C.; D'Alessandro, R.; Focardi, E.; Lenzi, P.; Meschini, M.; Paoletti, S.; Russo, L.; Sguazzoni, G.; Strom, D.; Viliani, L.; Benussi, L.; Bianco, S.; Fabbri, F.; Piccolo, D.; Primavera, F.; Calvelli, V.; Ferro, F.; Ravera, F.; Robutti, E.; Tosi, S.; Benaglia, A.; Beschi, A.; Brianza, L.; Brivio, F.; Ciriolo, V.; Dinardo, M. E.; Fiorendi, S.; Gennai, S.; Ghezzi, A.; Govoni, P.; Malberti, M.; Malvezzi, S.; Manzoni, R. A.; Menasce, D.; Moroni, L.; Paganoni, M.; Pauwels, K.; Pedrini, D.; Pigazzini, S.; Ragazzi, S.; Tabarelli de Fatis, T.; Buontempo, S.; Cavallo, N.; Di Guida, S.; Fabozzi, F.; Fienga, F.; Iorio, A. O. M.; Khan, W. A.; Lista, L.; Meola, S.; Paolucci, P.; Sciacca, C.; Thyssen, F.; Azzi, P.; Bacchetta, N.; Benato, L.; Bisello, D.; Boletti, A.; Carlin, R.; Carvalho Antunes De Oliveira, A.; Checchia, P.; Dall'Osso, M.; De Castro Manzano, P.; Dorigo, T.; Dosselli, U.; Gasparini, F.; Gasparini, U.; Gonella, F.; Gozzelino, A.; Lacaprara, S.; Lujan, P.; Pozzobon, N.; Ronchese, P.; Rossin, R.; Simonetto, F.; Torassa, E.; Ventura, S.; Zotto, P.; Zumerle, G.; Braghieri, A.; Magnani, A.; Montagna, P.; Ratti, S. P.; Re, V.; Ressegotti, M.; Riccardi, C.; Salvini, P.; Vai, I.; Vitulo, P.; Alunni Solestizi, L.; Biasini, M.; Bilei, G. M.; Cecchi, C.; Ciangottini, D.; Fanò, L.; Leonardi, R.; Manoni, E.; Mantovani, G.; Mariani, V.; Menichelli, M.; Rossi, A.; Santocchia, A.; Spiga, D.; Androsov, K.; Azzurri, P.; Bagliesi, G.; Boccali, T.; Borrello, L.; Castaldi, R.; Ciocci, M. A.; Dell'Orso, R.; Fedi, G.; Giannini, L.; Giassi, A.; Grippo, M. T.; Ligabue, F.; Lomtadze, T.; Manca, E.; Mandorli, G.; Messineo, A.; Palla, F.; Rizzi, A.; Savoy-Navarro, A.; Spagnolo, P.; Tenchini, R.; Tonelli, G.; Venturi, A.; Verdini, P. G.; Barone, L.; Cavallari, F.; Cipriani, M.; Daci, N.; Del Re, D.; Di Marco, E.; Diemoz, M.; Gelli, S.; Longo, E.; Margaroli, F.; Marzocchi, B.; Meridiani, P.; Organtini, G.; Paramatti, R.; Preiato, F.; Rahatlou, S.; Rovelli, C.; Santanastasio, F.; Amapane, N.; Arcidiacono, R.; Argiro, S.; Arneodo, M.; Bartosik, N.; Bellan, R.; Biino, C.; Cartiglia, N.; Cenna, F.; Costa, M.; Covarelli, R.; Degano, A.; Demaria, N.; Kiani, B.; Mariotti, C.; Maselli, S.; Migliore, E.; Monaco, V.; Monteil, E.; Monteno, M.; Obertino, M. M.; Pacher, L.; Pastrone, N.; Pelliccioni, M.; Pinna Angioni, G. L.; Romero, A.; Ruspa, M.; Sacchi, R.; Shchelina, K.; Sola, V.; Solano, A.; Staiano, A.; Traczyk, P.; Belforte, S.; Casarsa, M.; Cossutti, F.; Della Ricca, G.; Zanetti, A.; Kim, D. H.; Kim, G. N.; Kim, M. S.; Lee, J.; Lee, S.; Lee, S. W.; Moon, C. S.; Oh, Y. D.; Sekmen, S.; Son, D. C.; Yang, Y. C.; Lee, A.; Kim, H.; Moon, D. H.; Oh, G.; Brochero Cifuentes, J. A.; Goh, J.; Kim, T. J.; Cho, S.; Choi, S.; Go, Y.; Gyun, D.; Ha, S.; Hong, B.; Jo, Y.; Kim, Y.; Lee, K.; Lee, K. S.; Lee, S.; Lim, J.; Park, S. K.; Roh, Y.; Almond, J.; Kim, J.; Kim, J. S.; Lee, H.; Lee, K.; Nam, K.; Oh, S. B.; Radburn-Smith, B. C.; Seo, S. h.; Yang, U. K.; Yoo, H. D.; Yu, G. B.; Kim, H.; Kim, J. H.; Lee, J. S. H.; Park, I. C.; Choi, Y.; Hwang, C.; Lee, J.; Yu, I.; Dudenas, V.; Juodagalvis, A.; Vaitkus, J.; Ahmed, I.; Ibrahim, Z. A.; Md Ali, M. A. B.; Mohamad Idris, F.; Wan Abdullah, W. A. T.; Yusli, M. N.; Zolkapli, Z.; Reyes-Almanza, R.; Ramirez-Sanchez, G.; Duran-Osuna, M. C.; Castilla-Valdez, H.; De La Cruz-Burelo, E.; Heredia-De La Cruz, I.; Rabadan-Trejo, R. I.; Lopez-Fernandez, R.; Mejia Guisao, J.; Sanchez-Hernandez, A.; Carrillo Moreno, S.; Oropeza Barrera, C.; Vazquez Valencia, F.; Eysermans, J.; Pedraza, I.; Salazar Ibarguen, H. A.; Uribe Estrada, C.; Morelos Pineda, A.; Krofcheck, D.; Butler, P. H.; Ahmad, A.; Ahmad, M.; Hassan, Q.; Hoorani, H. R.; Saddique, A.; Shah, M. A.; Shoaib, M.; Waqas, M.; Bialkowska, H.; Bluj, M.; Boimska, B.; Frueboes, T.; Górski, M.; Kazana, M.; Nawrocki, K.; Szleper, M.; Zalewski, P.; Bunkowski, K.; Byszuk, A.; Doroba, K.; Kalinowski, A.; Konecki, M.; Krolikowski, J.; Misiura, M.; Olszewski, M.; Pyskir, A.; Walczak, M.; Bargassa, P.; Beirão Da Cruz E Silva, C.; Di Francesco, A.; Faccioli, P.; Galinhas, B.; Gallinaro, M.; Hollar, J.; Leonardo, N.; Lloret Iglesias, L.; Nemallapudi, M. V.; Seixas, J.; Strong, G.; Toldaiev, O.; Vadruccio, D.; Varela, J.; Afanasiev, S.; Alexakhin, V.; Bunin, P.; Gavrilenko, M.; Golunov, A.; Golutvin, I.; Gorbounov, N.; Karjavin, V.; Lanev, A.; Malakhov, A.; Matveev, V.; Palichik, V.; Perelygin, V.; Savina, M.; Shmatov, S.; Skatchkov, N.; Smirnov, V.; Zarubin, A.; Ivanov, Y.; Kim, V.; Kuznetsova, E.; Levchenko, P.; Murzin, V.; Oreshkin, V.; Smirnov, I.; Sosnov, D.; Sulimov, V.; Uvarov, L.; Vavilov, S.; Vorobyev, A.; Andreev, Yu.; Dermenev, A.; Gninenko, S.; Golubev, N.; Karneyeu, A.; Kirsanov, M.; Krasnikov, N.; Pashenkov, A.; Tlisov, D.; Toropin, A.; Epshteyn, V.; Gavrilov, V.; Lychkovskaya, N.; Popov, V.; Pozdnyakov, I.; Safronov, G.; Spiridonov, A.; Stepennov, A.; Toms, M.; Vlasov, E.; Zhokin, A.; Aushev, T.; Bylinkin, A.; Chadeeva, M.; Parygin, P.; Philippov, D.; Polikarpov, S.; Popova, E.; Rusinov, V.; Andreev, V.; Azarkin, M.; Dremin, I.; Kirakosyan, M.; Terkulov, A.; Baskakov, A.; Belyaev, A.; Boos, E.; Dubinin, M.; Dudko, L.; Ershov, A.; Gribushin, A.; Klyukhin, V.; Kodolova, O.; Lokhtin, I.; Miagkov, I.; Obraztsov, S.; Petrushanko, S.; Savrin, V.; Snigirev, A.; Blinov, V.; Skovpen, Y.; Shtol, D.; Azhgirey, I.; Bayshev, I.; Bitioukov, S.; Elumakhov, D.; Godizov, A.; Kachanov, V.; Kalinin, A.; Konstantinov, D.; Mandrik, P.; Petrov, V.; Ryutin, R.; Sobol, A.; Troshin, S.; Tyurin, N.; Uzunian, A.; Volkov, A.; Adzic, P.; Cirkovic, P.; Devetak, D.; Dordevic, M.; Milosevic, J.; Rekovic, V.; Alcaraz Maestre, J.; Bachiller, I.; Barrio Luna, M.; Cerrada, M.; Colino, N.; De La Cruz, B.; Delgado Peris, A.; Escalante Del Valle, A.; Fernandez Bedoya, C.; Fernández Ramos, J. P.; Flix, J.; Fouz, M. C.; Gonzalez Lopez, O.; Goy Lopez, S.; Hernandez, J. M.; Josa, M. I.; Moran, D.; Pérez-Calero Yzquierdo, A.; Puerta Pelayo, J.; Quintario Olmeda, A.; Redondo, I.; Romero, L.; Soares, M. S.; Álvarez Fernández, A.; Albajar, C.; de Trocóniz, J. F.; Missiroli, M.; Cuevas, J.; Erice, C.; Fernandez Menendez, J.; Gonzalez Caballero, I.; González Fernández, J. R.; Palencia Cortezon, E.; Sanchez Cruz, S.; Vischia, P.; Vizan Garcia, J. M.; Cabrillo, I. J.; Calderon, A.; Chazin Quero, B.; Curras, E.; Duarte Campderros, J.; Fernandez, M.; Garcia-Ferrero, J.; Gomez, G.; Lopez Virto, A.; Marco, J.; Martinez Rivero, C.; Martinez Ruiz del Arbol, P.; Matorras, F.; Piedra Gomez, J.; Rodrigo, T.; Ruiz-Jimeno, A.; Scodellaro, L.; Trevisani, N.; Vila, I.; Vilar Cortabitarte, R.; Abbaneo, D.; Akgun, B.; Auffray, E.; Baillon, P.; Ball, A. H.; Barney, D.; Bendavid, J.; Bianco, M.; Bloch, P.; Bocci, A.; Botta, C.; Camporesi, T.; Castello, R.; Cepeda, M.; Cerminara, G.; Chapon, E.; Chen, Y.; d'Enterria, D.; Dabrowski, A.; Daponte, V.; David, A.; De Gruttola, M.; De Roeck, A.; Deelen, N.; Dobson, M.; du Pree, T.; Dünser, M.; Dupont, N.; Elliott-Peisert, A.; Everaerts, P.; Fallavollita, F.; Franzoni, G.; Fulcher, J.; Funk, W.; Gigi, D.; Gilbert, A.; Gill, K.; Glege, F.; Gulhan, D.; Harris, P.; Hegeman, J.; Innocente, V.; Jafari, A.; Janot, P.; Karacheban, O.; Kieseler, J.; Knünz, V.; Kornmayer, A.; Kortelainen, M. J.; Krammer, M.; Lange, C.; Lecoq, P.; Lourenço, C.; Lucchini, M. T.; Malgeri, L.; Mannelli, M.; Martelli, A.; Meijers, F.; Merlin, J. A.; Mersi, S.; Meschi, E.; Milenovic, P.; Moortgat, F.; Mulders, M.; Neugebauer, H.; Ngadiuba, J.; Orfanelli, S.; Orsini, L.; Pape, L.; Perez, E.; Peruzzi, M.; Petrilli, A.; Petrucciani, G.; Pfeiffer, A.; Pierini, M.; Rabady, D.; Racz, A.; Reis, T.; Rolandi, G.; Rovere, M.; Sakulin, H.; Schäfer, C.; Schwick, C.; Seidel, M.; Selvaggi, M.; Sharma, A.; Silva, P.; Sphicas, P.; Stakia, A.; Steggemann, J.; Stoye, M.; Tosi, M.; Treille, D.; Triossi, A.; Tsirou, A.; Veckalns, V.; Verweij, M.; Zeuner, W. D.; Bertl, W.; Caminada, L.; Deiters, K.; Erdmann, W.; Horisberger, R.; Ingram, Q.; Kaestli, H. C.; Kotlinski, D.; Langenegger, U.; Rohe, T.; Wiederkehr, S. A.; Backhaus, M.; Bäni, L.; Berger, P.; Bianchini, L.; Casal, B.; Dissertori, G.; Dittmar, M.; Donegà, M.; Dorfer, C.; Grab, C.; Heidegger, C.; Hits, D.; Hoss, J.; Kasieczka, G.; Klijnsma, T.; Lustermann, W.; Mangano, B.; Marionneau, M.; Meinhard, M. T.; Meister, D.; Micheli, F.; Musella, P.; Nessi-Tedaldi, F.; Pandolfi, F.; Pata, J.; Pauss, F.; Perrin, G.; Perrozzi, L.; Quittnat, M.; Reichmann, M.; Sanz Becerra, D. A.; Schönenberger, M.; Shchutska, L.; Tavolaro, V. R.; Theofilatos, K.; Vesterbacka Olsson, M. L.; Wallny, R.; Zhu, D. H.; Aarrestad, T. K.; Amsler, C.; Canelli, M. F.; De Cosa, A.; Del Burgo, R.; Donato, S.; Galloni, C.; Hreus, T.; Kilminster, B.; Pinna, D.; Rauco, G.; Robmann, P.; Salerno, D.; Schweiger, K.; Seitz, C.; Takahashi, Y.; Zucchetta, A.; Candelise, V.; Chang, Y. H.; Cheng, K. y.; Doan, T. H.; Jain, Sh.; Khurana, R.; Kuo, C. M.; Lin, W.; Pozdnyakov, A.; Yu, S. S.; Kumar, Arun; Chang, P.; Chao, Y.; Chen, K. F.; Chen, P. H.; Fiori, F.; Hou, W.-S.; Hsiung, Y.; Liu, Y. F.; Lu, R.-S.; Paganis, E.; Psallidas, A.; Steen, A.; Tsai, J. f.; Asavapibhop, B.; Kovitanggoon, K.; Singh, G.; Srimanobhas, N.; Bat, A.; Boran, F.; Damarseckin, S.; Demiroglu, Z. S.; Dozen, C.; Dumanoglu, I.; Eskut, E.; Girgis, S.; Gokbulut, G.; Guler, Y.; Hos, I.; Kangal, E. E.; Kara, O.; Kiminsu, U.; Oglakci, M.; Onengut, G.; Ozdemir, K.; Ozturk, S.; Polatoz, A.; Tok, U. G.; Topakli, H.; Turkcapar, S.; Zorbakir, I. S.; Zorbilmez, C.; Bilin, B.; Karapinar, G.; Ocalan, K.; Yalvac, M.; Zeyrek, M.; Gülmez, E.; Kaya, M.; Kaya, O.; Tekten, S.; Yetkin, E. A.; Agaras, M. N.; Atay, S.; Cakir, A.; Cankocak, K.; Köseoglu, I.; Grynyov, B.; Levchuk, L.; Ball, F.; Beck, L.; Brooke, J. J.; Burns, D.; Clement, E.; Cussans, D.; Davignon, O.; Flacher, H.; Goldstein, J.; Heath, G. P.; Heath, H. F.; Kreczko, L.; Newbold, D. M.; Paramesvaran, S.; Sakuma, T.; Seif El Nasr-storey, S.; Smith, D.; Smith, V. J.; Bell, K. W.; Belyaev, A.; Brew, C.; Brown, R. M.; Calligaris, L.; Cieri, D.; Cockerill, D. J. A.; Coughlan, J. A.; Harder, K.; Harper, S.; Linacre, J.; Olaiya, E.; Petyt, D.; Shepherd-Themistocleous, C. H.; Thea, A.; Tomalin, I. R.; Williams, T.; Auzinger, G.; Bainbridge, R.; Borg, J.; Breeze, S.; Buchmuller, O.; Bundock, A.; Casasso, S.; Citron, M.; Colling, D.; Corpe, L.; Dauncey, P.; Davies, G.; De Wit, A.; Della Negra, M.; Di Maria, R.; Elwood, A.; Haddad, Y.; Hall, G.; Iles, G.; James, T.; Lane, R.; Laner, C.; Lyons, L.; Magnan, A.-M.; Malik, S.; Mastrolorenzo, L.; Matsushita, T.; Nash, J.; Nikitenko, A.; Palladino, V.; Pesaresi, M.; Raymond, D. M.; Richards, A.; Rose, A.; Scott, E.; Seez, C.; Shtipliyski, A.; Summers, S.; Tapper, A.; Uchida, K.; Vazquez Acosta, M.; Virdee, T.; Wardle, N.; Winterbottom, D.; Wright, J.; Zenz, S. C.; Cole, J. E.; Hobson, P. R.; Khan, A.; Kyberd, P.; Reid, I. D.; Teodorescu, L.; Zahid, S.; Borzou, A.; Call, K.; Dittmann, J.; Hatakeyama, K.; Liu, H.; Pastika, N.; Smith, C.; Bartek, R.; Dominguez, A.; Buccilli, A.; Cooper, S. I.; Henderson, C.; Rumerio, P.; West, C.; Arcaro, D.; Avetisyan, A.; Bose, T.; Gastler, D.; Rankin, D.; Richardson, C.; Rohlf, J.; Sulak, L.; Zou, D.; Benelli, G.; Cutts, D.; Garabedian, A.; Hadley, M.; Hakala, J.; Heintz, U.; Hogan, J. M.; Kwok, K. H. M.; Laird, E.; Landsberg, G.; Lee, J.; Mao, Z.; Narain, M.; Pazzini, J.; Piperov, S.; Sagir, S.; Syarif, R.; Yu, D.; Band, R.; Brainerd, C.; Breedon, R.; Burns, D.; Calderon De La Barca Sanchez, M.; Chertok, M.; Conway, J.; Conway, R.; Cox, P. T.; Erbacher, R.; Flores, C.; Funk, G.; Ko, W.; Lander, R.; Mclean, C.; Mulhearn, M.; Pellett, D.; Pilot, J.; Shalhout, S.; Shi, M.; Smith, J.; Stolp, D.; Tos, K.; Tripathi, M.; Wang, Z.; Bachtis, M.; Bravo, C.; Cousins, R.; Dasgupta, A.; Florent, A.; Hauser, J.; Ignatenko, M.; Mccoll, N.; Regnard, S.; Saltzberg, D.; Schnaible, C.; Valuev, V.; Bouvier, E.; Burt, K.; Clare, R.; Ellison, J.; Gary, J. W.; Ghiasi Shirazi, S. M. A.; Hanson, G.; Heilman, J.; Karapostoli, G.; Kennedy, E.; Lacroix, F.; Long, O. R.; Olmedo Negrete, M.; Paneva, M. I.; Si, W.; Wang, L.; Wei, H.; Wimpenny, S.; Yates, B. R.; Branson, J. G.; Cittolin, S.; Derdzinski, M.; Gerosa, R.; Gilbert, D.; Hashemi, B.; Holzner, A.; Klein, D.; Kole, G.; Krutelyov, V.; Letts, J.; Masciovecchio, M.; Olivito, D.; Padhi, S.; Pieri, M.; Sani, M.; Sharma, V.; Tadel, M.; Vartak, A.; Wasserbaech, S.; Wood, J.; Würthwein, F.; Yagil, A.; Zevi Della Porta, G.; Amin, N.; Bhandari, R.; Bradmiller-Feld, J.; Campagnari, C.; Dishaw, A.; Dutta, V.; Franco Sevilla, M.; Golf, F.; Gouskos, L.; Heller, R.; Incandela, J.; Ovcharova, A.; Qu, H.; Richman, J.; Stuart, D.; Suarez, I.; Yoo, J.; Anderson, D.; Bornheim, A.; Lawhorn, J. M.; Newman, H. B.; Nguyen, T.; Pena, C.; Spiropulu, M.; Vlimant, J. R.; Xie, S.; Zhang, Z.; Zhu, R. Y.; Andrews, M. B.; Ferguson, T.; Mudholkar, T.; Paulini, M.; Russ, J.; Sun, M.; Vogel, H.; Vorobiev, I.; Weinberg, M.; Cumalat, J. P.; Ford, W. T.; Jensen, F.; Johnson, A.; Krohn, M.; Leontsinis, S.; Mulholland, T.; Stenson, K.; Wagner, S. R.; Alexander, J.; Chaves, J.; Chu, J.; Dittmer, S.; Mcdermott, K.; Mirman, N.; Patterson, J. R.; Quach, D.; Rinkevicius, A.; Ryd, A.; Skinnari, L.; Soffi, L.; Tan, S. M.; Tao, Z.; Thom, J.; Tucker, J.; Wittich, P.; Zientek, M.; Abdullin, S.; Albrow, M.; Alyari, M.; Apollinari, G.; Apresyan, A.; Apyan, A.; Banerjee, S.; Bauerdick, L. A. T.; Beretvas, A.; Berryhill, J.; Bhat, P. C.; Bolla, G.; Burkett, K.; Butler, J. N.; Canepa, A.; Cerati, G. B.; Cheung, H. W. K.; Chlebana, F.; Cremonesi, M.; Duarte, J.; Elvira, V. D.; Freeman, J.; Gecse, Z.; Gottschalk, E.; Gray, L.; Green, D.; Grünendahl, S.; Gutsche, O.; Harris, R. M.; Hasegawa, S.; Hirschauer, J.; Hu, Z.; Jayatilaka, B.; Jindariani, S.; Johnson, M.; Joshi, U.; Klima, B.; Kreis, B.; Lammel, S.; Lincoln, D.; Lipton, R.; Liu, M.; Liu, T.; Lopes De Sá, R.; Lykken, J.; Maeshima, K.; Magini, N.; Marraffino, J. M.; Mason, D.; McBride, P.; Merkel, P.; Mrenna, S.; Nahn, S.; O'Dell, V.; Pedro, K.; Prokofyev, O.; Rakness, G.; Ristori, L.; Schneider, B.; Sexton-Kennedy, E.; Soha, A.; Spalding, W. J.; Spiegel, L.; Stoynev, S.; Strait, J.; Strobbe, N.; Taylor, L.; Tkaczyk, S.; Tran, N. V.; Uplegger, L.; Vaandering, E. W.; Vernieri, C.; Verzocchi, M.; Vidal, R.; Wang, M.; Weber, H. A.; Whitbeck, A.; Acosta, D.; Avery, P.; Bortignon, P.; Bourilkov, D.; Brinkerhoff, A.; Carnes, A.; Carver, M.; Curry, D.; Field, R. D.; Furic, I. K.; Gleyzer, S. V.; Joshi, B. M.; Konigsberg, J.; Korytov, A.; Kotov, K.; Ma, P.; Matchev, K.; Mei, H.; Mitselmakher, G.; Shi, K.; Sperka, D.; Terentyev, N.; Thomas, L.; Wang, J.; Wang, S.; Yelton, J.; Joshi, Y. R.; Linn, S.; Markowitz, P.; Rodriguez, J. L.; Ackert, A.; Adams, T.; Askew, A.; Hagopian, S.; Hagopian, V.; Johnson, K. F.; Kolberg, T.; Martinez, G.; Perry, T.; Prosper, H.; Saha, A.; Santra, A.; Sharma, V.; Yohay, R.; Baarmand, M. M.; Bhopatkar, V.; Colafranceschi, S.; Hohlmann, M.; Noonan, D.; Roy, T.; Yumiceva, F.; Adams, M. R.; Apanasevich, L.; Berry, D.; Betts, R. R.; Cavanaugh, R.; Chen, X.; Evdokimov, O.; Gerber, C. E.; Hangal, D. A.; Hofman, D. J.; Jung, K.; Kamin, J.; Sandoval Gonzalez, I. D.; Tonjes, M. B.; Trauger, H.; Varelas, N.; Wang, H.; Wu, Z.; Zhang, J.; Bilki, B.; Clarida, W.; Dilsiz, K.; Durgut, S.; Gandrajula, R. P.; Haytmyradov, M.; Khristenko, V.; Merlo, J.-P.; Mermerkaya, H.; Mestvirishvili, A.; Moeller, A.; Nachtman, J.; Ogul, H.; Onel, Y.; Ozok, F.; Penzo, A.; Snyder, C.; Tiras, E.; Wetzel, J.; Yi, K.; Blumenfeld, B.; Cocoros, A.; Eminizer, N.; Fehling, D.; Feng, L.; Gritsan, A. V.; Maksimovic, P.; Roskes, J.; Sarica, U.; Swartz, M.; Xiao, M.; You, C.; Al-bataineh, A.; Baringer, P.; Bean, A.; Boren, S.; Bowen, J.; Castle, J.; Khalil, S.; Kropivnitskaya, A.; Majumder, D.; Mcbrayer, W.; Murray, M.; Royon, C.; Sanders, S.; Schmitz, E.; Tapia Takaki, J. D.; Wang, Q.; Ivanov, A.; Kaadze, K.; Maravin, Y.; Mohammadi, A.; Saini, L. K.; Skhirtladze, N.; Toda, S.; Rebassoo, F.; Wright, D.; Anelli, C.; Baden, A.; Baron, O.; Belloni, A.; Eno, S. C.; Feng, Y.; Ferraioli, C.; Hadley, N. J.; Jabeen, S.; Jeng, G. Y.; Kellogg, R. G.; Kunkle, J.; Mignerey, A. C.; Ricci-Tam, F.; Shin, Y. H.; Skuja, A.; Tonwar, S. C.; Abercrombie, D.; Allen, B.; Azzolini, V.; Barbieri, R.; Baty, A.; Bi, R.; Brandt, S.; Busza, W.; Cali, I. A.; D'Alfonso, M.; Demiragli, Z.; Gomez Ceballos, G.; Goncharov, M.; Hsu, D.; Hu, M.; Iiyama, Y.; Innocenti, G. M.; Klute, M.; Kovalskyi, D.; Lee, Y.-J.; Levin, A.; Luckey, P. D.; Maier, B.; Marini, A. C.; Mcginn, C.; Mironov, C.; Narayanan, S.; Niu, X.; Paus, C.; Roland, C.; Roland, G.; Salfeld-Nebgen, J.; Stephans, G. S. F.; Tatar, K.; Velicanu, D.; Wang, J.; Wang, T. W.; Wyslouch, B.; Benvenuti, A. C.; Chatterjee, R. M.; Evans, A.; Hansen, P.; Hiltbrand, J.; Kalafut, S.; Kubota, Y.; Lesko, Z.; Mans, J.; Nourbakhsh, S.; Ruckstuhl, N.; Rusack, R.; Turkewitz, J.; Wadud, M. A.; Acosta, J. G.; Oliveros, S.; Avdeeva, E.; Bloom, K.; Claes, D. R.; Fangmeier, C.; Gonzalez Suarez, R.; Kamalieddin, R.; Kravchenko, I.; Monroy, J.; Siado, J. E.; Snow, G. R.; Stieger, B.; Dolen, J.; Godshalk, A.; Harrington, C.; Iashvili, I.; Nguyen, D.; Parker, A.; Rappoccio, S.; Roozbahani, B.; Alverson, G.; Barberis, E.; Freer, C.; Hortiangtham, A.; Massironi, A.; Morse, D. M.; Orimoto, T.; Teixeira De Lima, R.; Trocino, D.; Wamorkar, T.; Wang, B.; Wisecarver, A.; Wood, D.; Bhattacharya, S.; Charaf, O.; Hahn, K. A.; Mucia, N.; Odell, N.; Schmitt, M. H.; Sung, K.; Trovato, M.; Velasco, M.; Bucci, R.; Dev, N.; Hildreth, M.; Hurtado Anampa, K.; Jessop, C.; Karmgard, D. J.; Kellams, N.; Lannon, K.; Li, W.; Loukas, N.; Marinelli, N.; Meng, F.; Mueller, C.; Musienko, Y.; Planer, M.; Reinsvold, A.; Ruchti, R.; Siddireddy, P.; Smith, G.; Taroni, S.; Wayne, M.; Wightman, A.; Wolf, M.; Woodard, A.; Alimena, J.; Antonelli, L.; Bylsma, B.; Durkin, L. S.; Flowers, S.; Francis, B.; Hart, A.; Hill, C.; Ji, W.; Liu, B.; Luo, W.; Winer, B. L.; Wulsin, H. W.; Cooperstein, S.; Driga, O.; Elmer, P.; Hardenbrook, J.; Hebda, P.; Higginbotham, S.; Kalogeropoulos, A.; Lange, D.; Luo, J.; Marlow, D.; Mei, K.; Ojalvo, I.; Olsen, J.; Palmer, C.; Piroué, P.; Stickland, D.; Tully, C.; Malik, S.; Norberg, S.; Barker, A.; Barnes, V. E.; Das, S.; Folgueras, S.; Gutay, L.; Jha, M. K.; Jones, M.; Jung, A. W.; Khatiwada, A.; Miller, D. H.; Neumeister, N.; Peng, C. C.; Qiu, H.; Schulte, J. F.; Sun, J.; Wang, F.; Xiao, R.; Xie, W.; Cheng, T.; Parashar, N.; Stupak, J.; Chen, Z.; Ecklund, K. M.; Freed, S.; Geurts, F. J. M.; Guilbaud, M.; Kilpatrick, M.; Li, W.; Michlin, B.; Padley, B. P.; Roberts, J.; Rorie, J.; Shi, W.; Tu, Z.; Zabel, J.; Zhang, A.; Bodek, A.; de Barbaro, P.; Demina, R.; Duh, Y. t.; Ferbel, T.; Galanti, M.; Garcia-Bellido, A.; Han, J.; Hindrichs, O.; Khukhunaishvili, A.; Lo, K. H.; Tan, P.; Verzetti, M.; Ciesielski, R.; Goulianos, K.; Mesropian, C.; Agapitos, A.; Chou, J. P.; Gershtein, Y.; Gómez Espinosa, T. A.; Halkiadakis, E.; Heindl, M.; Hughes, E.; Kaplan, S.; Kunnawalkam Elayavalli, R.; Kyriacou, S.; Lath, A.; Montalvo, R.; Nash, K.; Osherson, M.; Saka, H.; Salur, S.; Schnetzer, S.; Sheffield, D.; Somalwar, S.; Stone, R.; Thomas, S.; Thomassen, P.; Walker, M.; Delannoy, A. G.; Foerster, M.; Heideman, J.; Riley, G.; Rose, K.; Spanier, S.; Thapa, K.; Bouhali, O.; Castaneda Hernandez, A.; Celik, A.; Dalchenko, M.; De Mattia, M.; Delgado, A.; Dildick, S.; Eusebi, R.; Gilmore, J.; Huang, T.; Kamon, T.; Mueller, R.; Pakhotin, Y.; Patel, R.; Perloff, A.; Perniè, L.; Rathjens, D.; Safonov, A.; Tatarinov, A.; Ulmer, K. A.; Akchurin, N.; Damgov, J.; De Guio, F.; Dudero, P. R.; Faulkner, J.; Gurpinar, E.; Kunori, S.; Lamichhane, K.; Lee, S. W.; Libeiro, T.; Mengke, T.; Muthumuni, S.; Peltola, T.; Undleeb, S.; Volobouev, I.; Wang, Z.; Greene, S.; Gurrola, A.; Janjam, R.; Johns, W.; Maguire, C.; Melo, A.; Ni, H.; Padeken, K.; Sheldon, P.; Tuo, S.; Velkovska, J.; Xu, Q.; Arenton, M. W.; Barria, P.; Cox, B.; Hirosky, R.; Joyce, M.; Ledovskoy, A.; Li, H.; Neu, C.; Sinthuprasith, T.; Wang, Y.; Wolfe, E.; Xia, F.; Harr, R.; Karchin, P. E.; Poudyal, N.; Sturdy, J.; Thapa, P.; Zaleski, S.; Brodski, M.; Buchanan, J.; Caillol, C.; Dasu, S.; Dodd, L.; Duric, S.; Gomber, B.; Grothe, M.; Herndon, M.; Hervé, A.; Hussain, U.; Klabbers, P.; Lanaro, A.; Levine, A.; Long, K.; Loveless, R.; Ruggles, T.; Savin, A.; Smith, N.; Smith, W. H.; Taylor, D.; Woods, N.; CMS Collaboration

2018-05-01

A search for gauge-mediated supersymmetry (SUSY) in final states with photons and large missing transverse momentum is presented. The data sample of pp collisions at √{ s } = 13TeV was collected with the CMS detector at the CERN LHC and corresponds to an integrated luminosity of 35.9 fb-1. Data are compared with models in which the lightest neutralino has bino- or wino-like components, resulting in decays to photons and gravitinos, where the gravitinos escape detection. The event selection is optimized for both electroweak (EWK) and strong production SUSY scenarios. The observed data are consistent with standard model predictions, and limits are set in the context of a general gauge mediation model in which gaugino masses up to 980 GeV are excluded at 95% confidence level. Gaugino masses below 780 and 950 GeV are excluded in two simplified models with EWK production of mass-degenerate charginos and neutralinos. Stringent limits are set on simplified models based on gluino and squark pair production, excluding gluino (squark) masses up to 2100 (1750) GeV depending on the assumptions made for the decay modes and intermediate particle masses. This analysis sets the highest mass limits to date in the studied EWK models, and in the considered strong production models when the mass difference between the gauginos and the squarks or gluinos is small.

AgarTrap: a simplified Agrobacterium-mediated transformation method for sporelings of the liverwort Marchantia polymorpha L.

Science.gov (United States)

Tsuboyama, Shoko; Kodama, Yutaka

2014-01-01

The liverwort Marchantia polymorpha L. is being developed as an emerging model plant, and several transformation techniques were recently reported. Examples are biolistic- and Agrobacterium-mediated transformation methods. Here, we report a simplified method for Agrobacterium-mediated transformation of sporelings, and it is termed Agar-utilized Transformation with Pouring Solutions (AgarTrap). The procedure of the AgarTrap was carried out by simply exchanging appropriate solutions in a Petri dish, and completed within a week, successfully yielding sufficient numbers of independent transformants for molecular analysis (e.g. characterization of gene/protein function) in a single experiment. The AgarTrap method will promote future molecular biological study in M. polymorpha.

Targeting cytokine/chemokine receptors: a challenge for molecular nuclear medicine.

NARCIS (Netherlands)

Signore, A.; Chianelli, M.; Bei, R.; Oyen, W.J.G.; Modesti, A.

2003-01-01

Radiolabelled cytokines and chemokines are a group of radiopharmaceuticals that, by highlighting in vivo the binding to specific high-affinity receptors expressed on selected cell populations, allow the molecular and functional characterisation of immune-mediated processes Recently, several authors

[Molecular imaging; current status and future prospects in USA].

Science.gov (United States)

Kobayashi, Hisataka

2007-02-01

The goal of this review is to introduce the definition, current status, and future prospects of the molecular imaging, which has recently been a hot topic in medicine and the biological science in USA. In vivo imaging methods to visualize the molecular events and functions in organs or animals/humans are overviewed and discussed especially in combinations of imaging modalities (machines) and contrast agents(chemicals) used in the molecular imaging. Next, the close relationship between the molecular imaging and the nanotechnology, an important part of nanomedicine, is stressed from the aspect of united multidisciplinary sciences such as physics, chemistry, biology, and medicine.

Psychological mediators related to clinical outcome in cognitive behavioural therapy for coronary heart disease: A sub-analysis from the SUPRIM trial.

Science.gov (United States)

Norlund, Fredrika; Olsson, Erik Mg; Pingel, Ronnie; Held, Claes; Svärdsudd, Kurt; Gulliksson, Mats; Burell, Gunilla

2017-06-01

Background The Secondary Prevention in Uppsala Primary Healthcare Project (SUPRIM) was a randomized controlled trial of a group-based cognitive behavioural therapy stress management programme for patients with coronary heart disease. The project was successful in reducing the risk of fatal or non-fatal first recurrent cardiovascular events. The aim of this study was to analyse the effect of cognitive behavioural therapy on self-rated stress, somatic anxiety, vital exhaustion and depression and to study the associations of these factors with the reduction in cardiovascular events. Methods A total of 362 patients were randomly assigned to intervention or usual care groups. The psychological outcomes were assessed five times during 24 months and analysed using linear mixed models. The mediating roles of the outcomes were analysed using joint modelling of the longitudinal and time to event data. Results The intervention had a positive effect on somatic anxiety ( p < 0.05), reflecting a beneficial development over time compared with the controls. Stress, vital exhaustion and depression did not differ between the groups over time. Mediator analysis suggested that somatic anxiety may have mediated the effect of treatment on cardiovascular events. Conclusions The intervention had a small positive effect on somatic anxiety, but did not affect stress, vital exhaustion or depression in patients with coronary heart disease. Somatic anxiety was associated with an increased risk of cardiovascular events and might act as a partial mediator in the treatment effect on cardiovascular events. However, the mechanisms between the intervention and the protective cardiovascular outcome remain to be identified.

Neighborhood Disadvantage, Stressful Life Events, and Adjustment among Mexican American Early Adolescents

Science.gov (United States)

Roosa, Mark W.; Burrell, Ginger L.; Nair, Rajni L.; Coxe, Stefany; Tein, Jenn-Yun; Knight, George P.

2010-01-01

This study examined a stress process model in which stressful life events and association with delinquent peers mediated the relationship of neighborhood disadvantage to Mexican American early adolescents' mental health. The authors also proposed that child gender, child generation, and neighborhood informal social control would moderate the…

Performing Re-mediation in Graphical Cyberspace: Mediating Agency, Body and Identity in Virtual Interactional Practices

DEFF Research Database (Denmark)

McIlvenny, Paul

and spectacular multi-media event raises many questions. How do we conceive of the recent developments in media technology and social computing that are impacting on what we have traditionally called 'the mass media'? How is interaction and talk mediated and adapted to new media genres? And how do participants......Promoted as the first academic conference to be held completely in graphical cyberspace, Avatars 98 took place in November 1998. The virtual conference site was built and inhabited using software that supports multi-party presence over the Internet in a simulated, navigable environment. During...... frameworks through the multimedia representations that were 'cast' and 'served' across the Internet. If such a ceremonial event had been broadcast through the institutional medium of television, broadcast talk would have been produced for an eavesdropping 'mass audience'. Instead, the digitally re...

Activation of Proinflammatory Responses in Cells of the Airway Mucosa by Particulate Matter: Oxidant- and Non-Oxidant-Mediated Triggering Mechanisms

Directory of Open Access Journals (Sweden)

Johan Øvrevik

2015-07-01

Full Text Available Inflammation is considered to play a central role in a diverse range of disease outcomes associated with exposure to various types of inhalable particulates. The initial mechanisms through which particles trigger cellular responses leading to activation of inflammatory responses are crucial to clarify in order to understand what physico-chemical characteristics govern the inflammogenic activity of particulate matter and why some particles are more harmful than others. Recent research suggests that molecular triggering mechanisms involved in activation of proinflammatory genes and onset of inflammatory reactions by particles or soluble particle components can be categorized into direct formation of reactive oxygen species (ROS with subsequent oxidative stress, interaction with the lipid layer of cellular membranes, activation of cell surface receptors, and direct interactions with intracellular molecular targets. The present review focuses on the immediate effects and responses in cells exposed to particles and central down-stream signaling mechanisms involved in regulation of proinflammatory genes, with special emphasis on the role of oxidant and non-oxidant triggering mechanisms. Importantly, ROS act as a central second-messenger in a variety of signaling pathways. Even non-oxidant mediated triggering mechanisms are therefore also likely to activate downstream redox-regulated events.

Molecular basis of cadmium toxicity

Energy Technology Data Exchange (ETDEWEB)

Nath, R; Prasad, R; Palinal, V K; Chopra, R K

1984-01-01

Cadmium has been shown to manifest its toxicity in human and animals by mainly accumulating in almost all of the organs. The kidney is the main target organ where it is concentrated mainly in the cortex. Environmental exposure of cadmium occurs via food, occupational industries, terrestrial and aquatic ecosystem. At molecular level, cadmium interferes with the utilization of essential metals e.g. Ca, Zn, Se, Cr and Fe and deficiencies of these essential metals including protein and vitamins, exaggerate cadmium toxicity, due to its increased absorption through the gut and greater retention in different organs as metallothionein (Cd-Mt). Cadmium transport, across the intestinal and renal brush border membrane vesicles, is carrier mediated and it competes with zinc and calcium. It has been postulated that cadmium shares the same transport system. Cadmium inhibits protein synthesis, carbohydrate metabolism and drug metabolizing enzymes in liver of animals. Chronic environmental exposure of cadmium produces hypertension in experimental animals. Functional changes accompanying cadmium nephropathy include low molecular weight proteinuria which is of tubular origin associated with excess excretion of proteins such as beta 2 microglobulin, metallothionein and high molecular weight proteinuria of glomerular origin (excretion of proteins such as albumin IgG, transferrin etc.). Recent data has shown that metallothionein is more nephrotoxic to animals. Cadmium is also toxic to central nervous system. It causes an alterations of cellular functions in lungs. Cadmium affects both humoral and cell mediated immune response in animals. Cadmium induces metallothionein in liver and kidney but under certain nutritional deficiencies like protein-calorie malnutrition and calcium deficiency, enhanced induction and greater accumulation of cadmium metallothionein has been observed.

Phosphorescence Control Mediated by Molecular Rotation and Aurophilic Interactions in Amphidynamic Crystals of 1,4-Bis[tri-(p-fluorophenyl)phosphane-gold(I)-ethynyl]benzene.

Science.gov (United States)

Jin, Mingoo; Chung, Tim S; Seki, Tomohiro; Ito, Hajime; Garcia-Garibay, Miguel A

2017-12-13

Here we present a structural design aimed at the control of phosphorescence emission as the result of changes in molecular rotation in a crystalline material. The proposed strategy includes the use of aurophilic interactions, both as a crystal engineering tool and as a sensitive emission probe, and the use of a dumbbell-shaped architecture intended to create a low packing density region that permits the rotation of a central phenylene. Molecular rotor 1, with a central 1,4-diethynylphenylene rotator linked to two gold(I) triphenylphosphane complexes, was prepared and its structure confirmed by single-crystal X-ray diffraction, which revealed chains mediated by dimeric aurophilic interactions. We showed that green-emitting crystals exhibit reversible luminescent color changes between 298 and 193 K, which correlate with changes in rotational motion determined by variable-temperature solid-state 2 H NMR spin-echo experiments. Fast two-fold rotation with a frequency of ca. 4.00 MHz (τ = 0.25 μs) at 298 K becomes essentially static below 193 K as emission steadily changes from green to yellow in this temperature interval. A correlation between phosphorescence lifetimes and rotational frequencies is interpreted in terms of conformational changes arising from rotation of the central phenylene, which causes a change in electronic communication between the gold-linked rotors, as suggested by DFT studies. These results and control experiments with analogue 2, possessing a hindered tetramethylphenylene that is unable to rotate in the crystal, suggest that the molecular rotation can be a useful tool for controlling luminescence in the crystalline state.

Massive expansion of marine archaea during a mid-Cretaceous oceanic anoxic event

DEFF Research Database (Denmark)

Kuypers, M.M.M.; Blokker, P.; Erbacher, J.

2001-01-01

molecular fossils indicates that these archaea were living chemoautotrophically. Their massive expansion may have been a response to the strong stratification of the ocean during this anoxic event. Indeed, the sedimentary record of archaeal membrane lipids suggests that this anoxic event marks a time......Biogeochemical and stable carbon isotopic analysis of black-shale sequences deposited during an Albian oceanic anoxic event (∼112 million years ago) indicate that up to 80 weight percent of sedimentary organic carbon is derived from marine, nonthermophilic archaea. The carbon-13 content of archaeal...

Southern-by-Sequencing: A Robust Screening Approach for Molecular Characterization of Genetically Modified Crops

Directory of Open Access Journals (Sweden)

Gina M. Zastrow-Hayes

2015-03-01

Full Text Available Molecular characterization of events is an integral part of the advancement process during genetically modified (GM crop product development. Assessment of these events is traditionally accomplished by polymerase chain reaction (PCR and Southern blot analyses. Southern blot analysis can be time-consuming and comparatively expensive and does not provide sequence-level detail. We have developed a sequence-based application, Southern-by-Sequencing (SbS, utilizing sequence capture coupled with next-generation sequencing (NGS technology to replace Southern blot analysis for event selection in a high-throughput molecular characterization environment. SbS is accomplished by hybridizing indexed and pooled whole-genome DNA libraries from GM plants to biotinylated probes designed to target the sequence of transformation plasmids used to generate events within the pool. This sequence capture process enriches the sequence data obtained for targeted regions of interest (transformation plasmid DNA. Taking advantage of the DNA adjacent to the targeted bases (referred to as next-to-target sequence that accompanies the targeted transformation plasmid sequence, the data analysis detects plasmid-to-genome and plasmid-to-plasmid junctions introduced during insertion into the plant genome. Analysis of these junction sequences provides sequence-level information as to the following: the number of insertion loci including detection of unlinked, independently segregating, small DNA fragments; copy number; rearrangements, truncations, or deletions of the intended insertion DNA; and the presence of transformation plasmid backbone sequences. This molecular evidence from SbS analysis is used to characterize and select GM plants meeting optimal molecular characterization criteria. SbS technology has proven to be a robust event screening tool for use in a high-throughput molecular characterization environment.

Searches for hadronically decaying Dark Matter mediator particles at ATLAS

CERN Document Server

Nindhito, Herjuno Rah

2016-01-01

Searches for hadronic resonances of the Dark Matter (DM) particles in the sub-TeV mass re- gion remain as a viable target at ATLAS. However, due to the bandwidth limitation, the events that available for performing an analysis were statistically limited. Reducing the event size by recording a fraction of the full event information overcomes this limitation. An analysis that is performed on those events is called Trigger-Level Analysis(TLA). This poster highlights the TLA strategy used to search for low-mass dijet resonances. No significant excesses are found in a region between 450 and 950 GeV. As an addition, limits are set on a simplified leptophobic Z’ model of DM mediator with axial coupling to quarks and DM particles as well as on Gaussian resonances.

Energetic particle pressure in intense ESP events

Science.gov (United States)

Lario, D.; Decker, R. B.; Roelof, E. C.; Viñas, A.-F.

2015-09-01

We study three intense energetic storm particle (ESP) events in which the energetic particle pressure PEP exceeded both the pressure of the background thermal plasma Pth and the pressure of the magnetic field PB. The region upstream of the interplanetary shocks associated with these events was characterized by a depression of the magnetic field strength coincident with the increase of the energetic particle intensities and, when plasma measurements were available, a depleted solar wind density. The general feature of cosmic-ray mediated shocks such as the deceleration of the upstream background medium into which the shock propagates is generally observed. However, for those shocks where plasma parameters are available, pressure balance is not maintained either upstream of or across the shock, which may result from the fact that PEP is not included in the calculation of the shock parameters.

Towards 'selection rules' in the radiation chemistry of molecular materials

International Nuclear Information System (INIS)

Feldman, V.I.; Inst. of Synthetic Polymetric Materials, Moscow; Moscow State Univ.

2002-01-01

Complete text of publication follows. There are a lot of experimental evidences suggesting that the primary radiation-induced events in organic solids and polymers are highly selective and sensitive to conformation, molecular packing, matrix environment, etc. Nevertheless, specific 'selection rules' in the radiation chemistry of molecules in solids are still not established. This contribution presents a review of our recent studies of the radiation damage in organic molecules in low-temperature matrices and polymers aimed at elucidation of basic physical factors controlling selectivity of the primary chemical events. The following aspects will be analyzed: 1. 'Fine tuning' effects in positive hole trapping in rigid systems containing molecular 'traps' with close ionization energy. 2. Selective chemical bond weakening in ionized molecules: experimental and theoretical results. 3. Matrix-assisted and matrix-controlled chemical reactions of ionized molecules in solid media (including the effect of 'matrix-catalysis'). 4. Effect of excess energy on the fate of ionized molecules in solid matrices: the role of intramolecular and intermolecular relaxation. Finally, the problem of experimental and theoretical simulation of the distribution of the radiation-induced events in complex molecular systems and polymers will be addressed

Diverse exocytic pathways for mast cell mediators.

Science.gov (United States)

Xu, Hao; Bin, Na-Ryum; Sugita, Shuzo

2018-04-17

Mast cells play pivotal roles in innate and adaptive immunities but are also culprits in allergy, autoimmunity, and cardiovascular diseases. Mast cells respond to environmental changes by initiating regulated exocytosis/secretion of various biologically active compounds called mediators (e.g. proteases, amines, and cytokines). Many of these mediators are stored in granules/lysosomes and rely on intricate degranulation processes for release. Mast cell stabilizers (e.g. sodium cromoglicate), which prevent such degranulation processes, have therefore been clinically employed to treat asthma and allergic rhinitis. However, it has become increasingly clear that different mast cell diseases often involve multiple mediators that rely on overlapping but distinct mechanisms for release. This review illustrates existing evidence that highlights the diverse exocytic pathways in mast cells. We also discuss strategies to delineate these pathways so as to identify unique molecular components which could serve as new drug targets for more effective and specific treatments against mast cell-related diseases. © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Molecular characterization of EG-VEGF-mediated angiogenesis: differential effects on microvascular and macrovascular endothelial cells.

Science.gov (United States)

Brouillet, Sophie; Hoffmann, Pascale; Benharouga, Mohamed; Salomon, Aude; Schaal, Jean-Patrick; Feige, Jean-Jacques; Alfaidy, Nadia

2010-08-15

Endocrine gland derived vascular endothelial growth factor (EG-VEGF) also called prokineticin (PK1), has been identified and linked to several biological processes including angiogenesis. EG-VEGF is abundantly expressed in the highest vascularized organ, the human placenta. Here we characterized its angiogenic effect using different experimental procedures. Immunohistochemistry was used to localize EG-VEGF receptors (PROKR1 and PROKR2) in placental and umbilical cord tissue. Primary microvascular placental endothelial cell (HPEC) and umbilical vein-derived macrovascular EC (HUVEC) were used to assess its effects on proliferation, migration, cell survival, pseudovascular organization, spheroid sprouting, permeability and paracellular transport. siRNA and neutralizing antibody strategies were used to differentiate PROKR1- from PROKR2-mediated effects. Our results show that 1) HPEC and HUVEC express both types of receptors 2) EG-VEGF stimulates HPEC's proliferation, migration and survival, but increases only survival in HUVECs. and 3) EG-VEGF was more potent than VEGF in stimulating HPEC sprout formation, pseudovascular organization, and it significantly increases HPEC permeability and paracellular transport. More importantly, we demonstrated that PROKR1 mediates EG-VEGF angiogenic effects, whereas PROKR2 mediates cellular permeability. Altogether, these data characterized angiogenic processes mediated by EG-VEGF, depicted a new angiogenic factor in the placenta, and suggest a novel view of the regulation of angiogenesis in placental pathologies.

Mediators' Emotional Responses to Self-Injurious Behavior: An Experimental Study.

Science.gov (United States)

Mossman, Dominique A.; Hastings, Richard P.; Brown, Tony

2002-01-01

Sixty mediators from British schools for children with mental retardation watched one of five matched videos depicting no self-injury, self-injury maintained by positive reinforcement, self-injury maintained by negative reinforcement, and self-injury unrelated to social events. Self-injury maintained by negative reinforcement was associated with…

PBCA-based polymeric microbubbles for molecular imaging and drug delivery

NARCIS (Netherlands)

Koczera, Patrick; Appold, Lia; Shi, Yang; Liu, Mengjiao; Dasgupta, Anshuman; Pathak, Vertika; Ojha, Tarun; Fokong, Stanley; Wu, Zhuojun; Van Zandvoort, Marc; Iranzo, Olga; Kuehne, Alexander J C; Pich, Andrij; Kiessling, Fabian; Lammers, Twan

2017-01-01

Microbubbles (MB) are routinely used as contrast agents for ultrasound (US) imaging. We describe different types of targeted and drug-loaded poly(n-butyl cyanoacrylate) (PBCA) MB, and demonstrate their suitability for multiple biomedical applications, including molecular US imaging and US-mediated

Recent Advances in Type-2-Cell-Mediated Immunity: Insights from Helminth Infection.

Science.gov (United States)

Harris, Nicola L; Loke, P'ng

2017-12-19

Type-2-cell-mediated immune responses play a critical role in mediating both host-resistance and disease-tolerance mechanisms during helminth infections. Recently, type 2 cell responses have emerged as major regulators of tissue repair and metabolic homeostasis even under steady-state conditions. In this review, we consider how studies of helminth infection have contributed toward our expanding cellular and molecular understanding of type-2-cell-mediated immunity, as well as new areas such as the microbiome. By studying how these successful parasites form chronic infections without overt pathology, we are gaining additional insights into allergic and inflammatory diseases, as well as normal physiology. Copyright © 2017 Elsevier Inc. All rights reserved.

Molecular Evolution at a Meiosis Gene Mediates Species Differences in the Rate and Patterning of Recombination.

Science.gov (United States)

Brand, Cara L; Cattani, M Victoria; Kingan, Sarah B; Landeen, Emily L; Presgraves, Daven C

2018-04-23

Crossing over between homologous chromosomes during meiosis repairs programmed DNA double-strand breaks, ensures proper segregation at meiosis I [1], shapes the genomic distribution of nucleotide variability in populations, and enhances the efficacy of natural selection among genetically linked sites [2]. Between closely related Drosophila species, large differences exist in the rate and chromosomal distribution of crossing over. Little, however, is known about the molecular genetic changes or population genetic forces that mediate evolved differences in recombination between species [3, 4]. Here, we show that a meiosis gene with a history of rapid evolution acts as a trans-acting modifier of species differences in crossing over. In transgenic flies, the dicistronic gene, mei-217/mei-218, recapitulates a large part of the species differences in the rate and chromosomal distribution of crossing over. These phenotypic differences appear to result from changes in protein sequence not gene expression. Our population genetics analyses show that the protein-coding sequence of mei-218, but not mei-217, has a history of recurrent positive natural selection. By modulating the intensity of centromeric and telomeric suppression of crossing over, evolution at mei-217/-218 has incidentally shaped gross differences in the chromosomal distribution of nucleotide variability between species. We speculate that recurrent bouts of adaptive evolution at mei-217/-218 might reflect a history of coevolution with selfish genetic elements. Copyright © 2018 Elsevier Ltd. All rights reserved.

Evidence of molecular evolution driven by recombination events influencing tropism in a novel human adenovirus that causes epidemic keratoconjunctivitis.

Directory of Open Access Journals (Sweden)

Michael P Walsh

2009-06-01

the first genomic, bioinformatic, and biological descriptions of the molecular evolution events engendering an emerging pathogenic adenovirus.

Glycogen Synthase Kinase 3 Inactivation Induces Cell Senescence through Sterol Regulatory Element Binding Protein 1-Mediated Lipogenesis in Chang Cells.

Science.gov (United States)

Kim, You-Mie; Song, Insun; Seo, Yong-Hak; Yoon, Gyesoon

2013-12-01

Enhanced lipogenesis plays a critical role in cell senescence via induction of expression of the mature form of sterol regulatory element binding protein 1 (SREBP1), which contributes to an increase in organellar mass, one of the indicators of senescence. We investigated the molecular mechanisms by which signaling molecules control SREBP1-mediated lipogenesis and senescence. We developed cellular models for stress-induced senescence, by exposing Chang cells, which are immortalized human liver cells, to subcytotoxic concentrations (200 µM) of deferoxamine (DFO) and H2O2. In this model of stress-induced cell senescence using DFO and H2O2, the phosphorylation profile of glycogen synthase kinase 3α (GSK3α) and β corresponded closely to the expression profile of the mature form of SREBP-1 protein. Inhibition of GSK3 with a subcytotoxic concentration of the selective GSK3 inhibitor SB415286 significantly increased mature SREBP1 expression, as well as lipogenesis and organellar mass. In addition, GSK3 inhibition was sufficient to induce senescence in Chang cells. Suppression of GSK3 expression with siRNAs specific to GSK3α and β also increased mature SREBP1 expression and induced senescence. Finally, blocking lipogenesis with fatty acid synthase inhibitors (cerulenin and C75) and siRNA-mediated silencing of SREBP1 and ATP citrate lyase (ACL) significantly attenuated GSK3 inhibition-induced senescence. GSK3 inactivation is an important upstream event that induces SREBP1-mediated lipogenesis and consequent cell senescence.

Clinical Findings Documenting Cellular and Molecular Abnormalities of Glia in Depressive Disorders

Directory of Open Access Journals (Sweden)

Boldizsár Czéh

2018-02-01

Full Text Available Depressive disorders are complex, multifactorial mental disorders with unknown neurobiology. Numerous theories aim to explain the pathophysiology. According to the “gliocentric theory”, glial abnormalities are responsible for the development of the disease. The aim of this review article is to summarize the rapidly growing number of cellular and molecular evidences indicating disturbed glial functioning in depressive disorders. We focus here exclusively on the clinical studies and present the in vivo neuroimaging findings together with the postmortem molecular and histopathological data. Postmortem studies demonstrate glial cell loss while the in vivo imaging data reveal disturbed glial functioning and altered white matter microstructure. Molecular studies report on altered gene expression of glial specific genes. In sum, the clinical findings provide ample evidences on glial pathology and demonstrate that all major glial cell types are affected. However, we still lack convincing theories explaining how the glial abnormalities develop and how exactly contribute to the emotional and cognitive disturbances. Abnormal astrocytic functioning may lead to disturbed metabolism affecting ion homeostasis and glutamate clearance, which in turn, affect synaptic communication. Abnormal oligodendrocyte functioning may disrupt the connectivity of neuronal networks, while microglial activation indicates neuroinflammatory processes. These cellular changes may relate to each other or they may indicate different endophenotypes. A theory has been put forward that the stress-induced inflammation—mediated by microglial activation—triggers a cascade of events leading to damaged astrocytes and oligodendroglia and consequently to their dysfunctions. The clinical data support the “gliocentric” theory, but future research should clarify whether these glial changes are truly the cause or simply the consequences of this devastating disorder.

Nuclear receptors and myokines : mediators of exercise-induced skeletal muscle metabolism

NARCIS (Netherlands)

van Gogh, IJA

2016-01-01

Skeletal muscle is a crucial organ in mediating (exercise-induced) beneficial health effects. In this thesis we gained important knowledge on the molecular biology of the muscle. With our focus on the muscle, we investigated the crosstalk with other organs, the regulation of myokines and the role of

MOLECULAR DYNAMICS COMPUTER SIMULATIONS OF MULTIDRUG RND EFFLUX PUMPS

Directory of Open Access Journals (Sweden)

Paolo Ruggerone

2013-02-01

Full Text Available Over-expression of multidrug efflux pumps of the Resistance Nodulation Division (RND protein super family counts among the main causes for microbial resistance against pharmaceuticals. Understanding the molecular basis of this process is one of the major challenges of modern biomedical research, involving a broad range of experimental and computational techniques. Here we review the current state of RND transporter investigation employing molecular dynamics simulations providing conformational samples of transporter components to obtain insights into the functional mechanism underlying efflux pump-mediated antibiotics resistance in Escherichia coli and Pseudomonas aeruginosa.

Molecular Dynamics Computer Simulations of Multidrug RND Efflux Pumps

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Paolo Ruggerone

2013-02-01

Full Text Available Over-expression of multidrug efflux pumps of the Resistance Nodulation Division (RND protein super family counts among the main causes for microbial resistance against pharmaceuticals. Understanding the molecular basis of this process is one of the major challenges of modern biomedical research, involving a broad range of experimental and computational techniques. Here we review the current state of RND transporter investigation employing molecular dynamics simulations providing conformational samples of transporter components to obtain insights into the functional mechanism underlying efflux pump-mediated antibiotics resistance in Escherichia coli and Pseudomonas aeruginosa.

The Influence of Receptor-Mediated Interactions on Reaction-Diffusion Mechanisms of Cellular Self-organisation

KAUST Repository

Klika, Vá clav; Baker, Ruth E.; Headon, Denis; Gaffney, Eamonn A.

2011-01-01

formation, motivating numerous theoretical and experimental studies, though its verification at the molecular level in biological systems has remained elusive. In this work, we consider the influence of receptor-mediated dynamics within the framework

Suppression of Mediator is regulated by Cdk8-dependent Grr1 turnover of the Med3 coactivator.

Science.gov (United States)

Gonzalez, Deyarina; Hamidi, Nurul; Del Sol, Ricardo; Benschop, Joris J; Nancy, Thomas; Li, Chao; Francis, Lewis; Tzouros, Manuel; Krijgsveld, Jeroen; Holstege, Frank C P; Conlan, R Steven

2014-02-18

Mediator, an evolutionary conserved large multisubunit protein complex with a central role in regulating RNA polymerase II-transcribed genes, serves as a molecular switchboard at the interface between DNA binding transcription factors and the general transcription machinery. Mediator subunits include the Cdk8 module, which has both positive and negative effects on activator-dependent transcription through the activity of the cyclin-dependent kinase Cdk8, and the tail module, which is required for positive and negative regulation of transcription, correct preinitiation complex formation in basal and activated transcription, and Mediator recruitment. Currently, the molecular mechanisms governing Mediator function remain largely undefined. Here we demonstrate an autoregulatory mechanism used by Mediator to repress transcription through the activity of distinct components of different modules. We show that the function of the tail module component Med3, which is required for transcription activation, is suppressed by the kinase activity of the Cdk8 module. Med3 interacts with, and is phosphorylated by, Cdk8; site-specific phosphorylation triggers interaction with and degradation by the Grr1 ubiquitin ligase, thereby preventing transcription activation. This active repression mechanism involving Grr1-dependent ubiquitination of Med3 offers a rationale for the substoichiometric levels of the tail module that are found in purified Mediator and the corresponding increase in tail components seen in cdk8 mutants.

Apical External Root Resorption and Repair in Orthodontic Tooth Movement: Biological Events.

Science.gov (United States)

Feller, Liviu; Khammissa, Razia A G; Thomadakis, George; Fourie, Jeanine; Lemmer, Johan

2016-01-01

Some degree of external root resorption is a frequent, unpredictable, and unavoidable consequence of orthodontic tooth movement mediated by odontoclasts/cementoclasts originating from circulating precursor cells in the periodontal ligament. Its pathogenesis involves mechanical forces initiating complex interactions between signalling pathways activated by various biological agents. Resorption of cementum is regulated by mechanisms similar to those controlling osteoclastogenesis and bone resorption. Following root resorption there is repair by cellular cementum, but factors mediating the transition from resorption to repair are not clear. In this paper we review some of the biological events associated with orthodontically induced external root resorption.

Apical External Root Resorption and Repair in Orthodontic Tooth Movement: Biological Events

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Liviu Feller

2016-01-01

Full Text Available Some degree of external root resorption is a frequent, unpredictable, and unavoidable consequence of orthodontic tooth movement mediated by odontoclasts/cementoclasts originating from circulating precursor cells in the periodontal ligament. Its pathogenesis involves mechanical forces initiating complex interactions between signalling pathways activated by various biological agents. Resorption of cementum is regulated by mechanisms similar to those controlling osteoclastogenesis and bone resorption. Following root resorption there is repair by cellular cementum, but factors mediating the transition from resorption to repair are not clear. In this paper we review some of the biological events associated with orthodontically induced external root resorption.

Kinetics of molecular transformations in connective tissue hyaluronic acid

International Nuclear Information System (INIS)

Phillips, G.O.

1990-01-01

When exposed to ionizing radiations or inflammatory disease, the glycosaminolycan component of connective tissue is preferentially degraded, probably by a free-radical mediate pathway. The resulting changes in molecular structure adversely change the properties of the matrix. Rooster comb hyaluronic acid of high molecular weight was used to investigate the mechanisms of these structural changes at macro and molecular level. Intrinsic viscosity and gel permeation chromatography measurements are suitable for demonstrating that random chain session occurs. Fast kinetic techniques are necessary to identify the mechanisms of single strand breaks. Pulse conductivity and low-angle laser light scattering pulse radiolysis can quantify the rate and yield of strand breaks. Competitive radical scavenging methods have also allowed the quantification of the rate of spontaneous and alkali-catalyzed hydrolysis of a-hydroxy radicals on polysaccharide chains, which control molecular structure changes

Detection of Side Chain Rearrangements Mediating the Motions of Transmembrane Helices in Molecular Dynamics Simulations of G Protein-Coupled Receptors

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Zied Gaieb

Full Text Available Structure and dynamics are essential elements of protein function. Protein structure is constantly fluctuating and undergoing conformational changes, which are captured by molecular dynamics (MD simulations. We introduce a computational framework that provides a compact representation of the dynamic conformational space of biomolecular simulations. This method presents a systematic approach designed to reduce the large MD simulation spatiotemporal datasets into a manageable set in order to guide our understanding of how protein mechanics emerge from side chain organization and dynamic reorganization. We focus on the detection of side chain interactions that undergo rearrangements mediating global domain motions and vice versa. Side chain rearrangements are extracted from side chain interactions that undergo well-defined abrupt and persistent changes in distance time series using Gaussian mixture models, whereas global domain motions are detected using dynamic cross-correlation. Both side chain rearrangements and global domain motions represent the dynamic components of the protein MD simulation, and are both mapped into a network where they are connected based on their degree of coupling. This method allows for the study of allosteric communication in proteins by mapping out the protein dynamics into an intramolecular network to reduce the large simulation data into a manageable set of communities composed of coupled side chain rearrangements and global domain motions. This computational framework is suitable for the study of tightly packed proteins, such as G protein-coupled receptors, and we present an application on a seven microseconds MD trajectory of CC chemokine receptor 7 (CCR7 bound to its ligand CCL21. Keywords: Molecular dynamics, Change-point detection, Side chain reorganization, Helical domain motion, Intramolecular network, Membrane proteins, GPCR, GPCR computational modeling, GPCR allostery

Mediator independently orchestrates multiple steps of preinitiation complex assembly in vivo.

Science.gov (United States)

Eyboulet, Fanny; Wydau-Dematteis, Sandra; Eychenne, Thomas; Alibert, Olivier; Neil, Helen; Boschiero, Claire; Nevers, Marie-Claire; Volland, Hervé; Cornu, David; Redeker, Virginie; Werner, Michel; Soutourina, Julie

2015-10-30

Mediator is a large multiprotein complex conserved in all eukaryotes, which has a crucial coregulator function in transcription by RNA polymerase II (Pol II). However, the molecular mechanisms of its action in vivo remain to be understood. Med17 is an essential and central component of the Mediator head module. In this work, we utilised our large collection of conditional temperature-sensitive med17 mutants to investigate Mediator's role in coordinating preinitiation complex (PIC) formation in vivo at the genome level after a transfer to a non-permissive temperature for 45 minutes. The effect of a yeast mutation proposed to be equivalent to the human Med17-L371P responsible for infantile cerebral atrophy was also analyzed. The ChIP-seq results demonstrate that med17 mutations differentially affected the global presence of several PIC components including Mediator, TBP, TFIIH modules and Pol II. Our data show that Mediator stabilizes TFIIK kinase and TFIIH core modules independently, suggesting that the recruitment or the stability of TFIIH modules is regulated independently on yeast genome. We demonstrate that Mediator selectively contributes to TBP recruitment or stabilization to chromatin. This study provides an extensive genome-wide view of Mediator's role in PIC formation, suggesting that Mediator coordinates multiple steps of a PIC assembly pathway. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Rare recombination events generate sequence diversity among balancer chromosomes in Drosophila melanogaster.

Science.gov (United States)

Miller, Danny E; Cook, Kevin R; Yeganeh Kazemi, Nazanin; Smith, Clarissa B; Cockrell, Alexandria J; Hawley, R Scott; Bergman, Casey M

2016-03-08

Multiply inverted balancer chromosomes that suppress exchange with their homologs are an essential part of the Drosophila melanogaster genetic toolkit. Despite their widespread use, the organization of balancer chromosomes has not been characterized at the molecular level, and the degree of sequence variation among copies of balancer chromosomes is unknown. To map inversion breakpoints and study potential diversity in descendants of a structurally identical balancer chromosome, we sequenced a panel of laboratory stocks containing the most widely used X chromosome balancer, First Multiple 7 (FM7). We mapped the locations of FM7 breakpoints to precise euchromatic coordinates and identified the flanking sequence of breakpoints in heterochromatic regions. Analysis of SNP variation revealed megabase-scale blocks of sequence divergence among currently used FM7 stocks. We present evidence that this divergence arose through rare double-crossover events that replaced a female-sterile allele of the singed gene (sn(X2)) on FM7c with a sequence from balanced chromosomes. We propose that although double-crossover events are rare in individual crosses, many FM7c chromosomes in the Bloomington Drosophila Stock Center have lost sn(X2) by this mechanism on a historical timescale. Finally, we characterize the original allele of the Bar gene (B(1)) that is carried on FM7, and validate the hypothesis that the origin and subsequent reversion of the B(1) duplication are mediated by unequal exchange. Our results reject a simple nonrecombining, clonal mode for the laboratory evolution of balancer chromosomes and have implications for how balancer chromosomes should be used in the design and interpretation of genetic experiments in Drosophila.

Pulp Inflammation Diagnosis from Clinical to Inflammatory Mediators: A Systematic Review.

Science.gov (United States)

Zanini, Marjorie; Meyer, Elisabeth; Simon, Stéphane

2017-07-01

Similar to other tissues, the dental pulp mounts an inflammatory reaction as a way to eliminate pathogens and stimulate repair. Pulp inflammation is prerequisite for dentin pulp complex repair and regeneration; otherwise, chronic disease or pulp necrosis occurs. Evaluation of pulp inflammation severity is necessary to predict the clinical success of maintaining pulp vitality. Clinical limitations to evaluating in situ inflammatory status are well-described. A molecular approach that aids clinical distinction between reversible and irreversible pulpitis could improve the success rate of vital pulp therapy. The aim of this article is to review inflammatory mediator expression in the context of clinical diagnosis. We searched PubMed and Cochrane databases for articles published between 1970 and December 2016. Only published studies of inflammatory mediator expression related to clinical diagnosis were eligible for inclusion and analysis. Thirty-two articles were analyzed. Two molecular approaches were described by study methods, protein expression analysis and gene expression analysis. Our review indicates that interleukin-8, matrix metalloproteinase 9, tumor necrosis factor-α, and receptor for advanced glycation end products expression increase at both the gene and protein levels during inflammation. Clinical irreversible pulpitis is related to specific levels of inflammatory mediator expression. The difference in expression between reversible and irreversible disease is both quantitative and qualitative. On the basis of our analysis, in situ quantification of inflammatory mediators may aid in the clinical distinction between reversible and irreversible pulpitis. Copyright © 2017 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Solution Structure of the N-Terminal Domain of Mediator Subunit MED26 and Molecular Characterization of Its Interaction with EAF1 and TAF7.

Science.gov (United States)

Lens, Zoé; Cantrelle, François-Xavier; Peruzzini, Riccardo; Hanoulle, Xavier; Dewitte, Frédérique; Ferreira, Elisabeth; Baert, Jean-Luc; Monté, Didier; Aumercier, Marc; Villeret, Vincent; Verger, Alexis; Landrieu, Isabelle

2017-10-13

MED26 is a subunit of Mediator, a large complex central to the regulation of gene transcription by RNA Polymerase II. MED26 plays a role in the switch between the initiation and elongation phases of RNA Polymerase II-mediated transcription process. Regulation of these steps requires successive binding of MED26 N-terminal domain (NTD) to TATA-binding protein-associated factor 7 (TAF7) and Eleven-nineteen lysine-rich in leukemia-Associated Factor 1 (EAF1). In order to investigate the mechanism of regulation by MED26, MED26-NTD structure was solved by NMR, revealing a 4-helix bundle. EAF1 (239-268) and TAF7 (205-235) peptide interactions were both mapped to the same groove formed by H3 and H4 helices of MED26-NTD. Both interactions are characterized by dissociation constants in the 10-μM range. Further experiments revealed a folding-upon-binding mechanism that leads to the formation of EAF1 (N247-S260) and TAF7 (L214-S227) helices. Chemical shift perturbations and nuclear Overhauser enhancement contacts support the involvement of residues I222/F223 in anchoring TAF7 helix to a hydrophobic pocket of MED26-NTD, including residues L48, W80 and I84. In addition, Ala mutations of charged residues located in the C-terminal disordered part of TAF7 and EAF1 peptides affected the binding, with a loss of affinity characterized by a 10-time increase of dissociation constants. A structural model of MED26-NTD/TAF7 complex shows bi-partite components, combining ordered and disordered segments, as well as hydrophobic and electrostatic contributions to the binding. This study provides molecular detail that will help to decipher the mechanistic basis for the initiation to elongation switch-function mediated by MED26-NTD. Copyright © 2017 Elsevier Ltd. All rights reserved.

Molecular collision theory

CERN Document Server

Child, M S

2010-01-01

This high-level monograph offers an excellent introduction to the theory required for interpretation of an increasingly sophisticated range of molecular scattering experiments. There are five helpful appendixes dealing with continuum wavefunctions, Green's functions, semi-classical connection formulae, curve-crossing in the momentum representation, and elements of classical mechanics.The contents of this volume have been chosen to emphasize the quantum mechanical and semi-classical nature of collision events, with little attention given to purely classical behavior. The treatment is essentiall

Parasitic nematodes modulate PIN-mediated auxin transport to facilitate infection.

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Wim Grunewald

2009-01-01

Full Text Available Plant-parasitic nematodes are destructive plant pathogens that cause significant yield losses. They induce highly specialized feeding sites (NFS in infected plant roots from which they withdraw nutrients. In order to establish these NFS, it is thought that the nematodes manipulate the molecular and physiological pathways of their hosts. Evidence is accumulating that the plant signalling molecule auxin is involved in the initiation and development of the feeding sites of sedentary plant-parasitic nematodes. Intercellular transport of auxin is essential for various aspects of plant growth and development. Here, we analysed the spatial and temporal expression of PIN auxin transporters during the early events of NFS establishment using promoter-GUS/GFP fusion lines. Additionally, single and double pin mutants were used in infection studies to analyse the role of the different PIN proteins during cyst nematode infection. Based on our results, we postulate a model in which PIN1-mediated auxin transport is needed to deliver auxin to the initial syncytial cell, whereas PIN3 and PIN4 distribute the accumulated auxin laterally and are involved in the radial expansion of the NFS. Our data demonstrate that cyst nematodes are able to hijack the auxin distribution network in order to facilitate the infection process.

Parasitic nematodes modulate PIN-mediated auxin transport to facilitate infection.

Science.gov (United States)

Grunewald, Wim; Cannoot, Bernard; Friml, Jirí; Gheysen, Godelieve

2009-01-01

Plant-parasitic nematodes are destructive plant pathogens that cause significant yield losses. They induce highly specialized feeding sites (NFS) in infected plant roots from which they withdraw nutrients. In order to establish these NFS, it is thought that the nematodes manipulate the molecular and physiological pathways of their hosts. Evidence is accumulating that the plant signalling molecule auxin is involved in the initiation and development of the feeding sites of sedentary plant-parasitic nematodes. Intercellular transport of auxin is essential for various aspects of plant growth and development. Here, we analysed the spatial and temporal expression of PIN auxin transporters during the early events of NFS establishment using promoter-GUS/GFP fusion lines. Additionally, single and double pin mutants were used in infection studies to analyse the role of the different PIN proteins during cyst nematode infection. Based on our results, we postulate a model in which PIN1-mediated auxin transport is needed to deliver auxin to the initial syncytial cell, whereas PIN3 and PIN4 distribute the accumulated auxin laterally and are involved in the radial expansion of the NFS. Our data demonstrate that cyst nematodes are able to hijack the auxin distribution network in order to facilitate the infection process.

Regulation of dynein-mediated autophagosomes trafficking by ASM in CASMCs.

Science.gov (United States)

Xu, Ming; Zhang, Qiufang; Li, Pin-Lan; Nguyen, Thaison; Li, Xiang; Zhang, Yang

2016-01-01

Acid sphingomyelinase (ASM; gene symbol Smpd1) has been shown to play a crucial role in autophagy maturation by controlling lysosomal fusion with autophagosomes in coronary arterial smooth muscle cells (CASMCs). However, the underlying molecular mechanism by which ASM controls autophagolysosomal fusion remains unknown. In primary cultured CASMCs, lysosomal Ca2+ induced by 7-ketocholesterol (7-Ket, an atherogenic stimulus and autophagy inducer) was markedly attenuated by ASM deficiency or TRPML1 gene silencing suggesting that ASM signaling is required for TRPML1 channel activity and subsequent lysosomal Ca(2+) release. In these CASMCs, ASM deficiency or TRPML1 gene silencing markedly inhibited 7-Ket-induced dynein activation. In addition, 7-Ket-induced autophagosome trafficking, an event associated with lysosomal Ca(2+) release and dynein activity, was significantly inhibited in ASM-deficient (Smpd1(-/-)) CASMCs compared to that in Smpd1(+/+) CASMCs. Finally, overexpression of TRPML1 proteins restored 7-Ket-induced lysosomal Ca(2+) release and autophagosome trafficking in Smpd1-/- CASMCs. Collectively, these results suggest that ASM plays a critical role in regulating lysosomal TRPML1-Ca(2+) signaling and subsequent dynein-mediated autophagosome trafficking, which leads its role in controlling autophagy maturation in CASMCs under atherogenic stimulation.

Gold nanoparticle mediated laser transfection for efficient siRNA mediated gene knock down.

Directory of Open Access Journals (Sweden)

Dag Heinemann

Full Text Available Laser based transfection methods have proven to be an efficient and gentle alternative to established molecule delivery methods like lipofection or electroporation. Among the laser based methods, gold nanoparticle mediated laser transfection bears the major advantage of high throughput and easy usability. This approach uses plasmon resonances on gold nanoparticles unspecifically attached to the cell membrane to evoke transient and spatially defined cell membrane permeabilization. In this study, we explore the parameter regime for gold nanoparticle mediated laser transfection for the delivery of molecules into cell lines and prove its suitability for siRNA mediated gene knock down. The developed setup allows easy usage and safe laser operation in a normal lab environment. We applied a 532 nm Nd:YAG microchip laser emitting 850 ps pulses at a repetition rate of 20.25 kHz. Scanning velocities of the laser spot over the sample of up to 200 mm/s were tested without a decline in perforation efficiency. This velocity leads to a process speed of ∼8 s per well of a 96 well plate. The optimal particle density was determined to be ∼6 particles per cell using environmental scanning electron microscopy. Applying the optimized parameters transfection efficiencies of 88% were achieved in canine pleomorphic adenoma ZMTH3 cells using a fluorescent labeled siRNA while maintaining a high cell viability of >90%. Gene knock down of d2-EGFP was demonstrated and validated by fluorescence repression and western blot analysis. On basis of our findings and established mathematical models we suppose a mixed transfection mechanism consisting of thermal and multiphoton near field effects. Our findings emphasize that gold nanoparticle mediated laser transfection provides an excellent tool for molecular delivery for both, high throughput purposes and the transfection of sensitive cells types.

Gold nanoparticle mediated laser transfection for efficient siRNA mediated gene knock down.

Science.gov (United States)

Heinemann, Dag; Schomaker, Markus; Kalies, Stefan; Schieck, Maximilian; Carlson, Regina; Murua Escobar, Hugo; Ripken, Tammo; Meyer, Heiko; Heisterkamp, Alexander

2013-01-01

Laser based transfection methods have proven to be an efficient and gentle alternative to established molecule delivery methods like lipofection or electroporation. Among the laser based methods, gold nanoparticle mediated laser transfection bears the major advantage of high throughput and easy usability. This approach uses plasmon resonances on gold nanoparticles unspecifically attached to the cell membrane to evoke transient and spatially defined cell membrane permeabilization. In this study, we explore the parameter regime for gold nanoparticle mediated laser transfection for the delivery of molecules into cell lines and prove its suitability for siRNA mediated gene knock down. The developed setup allows easy usage and safe laser operation in a normal lab environment. We applied a 532 nm Nd:YAG microchip laser emitting 850 ps pulses at a repetition rate of 20.25 kHz. Scanning velocities of the laser spot over the sample of up to 200 mm/s were tested without a decline in perforation efficiency. This velocity leads to a process speed of ∼8 s per well of a 96 well plate. The optimal particle density was determined to be ∼6 particles per cell using environmental scanning electron microscopy. Applying the optimized parameters transfection efficiencies of 88% were achieved in canine pleomorphic adenoma ZMTH3 cells using a fluorescent labeled siRNA while maintaining a high cell viability of >90%. Gene knock down of d2-EGFP was demonstrated and validated by fluorescence repression and western blot analysis. On basis of our findings and established mathematical models we suppose a mixed transfection mechanism consisting of thermal and multiphoton near field effects. Our findings emphasize that gold nanoparticle mediated laser transfection provides an excellent tool for molecular delivery for both, high throughput purposes and the transfection of sensitive cells types.

Gold Nanoparticle Mediated Laser Transfection for Efficient siRNA Mediated Gene Knock Down

Science.gov (United States)

Heinemann, Dag; Schomaker, Markus; Kalies, Stefan; Schieck, Maximilian; Carlson, Regina; Escobar, Hugo Murua; Ripken, Tammo; Meyer, Heiko; Heisterkamp, Alexander

2013-01-01

Laser based transfection methods have proven to be an efficient and gentle alternative to established molecule delivery methods like lipofection or electroporation. Among the laser based methods, gold nanoparticle mediated laser transfection bears the major advantage of high throughput and easy usability. This approach uses plasmon resonances on gold nanoparticles unspecifically attached to the cell membrane to evoke transient and spatially defined cell membrane permeabilization. In this study, we explore the parameter regime for gold nanoparticle mediated laser transfection for the delivery of molecules into cell lines and prove its suitability for siRNA mediated gene knock down. The developed setup allows easy usage and safe laser operation in a normal lab environment. We applied a 532 nm Nd:YAG microchip laser emitting 850 ps pulses at a repetition rate of 20.25 kHz. Scanning velocities of the laser spot over the sample of up to 200 mm/s were tested without a decline in perforation efficiency. This velocity leads to a process speed of ∼8 s per well of a 96 well plate. The optimal particle density was determined to be ∼6 particles per cell using environmental scanning electron microscopy. Applying the optimized parameters transfection efficiencies of 88% were achieved in canine pleomorphic adenoma ZMTH3 cells using a fluorescent labeled siRNA while maintaining a high cell viability of >90%. Gene knock down of d2-EGFP was demonstrated and validated by fluorescence repression and western blot analysis. On basis of our findings and established mathematical models we suppose a mixed transfection mechanism consisting of thermal and multiphoton near field effects. Our findings emphasize that gold nanoparticle mediated laser transfection provides an excellent tool for molecular delivery for both, high throughput purposes and the transfection of sensitive cells types. PMID:23536802

HNF4alpha dysfunction as a molecular rational for cyclosporine induced hypertension.

Science.gov (United States)

Niehof, Monika; Borlak, Jürgen

2011-01-27

Induction of tolerance against grafted organs is achieved by the immunosuppressive agent cyclosporine, a prominent member of the calcineurin inhibitors. Unfortunately, its lifetime use is associated with hypertension and nephrotoxicity. Several mechanism for cyclosporine induced hypertension have been proposed, i.e. activation of the sympathetic nervous system, endothelin-mediated systemic vasoconstriction, impaired vasodilatation secondary to reduction in prostaglandin and nitric oxide, altered cytosolic calcium translocation, and activation of the renin-angiotensin system (RAS). In this regard the molecular basis for undue RAS activation and an increased signaling of the vasoactive oligopeptide angiotensin II (AngII) remain elusive. Notably, angiotensinogen (AGT) is the precursor of AngII and transcriptional regulation of AGT is controlled by the hepatic nuclear factor HNF4alpha. To better understand the molecular events associated with cyclosporine induced hypertension, we investigated the effect of cyclosporine on HNF4alpha expression and activity and searched for novel HNF4alpha target genes among members of the RAS cascade. Using bioinformatic algorithm and EMSA bandshift assays we identified angiotensin II receptor type 1 (AGTR1), angiotensin I converting enzyme (ACE), and angiotensin I converting enzyme 2 (ACE2) as genes targeted by HNF4alpha. Notably, cyclosporine represses HNF4alpha gene and protein expression and its DNA-binding activity at consensus sequences to AGT, AGTR1, ACE, and ACE2. Consequently, the gene expression of AGT, AGTR1, and ACE2 was significantly reduced as evidenced by quantitative real-time RT-PCR. While RAS is composed of a sophisticated interplay between multiple factors we propose a decrease of ACE2 to enforce AngII signaling via AGTR1 to ultimately result in vasoconstriction and hypertension. Taken collectively we demonstrate cyclosporine to repress HNF4alpha activity through calcineurin inhibitor mediated inhibition of nuclear

HNF4alpha dysfunction as a molecular rational for cyclosporine induced hypertension.

Directory of Open Access Journals (Sweden)

Monika Niehof

Full Text Available Induction of tolerance against grafted organs is achieved by the immunosuppressive agent cyclosporine, a prominent member of the calcineurin inhibitors. Unfortunately, its lifetime use is associated with hypertension and nephrotoxicity. Several mechanism for cyclosporine induced hypertension have been proposed, i.e. activation of the sympathetic nervous system, endothelin-mediated systemic vasoconstriction, impaired vasodilatation secondary to reduction in prostaglandin and nitric oxide, altered cytosolic calcium translocation, and activation of the renin-angiotensin system (RAS. In this regard the molecular basis for undue RAS activation and an increased signaling of the vasoactive oligopeptide angiotensin II (AngII remain elusive. Notably, angiotensinogen (AGT is the precursor of AngII and transcriptional regulation of AGT is controlled by the hepatic nuclear factor HNF4alpha. To better understand the molecular events associated with cyclosporine induced hypertension, we investigated the effect of cyclosporine on HNF4alpha expression and activity and searched for novel HNF4alpha target genes among members of the RAS cascade. Using bioinformatic algorithm and EMSA bandshift assays we identified angiotensin II receptor type 1 (AGTR1, angiotensin I converting enzyme (ACE, and angiotensin I converting enzyme 2 (ACE2 as genes targeted by HNF4alpha. Notably, cyclosporine represses HNF4alpha gene and protein expression and its DNA-binding activity at consensus sequences to AGT, AGTR1, ACE, and ACE2. Consequently, the gene expression of AGT, AGTR1, and ACE2 was significantly reduced as evidenced by quantitative real-time RT-PCR. While RAS is composed of a sophisticated interplay between multiple factors we propose a decrease of ACE2 to enforce AngII signaling via AGTR1 to ultimately result in vasoconstriction and hypertension. Taken collectively we demonstrate cyclosporine to repress HNF4alpha activity through calcineurin inhibitor mediated inhibition

A controlled vocabulary for pathway entities and events.

Science.gov (United States)

Jupe, Steve; Jassal, Bijay; Williams, Mark; Wu, Guanming

2014-01-01

Entities involved in pathways and the events they participate in require descriptive and unambiguous names that are often not available in the literature or elsewhere. Reactome is a manually curated open-source resource of human pathways. It is accessible via a website, available as downloads in standard reusable formats and via Representational State Transfer (REST)-ful and Simple Object Access Protocol (SOAP) application programming interfaces (APIs). We have devised a controlled vocabulary (CV) that creates concise, unambiguous and unique names for reactions (pathway events) and all the molecular entities they involve. The CV could be reapplied in any situation where names are used for pathway entities and events. Adoption of this CV would significantly improve naming consistency and readability, with consequent benefits for searching and data mining within and between databases. Database URL: http://www.reactome.org. © The Author(s) 2014. Published by Oxford University Press.

Molecular hydrogen in sports medicine: new therapeutic perspectives.

Science.gov (United States)

Ostojic, S M

2015-04-01

In the past 2 decades, molecular hydrogen emerged as a novel therapeutic agent, with antioxidant, anti-inflammatory and anti-apoptotic effects demonstrated in plethora of animal disease models and human studies. Beneficial effects of molecular hydrogen in clinical environment are observed especially in oxidative stress-mediated diseases, such as diabetes mellitus, brain stem infarction, rheumatoid arthritis, or neurodegenerative diseases. A number of more recent studies have reported that molecular hydrogen affects cell signal transduction and acts as an alkalizing agent, with these newly identified mechanisms of action having the potential to widen its application in clinical medicine even further. In particular, hydrogen therapy may be an effective and specific innovative treatment for exercise-induced oxidative stress and sports injury, with potential for the improvement of exercise performance. This review will summarize recent research findings regarding the clinical aspects of molecular hydrogen use, emphasizing its application in the field of sports medicine. © Georg Thieme Verlag KG Stuttgart · New York.

NOD1CARD Might Be Using Multiple Interfaces for RIP2-Mediated CARD-CARD Interaction: Insights from Molecular Dynamics Simulation.

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Jitendra Maharana

Full Text Available The nucleotide-binding and oligomerization domain (NOD-containing protein 1 (NOD1 plays the pivotal role in host-pathogen interface of innate immunity and triggers immune signalling pathways for the maturation and release of pro-inflammatory cytokines. Upon the recognition of iE-DAP, NOD1 self-oligomerizes in an ATP-dependent fashion and interacts with adaptor molecule receptor-interacting protein 2 (RIP2 for the propagation of innate immune signalling and initiation of pro-inflammatory immune responses. This interaction (mediated by NOD1 and RIP2 helps in transmitting the downstream signals for the activation of NF-κB signalling pathway, and has been arbitrated by respective caspase-recruitment domains (CARDs. The so-called CARD-CARD interaction still remained contradictory due to inconsistent results. Henceforth, to understand the mode and the nature of the interaction, structural bioinformatics approaches were employed. MD simulation of modelled 1:1 heterodimeric complexes revealed that the type-Ia interface of NOD1CARD and the type-Ib interface of RIP2CARD might be the suitable interfaces for the said interaction. Moreover, we perceived three dynamically stable heterotrimeric complexes with an NOD1:RIP2 ratio of 1:2 (two numbers and 2:1. Out of which, in the first trimeric complex, a type-I NOD1-RIP2 heterodimer was found interacting with an RIP2CARD using their type-IIa and IIIa interfaces. However, in the second and third heterotrimer, we observed type-I homodimers of NOD1 and RIP2 CARDs were interacting individually with RIP2CARD and NOD1CARD (in type-II and type-III interface, respectively. Overall, this study provides structural and dynamic insights into the NOD1-RIP2 oligomer formation, which will be crucial in understanding the molecular basis of NOD1-mediated CARD-CARD interaction in higher and lower eukaryotes.

Real-time Molecular Study of Bystander Effects of Low dose Low LET radiation Using Living Cell Imaging and Nanoparticale Optics

Energy Technology Data Exchange (ETDEWEB)

Natarajan, Mohan [UT Health Science Center at San Antonio; Xu, Nancy R [Old Dominion University; Mohan, Sumathy [UT Health Science Center at San Antonio

2013-06-03

In this study two novel approaches are proposed to investigate precisely the low dose low LET radiation damage and its effect on bystander cells in real time. First, a flow shear model system, which would provide us a near in vivo situation where endothelial cells in the presence of extra cellular matrix experiencing continuous flow shear stress, will be used. Endothelial cells on matri-gel (simulated extra cellular matrix) will be subjected to physiological flow shear (that occurs in normal blood vessels). Second, a unique tool (Single nano particle/single live cell/single molecule microscopy and spectroscopy; Figure A) will be used to track the molecular trafficking by single live cell imaging. Single molecule chemical microscopy allows one to single out and study rare events that otherwise might be lost in assembled average measurement, and monitor many target single molecules simultaneously in real-time. Multi color single novel metal nanoparticle probes allow one to prepare multicolor probes (Figure B) to monitor many single components (events) simultaneously and perform multi-complex analysis in real-time. These nano-particles resist to photo bleaching and hence serve as probes for unlimited timeframe of analysis. Single live cell microscopy allows one to image many single cells simultaneously in real-time. With the combination of these unique tools, we will be able to study under near-physiological conditions the cellular and sub-cellular responses (even subtle changes at one molecule level) to low and very low doses of low LET radiation in real time (milli-second or nano-second) at sub-10 nanometer spatial resolution. This would allow us to precisely identify, at least in part, the molecular mediators that are responsible of radiation damage in the irradiated cells and the mediators that are responsible for initiating the signaling in the neighboring cells. Endothelial cells subjected to flow shear (2 dynes/cm2 or 16 dynes/cm2) and exposed to 0.1, 1 and 10

Mediation Analysis with Multiple Mediators

OpenAIRE

VanderWeele, T.J.; Vansteelandt, S.

2014-01-01

Recent advances in the causal inference literature on mediation have extended traditional approaches to direct and indirect effects to settings that allow for interactions and non-linearities. In this paper, these approaches from causal inference are further extended to settings in which multiple mediators may be of interest. Two analytic approaches, one based on regression and one based on weighting are proposed to estimate the effect mediated through multiple mediators and the effects throu...

Radionuclide molecular target therapy for lung cancer

International Nuclear Information System (INIS)

Zhang Fuhai; Meng Zhaowei; Tan Jian

2012-01-01

Lung cancer harms people's health or even lives severely. Currently, the morbidity and mortality of lung cancer are ascending all over the world. Accounting for 38.08% of malignant tumor caused death in male and 16% in female in cities,ranking top in both sex. Especially, the therapy of non-small cell lung cancer has not been obviously improved for many years. Recently, sodium/iodide transporter gene transfection and the therapy of molecular target drugs mediated radionuclide are being taken into account and become the new research directions in treatment of advanced lung cancer patients with the development of technology and theory for medical molecular biology and the new knowledge of lung cancer's pathogenesis. (authors)

Metal-mediated DNA base pairing: alternatives to hydrogen-bonded Watson-Crick base pairs.

Science.gov (United States)

Takezawa, Yusuke; Shionoya, Mitsuhiko

2012-12-18

With its capacity to store and transfer the genetic information within a sequence of monomers, DNA forms its central role in chemical evolution through replication and amplification. This elegant behavior is largely based on highly specific molecular recognition between nucleobases through the specific hydrogen bonds in the Watson-Crick base pairing system. While the native base pairs have been amazingly sophisticated through the long history of evolution, synthetic chemists have devoted considerable efforts to create alternative base pairing systems in recent decades. Most of these new systems were designed based on the shape complementarity of the pairs or the rearrangement of hydrogen-bonding patterns. We wondered whether metal coordination could serve as an alternative driving force for DNA base pairing and why hydrogen bonding was selected on Earth in the course of molecular evolution. Therefore, we envisioned an alternative design strategy: we replaced hydrogen bonding with another important scheme in biological systems, metal-coordination bonding. In this Account, we provide an overview of the chemistry of metal-mediated base pairing including basic concepts, molecular design, characteristic structures and properties, and possible applications of DNA-based molecular systems. We describe several examples of artificial metal-mediated base pairs, such as Cu(2+)-mediated hydroxypyridone base pair, H-Cu(2+)-H (where H denotes a hydroxypyridone-bearing nucleoside), developed by us and other researchers. To design the metallo-base pairs we carefully chose appropriate combinations of ligand-bearing nucleosides and metal ions. As expected from their stronger bonding through metal coordination, DNA duplexes possessing metallo-base pairs exhibited higher thermal stability than natural hydrogen-bonded DNAs. Furthermore, we could also use metal-mediated base pairs to construct or induce other high-order structures. These features could lead to metal-responsive functional

The Applicability of Cognitive Mediational and Moderational Models to Explain Children's Depression Inventory Factor Scores in Urban Youth

Science.gov (United States)

Reinemann, Dawn H. S.; Teeter Ellison, Phyllis A.

2004-01-01

This investigation examined whether cognition serves as a direct factor, mediates, or moderates the relationship between stressful life events and Children's Depression Inventory (CDI; Kovacs, 1992) factor scores in urban, ethnic minority youth. Ninety-eight middle school students completed measures of stressful life events, cognition (cognitive…

Chemical groups and structural characterization of lignin via thiol-mediated demethylation

Science.gov (United States)

Lihong Hu; Hui Pan; Yonghong Zhou; Chung-Yun Hse; Chengguo Liu; Baofang Zhang; Bin Xu

2014-01-01

A new approach to increase the reactivity of lignin by thiol-mediated demethylation was investigated in this study. Demethylated lignin was characterized by the changes in its hydroxyl and methoxyl groups, molecular weight, and other properties using titration and spectroscopy methods including FT-IR, 1H NMR, UV,and GPC. The total...

Search for supersymmetry in events with at least one photon, missing transverse momentum, and large transverse event activity in proton-proton collisions at 13 TeV

CERN Document Server

CMS Collaboration

2017-01-01

A search for physics beyond the standard model in final states with at least one photon, large transverse momentum imbalance, and large total transverse event activity is presented. This event selection provides good sensitivity for gauge mediated supersymmetry models in which pair-produced gluinos or squarks decay via short-living neutralinos to photons and gravitinos. The data sample corresponds to an integrated luminosity of $35.9~\\mathrm{fb}^{-1}$ of proton-proton collisions recorded by the CMS experiment at the LHC in 2016. No excess of events above the standard model background is observed. The data is interpreted in simplified models of gluino- and squark pair production, in which gluinos and squarks decay via gauginos to photons. Gluino masses of up to $2~\\mathrm{TeV}$ masses up to $1.6~\\mathrm{TeV}$ are excluded.

Molecular Machines Determining the Fate of Endocytosed Synaptic Vesicles in Nerve Terminals.

Science.gov (United States)

Fassio, Anna; Fadda, Manuela; Benfenati, Fabio

2016-01-01

The cycle of a synaptic vesicle (SV) within the nerve terminal is a step-by-step journey with the final goal of ensuring the proper synaptic strength under changing environmental conditions. The SV cycle is a precisely regulated membrane traffic event in cells and, because of this, a plethora of membrane-bound and cytosolic proteins are devoted to assist SVs in each step of the journey. The cycling fate of endocytosed SVs determines both the availability for subsequent rounds of release and the lifetime of SVs in the terminal and is therefore crucial for synaptic function and plasticity. Molecular players that determine the destiny of SVs in nerve terminals after a round of exo-endocytosis are largely unknown. Here we review the functional role in SV fate of phosphorylation/dephosphorylation of SV proteins and of small GTPases acting on membrane trafficking at the synapse, as they are emerging as key molecules in determining the recycling route of SVs within the nerve terminal. In particular, we focus on: (i) the cyclin-dependent kinase-5 (cdk5) and calcineurin (CN) control of the recycling pool of SVs; (ii) the role of small GTPases of the Rab and ADP-ribosylation factor (Arf) families in defining the route followed by SV in their nerve terminal cycle. These regulatory proteins together with their synaptic regulators and effectors, are molecular nanomachines mediating homeostatic responses in synaptic plasticity and potential targets of drugs modulating the efficiency of synaptic transmission.

MOLECULAR MACHINES DETERMINING THE FATE OF ENDOCYTOSED SYNAPTIC VESICLES IN NERVE TERMINALS

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Anna eFassio

2016-05-01

Full Text Available The cycle of a synaptic vesicle (SV within the nerve terminal is a step-by-step journey with the final goal of ensuring the proper synaptic strength under changing environmental conditions.The SV cycle is a precisely regulated membrane traffic event in cells and, because of this, a plethora of membrane-bound and cytosolic proteins are devoted to assist SVs in each step of the journey. The cycling fate of endocytosed SVs determines both the availability for subsequent rounds of release and the lifetime of SVs in the terminal and is therefore crucial for synaptic function and plasticity. Molecular players that determine the destiny of SVs in nerve terminals after a round of exo-endocytosis are largely unknown. Here we review the functional role in SV fate of phosphorylation/dephosphorylation of SV proteins and of small GTPases acting on membrane trafficking at the synapse, as they are emerging as key molecules in determining the recycling route of SVs within the nerve terminal. In particular, we focus on (i the cyclin-dependent kinase-5 and calcineurin control of the recycling pool of SVs; (ii the role of small GTPases of the Rab and ADP-ribosylation factor (Arf families in defining the route followed by SV in their nerve terminal cycle. These regulatory proteins together with their synaptic regulators and effectors, are molecular nanomachines mediating homeostatic responses in synaptic plasticity and potential targets of drugs modulating the efficiency of synaptic transmission.

Studies on the molecular mechanism of nucleotide excision repair in human cells

International Nuclear Information System (INIS)

Friedberg, E.C.

1987-01-01

Studies in this laboratory have focused on attempts to define the mechanism of nucleotide excision repair of DNA in human cells, with a view to understanding the molecular pathogenesis of the disease XP. With the advent of recombinant DNA technology, they directed their efforts to the molecular cloning of human genes defective in XP, with a view to using the cloned genes to overexpress proteins of interest for biochemical investigations. Initial studies exploited the selectable phenotype of marked sensitivity to killing of XP group A cells by UV radiation and by other DNA damaging agents. However, except for a single report in 1982 there has been no reproducible demonstration of complementation of the UV sensitivity of XP cells by DNA-mediated transfection. The apparent difficulties associated with transfection of XP cells have been the subject of several recent studies. In view of the multiple problems associated with stable transfection of XP cells using total genomic DNA, they have embarked on an alternative strategy designed to facilitate the cloning of human XP genes. This strategy involves the transfer of single human chromosomes into XP cells and screening for this relatively high frequency event. The idea is to identify chromosomes on which particular XP genes reside and then to isolate non-complementing derivatives of these chromosomes so that highly enriched DNA pools containing genes of interest can be generated by employing one or more subtractive strategies

Segregated populations of hippocampal principal CA1 neurons mediating conditioning and extinction of contextual fear.

Science.gov (United States)

Tronson, Natalie C; Schrick, Christina; Guzman, Yomayra F; Huh, Kyu Hwan; Srivastava, Deepak P; Penzes, Peter; Guedea, Anita L; Gao, Can; Radulovic, Jelena

2009-03-18

Learning processes mediating conditioning and extinction of contextual fear require activation of several key signaling pathways in the hippocampus. Principal hippocampal CA1 neurons respond to fear conditioning by a coordinated activation of multiple protein kinases and immediate early genes, such as cFos, enabling rapid and lasting consolidation of contextual fear memory. The extracellular signal-regulated kinase (Erk) additionally acts as a central mediator of fear extinction. It is not known however, whether these molecular events take place in overlapping or nonoverlapping neuronal populations. By using mouse models of conditioning and extinction of fear, we set out to determine the time course of cFos and Erk activity, their cellular overlap, and regulation by afferent cholinergic input from the medial septum. Analyses of cFos(+) and pErk(+) cells by immunofluorescence revealed predominant nuclear activation of either protein during conditioning and extinction of fear, respectively. Transgenic cFos-LacZ mice were further used to label in vivo Fos(+) hippocampal cells during conditioning followed by pErk immunostaining after extinction. The results showed that these signaling molecules were activated in segregated populations of hippocampal principal neurons. Furthermore, immunotoxin-induced lesions of medial septal neurons, providing cholinergic input into the hippocampus, selectively abolished Erk activation and extinction of fear without affecting cFos responses and conditioning. These results demonstrate that extinction mechanisms based on Erk signaling involve a specific population of CA1 principal neurons distinctively regulated by afferent cholinergic input from the medial septum.

Molecular aspects of tumor cell migration and invasion

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Giuseppina Bozzuto

2010-03-01

Full Text Available Cell migration and invasion are crucial steps in many physiological events. However, they are also implicated in the physiopathology of many diseases, such as cancer. To spread through the tissues, tumor cells use mechanisms that involve several molecular actors: adhesion receptor families, receptor tyrosine kinases, cytoskeleton proteins, adapter and signalling proteins interplay in a complex scenario. The balance of cellular signals for proliferation and survival responses also regulates migratory behaviours of tumor cells. To complicate the scene of crime drug resistance players can interfere thus worsening this delicate situation. The complete understanding of this molecular jungle is an impossible mission: some molecular aspects are reviewed in this paper.

The mediating role of state maladaptive emotion regulation in the relation between social anxiety symptoms and self-evaluation bias.

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Sarfan, Laurel D; Cody, Meghan W; Clerkin, Elise M

2018-03-16

Although social anxiety symptoms are robustly linked to biased self-evaluations across time, the mechanisms of this relation remain unclear. The present study tested three maladaptive emotion regulation strategies - state post-event processing, state experiential avoidance, and state expressive suppression - as potential mediators of this relation. Undergraduate participants (N = 88; 61.4% Female) rated their social skill in an impromptu conversation task and then returned to the laboratory approximately two days later to evaluate their social skill in the conversation again. Consistent with expectations, state post-event processing and state experiential avoidance mediated the relation between social anxiety symptoms and worsening self-evaluations of social skill (controlling for research assistant evaluations), particularly for positive qualities (e.g. appeared confident, demonstrated social skill). State expressive suppression did not mediate the relation between social anxiety symptoms and changes in self-evaluation bias across time. These findings highlight the role that spontaneous, state experiential avoidance and state post-event processing may play in the relation between social anxiety symptoms and worsening self-evaluation biases of social skill across time.

Mechanisms and ecological implications of plant-mediated interactions between belowground and aboveground insect herbivores

NARCIS (Netherlands)

Papadopoulou, G.V.; Dam, N.M. van

2017-01-01

Plant-mediated interactions between belowground (BG) and aboveground (AG) herbivores have received increasing interest recently. However, the molecular mechanisms underlying ecological consequences of BG–AG interactions are not fully clear yet. Herbivore-induced plant defenses are complex and

β cell membrane remodelling and procoagulant events occur in inflammation-driven insulin impairment: a GLP-1 receptor dependent and independent control.

Science.gov (United States)

Gleizes, Céline; Kreutter, Guillaume; Abbas, Malak; Kassem, Mohamad; Constantinescu, Andrei Alexandru; Boisramé-Helms, Julie; Yver, Blandine; Toti, Florence; Kessler, Laurence

2016-02-01

Inflammation and hyperglycaemia are associated with a prothrombotic state. Cell-derived microparticles (MPs) are the conveyors of active procoagulant tissue factor (TF) and circulate at high concentration in diabetic patients. Liraglutide, a glucagon-like peptide (GLP)-1 analogue, is known to promote insulin secretion and β-cell preservation. In this in vitro study, we examined the link between insulin impairment, procoagulant activity and plasma membrane remodelling, under inflammatory conditions. Rin-m5f β-cell function, TF activity mediated by MPs and their modulation by 1 μM liraglutide were examined in a cell cross-talk model. Methyl-β-cyclodextrine (MCD), a cholesterol depletor, was used to evaluate the involvement of raft on TF activity, MP shedding and insulin secretion as well as Soluble N-éthylmaleimide-sensitive-factor Attachment protein Receptor (SNARE)-dependent exocytosis. Cytokines induced a two-fold increase in TF activity at MP surface that was counteracted by liraglutide. Microparticles prompted TF activity on the target cells and a two-fold decrease in insulin secretion via protein kinase A (PKA) and p38 signalling, that was also abolished by liraglutide. Large lipid raft clusters were formed in response to cytokines and liraglutide or MCD-treated cells showed similar patterns. Cells pre-treated by saturating concentration of the GLP-1r antagonist exendin (9-39), showed a partial abolishment of the liraglutide-driven insulin secretion and liraglutide-decreased TF activity. Measurement of caspase 3 cleavage and MP shedding confirmed the contribution of GLP-1r-dependent and -independent pathways. Our results confirm an integrative β-cell response to GLP-1 that targets receptor-mediated signalling and membrane remodelling pointing at the coupling of insulin secretion and inflammation-driven procoagulant events. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and

Proceedings of II Molecular Imaging Symposium Cuba - Japan

International Nuclear Information System (INIS)

2016-01-01

In the Central Theater, University Hospital 'General Calixto Garcia' took place the II Symposium on Molecular Imaging Cuba Japan in the framework of the Scientific Convention for the 120th anniversary of the hospital. The event was organized by the hospital itself with the support of the Society of Medical Physics (medical physics section), CEADEN, the Embassy of Japan and the Theragnostic Compounds R&D Center Neuroscience Research Institute Gachon University, Incheon Korea. It was attended by 80 national scientific leaders and with the invaluable presence of Dr. Tatsuo IDO, Emeritus professor of Tohoku University (Sendai, Japan) who presented the results of the scientific papers presented this year in national and international events , referring to the new technologies of molecular imaging and the importance of medical physics in its development. During the meeting the importance of the new technologies of molecular imaging, its undisputed diagnosis intake and medical treatment and the value of human capital struggled to deal with the new technologies, the view that these are only used best when it is understood that they are multidisciplinary systems where each specialist and technical personnel plays an indispensable role. The challenge has medical physics to address these new technologies and the need for changes in the theoretical and practical training in the specialty. These analyzes will be given continuity in the next symposia molecular imaging. (author)

Nutritionally Mediated Oxidative Stress and Inflammation

Directory of Open Access Journals (Sweden)

Alexandra Muñoz

2013-01-01

Full Text Available There are many sources of nutritionally mediated oxidative stress that trigger inflammatory cascades along short and long time frames. These events are primarily mediated via NFκB. On the short-term scale postprandial inflammation is characterized by an increase in circulating levels of IL-6 and TNF-α and is mirrored on the long-term by proinflammatory gene expression changes in the adipocytes and peripheral blood mononuclear cells (PBMCs of obese individuals. Specifically the upregulation of CCL2/MCP-1, CCL3/MIP-1α, CCL4/MIP-1β, CXCL2/MIP-2α, and CXCL3/MIP-2β is noted because these changes have been observed in both adipocytes and PBMC of obese humans. In comparing numerous human intervention studies it is clear that pro-inflammatory and anti-inflammatory consumption choices mediate gene expression in humans adipocytes and peripheral blood mononuclear cells. Arachidonic acid and saturated fatty acids (SFAs both demonstrate an ability to increase pro-inflammatory IL-8 along with numerous other inflammatory factors including IL-6, TNFα, IL-1β, and CXCL1 for arachidonic acid and IGB2 and CTSS for SFA. Antioxidant rich foods including olive oil, fruits, and vegetables all demonstrate an ability to lower levels of IL-6 in PBMCs. Thus, dietary choices play a complex role in the mediation of unavoidable oxidative stress and can serve to exacerbate or dampen the level of inflammation.

Molecular Tools for Facilitative Carbohydrate Transporters (Gluts).

Science.gov (United States)

Tanasova, Marina; Fedie, Joseph R

2017-09-19

Facilitative carbohydrate transporters-Gluts-have received wide attention over decades due to their essential role in nutrient uptake and links with various metabolic disorders, including diabetes, obesity, and cancer. Endeavors directed towards understanding the mechanisms of Glut-mediated nutrient uptake have resulted in a multidisciplinary research field spanning protein chemistry, chemical biology, organic synthesis, crystallography, and biomolecular modeling. Gluts became attractive targets for cancer research and medicinal chemistry, leading to the development of new approaches to cancer diagnostics and providing avenues for cancer-targeting therapeutics. In this review, the current state of knowledge of the molecular interactions behind Glut-mediated sugar uptake, Glut-targeting probes, therapeutics, and inhibitors are discussed. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Brassinosteroids antagonize gibberellin- and salicylate-mediated root immunity in rice.

Science.gov (United States)

De Vleesschauwer, David; Van Buyten, Evelien; Satoh, Kouji; Balidion, Johny; Mauleon, Ramil; Choi, Il-Ryong; Vera-Cruz, Casiana; Kikuchi, Shoshi; Höfte, Monica

2012-04-01

Brassinosteroids (BRs) are a unique class of plant steroid hormones that orchestrate myriad growth and developmental processes. Although BRs have long been known to protect plants from a suite of biotic and abiotic stresses, our understanding of the underlying molecular mechanisms is still rudimentary. Aiming to further decipher the molecular logic of BR-modulated immunity, we have examined the dynamics and impact of BRs during infection of rice (Oryza sativa) with the root oomycete Pythium graminicola. Challenging the prevailing view that BRs positively regulate plant innate immunity, we show that P. graminicola exploits BRs as virulence factors and hijacks the rice BR machinery to inflict disease. Moreover, we demonstrate that this immune-suppressive effect of BRs is due, at least in part, to negative cross talk with salicylic acid (SA) and gibberellic acid (GA) pathways. BR-mediated suppression of SA defenses occurred downstream of SA biosynthesis, but upstream of the master defense regulators NONEXPRESSOR OF PATHOGENESIS-RELATED GENES1 and OsWRKY45. In contrast, BR alleviated GA-directed immune responses by interfering at multiple levels with GA metabolism, resulting in indirect stabilization of the DELLA protein and central GA repressor SLENDER RICE1 (SLR1). Collectively, these data favor a model whereby P. graminicola coopts the plant BR pathway as a decoy to antagonize effectual SA- and GA-mediated defenses. Our results highlight the importance of BRs in modulating plant immunity and uncover pathogen-mediated manipulation of plant steroid homeostasis as a core virulence strategy.

Identification of a small heat-shock protein associated with a ras-mediated signaling pathway in ectomycorrhizal symbiosis

Science.gov (United States)

Shiv Hiremath; Kirsten Lehtoma; Gopi K. Podila

2009-01-01

Initiation, development, and establishment of a functional ectomycorrhiza involve a series of biochemical events mediated by a number of genes from the fungus as well as the host plant. We have identified a heat shock protein gene from Laccaria bicolor (Lbhsp) that appears to play a role in these events. The size and...

Negative Life Events Vary by Neighborhood and Mediate the Relation Between Neighborhood Context and Psychological Well-Being

Science.gov (United States)

Although a considerable amount of neighborhood research has addressed how fear of negative events may activate stress responses, few studies have noted the potentially embedded nature of negative life events within spatial riskscapes. Co-occurring contextual social and physical h...

Predictive Sampling of Rare Conformational Events in Aqueous Solution: Designing a Generalized Orthogonal Space Tempering Method.

Science.gov (United States)

Lu, Chao; Li, Xubin; Wu, Dongsheng; Zheng, Lianqing; Yang, Wei

2016-01-12

In aqueous solution, solute conformational transitions are governed by intimate interplays of the fluctuations of solute-solute, solute-water, and water-water interactions. To promote molecular fluctuations to enhance sampling of essential conformational changes, a common strategy is to construct an expanded Hamiltonian through a series of Hamiltonian perturbations and thereby broaden the distribution of certain interactions of focus. Due to a lack of active sampling of configuration response to Hamiltonian transitions, it is challenging for common expanded Hamiltonian methods to robustly explore solvent mediated rare conformational events. The orthogonal space sampling (OSS) scheme, as exemplified by the orthogonal space random walk and orthogonal space tempering methods, provides a general framework for synchronous acceleration of slow configuration responses. To more effectively sample conformational transitions in aqueous solution, in this work, we devised a generalized orthogonal space tempering (gOST) algorithm. Specifically, in the Hamiltonian perturbation part, a solvent-accessible-surface-area-dependent term is introduced to implicitly perturb near-solute water-water fluctuations; more importantly in the orthogonal space response part, the generalized force order parameter is generalized as a two-dimension order parameter set, in which essential solute-solvent and solute-solute components are separately treated. The gOST algorithm is evaluated through a molecular dynamics simulation study on the explicitly solvated deca-alanine (Ala10) peptide. On the basis of a fully automated sampling protocol, the gOST simulation enabled repetitive folding and unfolding of the solvated peptide within a single continuous trajectory and allowed for detailed constructions of Ala10 folding/unfolding free energy surfaces. The gOST result reveals that solvent cooperative fluctuations play a pivotal role in Ala10 folding/unfolding transitions. In addition, our assessment

Prevalence of internet addiction and its association with stressful life events and psychological symptoms among adolescent internet users.

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Tang, Jie; Yu, Yizhen; Du, Yukai; Ma, Ying; Zhang, Dongying; Wang, Jiaji

2014-03-01

Internet addiction (IA) among adolescents is a serious public health problem around the world. However, there have been few studies that examine the association between IA and stressful life events and psychological symptoms among Chinese adolescent internet users. We examined the association between IA and stressful life events and psychological symptoms among a random sample of school students who were internet users (N=755) in Wuhan, China. Internet addiction, stressful life events, coping style and psychological symptoms were measured by self-rated scales. The prevalence rate of internet addiction was 6.0% among adolescent internet users. Logistic regression analyses indicated that stressors from interpersonal problem and school related problem and anxiety symptoms were significantly associated with IA after controlling for demographic characteristics. Analyses examining the coping style with the IA revealed that negative coping style may mediate the effects of stressful life events to increase the risk of IA. However, no significant interaction of stressful life events and psychological symptoms was found. These findings of the current study indicate a high prevalence of internet addiction among Chinese adolescent internet users and highlight the importance of stressors from interpersonal problem and school related problem as a risk factor for IA which mainly mediated through negative coping style. Copyright © 2013 Elsevier Ltd. All rights reserved.

Fast transient current response to switching events in short chains of molecular islands

Czech Academy of Sciences Publication Activity Database

Kalvová, Anděla; Špička, Václav; Velický, B.

2013-01-01

Roč. 26, č. 4 (2013), s. 773-777 ISSN 1557-1939 R&D Projects: GA ČR GAP204/12/0897 Institutional support: RVO:68378271 Keywords : nonequilibrium * molecular islands * initial correlations * transient currents Subject RIV: BE - Theoretical Physics Impact factor: 0.930, year: 2013

Immunoglobulin E-Mediated Autoimmunity

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Marcus Maurer

2018-04-01

Full Text Available The study of autoimmunity mediated by immunoglobulin E (IgE autoantibodies, which may be termed autoallergy, is in its infancy. It is now recognized that systemic lupus erythematosus, bullous pemphigoid (BP, and chronic urticaria, both spontaneous and inducible, are most likely to be mediated, at least in part, by IgE autoantibodies. The situation in other conditions, such as autoimmune uveitis, rheumatoid arthritis, hyperthyroid Graves’ disease, autoimmune pancreatitis, and even asthma, is far less clear but evidence for autoallergy is accumulating. To be certain of an autoallergic mechanism, it is necessary to identify both IgE autoantibodies and their targets as has been done with the transmembrane protein BP180 and the intracellular protein BP230 in BP and IL-24 in chronic spontaneous urticaria. Also, IgE-targeted therapies, such as anti-IgE, must have been shown to be of benefit to patients as has been done with both of these conditions. This comprehensive review of the literature on IgE-mediated autoallergy focuses on three related questions. What do we know about the prevalence of IgE autoantibodies and their targets in different diseases? What do we know about the relevance of IgE autoantibodies in different diseases? What do we know about the cellular and molecular effects of IgE autoantibodies? In addition to providing answers to these questions, based on a broad review of the literature, we outline the current gaps of knowledge in our understanding of IgE autoantibodies and describe approaches to address them.

Reactive Oxygen Species-Mediated Mechanisms of Action of Targeted Cancer Therapy

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Hanna-Riikka Teppo

2017-01-01

Full Text Available Targeted cancer therapies, involving tyrosine kinase inhibitors and monoclonal antibodies, for example, have recently led to substantial prolongation of survival in many metastatic cancers. Compared with traditional chemotherapy and radiotherapy, where reactive oxygen species (ROS have been directly linked to the mediation of cytotoxic effects and adverse events, the field of oxidative stress regulation is still emerging in targeted cancer therapies. Here, we provide a comprehensive review regarding the current evidence of ROS-mediated effects of antibodies and tyrosine kinase inhibitors, use of which has been indicated in the treatment of solid malignancies and lymphomas. It can be concluded that there is rapidly emerging evidence of ROS-mediated effects of some of these compounds, which is also relevant in the context of drug resistance and how to overcome it.

Say it with flowers! An fMRI study of object mediated communication

DEFF Research Database (Denmark)

Tylén, Kristian; Wallentin, Mikkel; Roepstorff, Andreas

2009-01-01

Human communicational interaction can be mediated by a host of expressive means from words in a natural language to gestures and material symbols. Given the proper contextual setting even an everyday object can gain a mediating function in a communicational situation. In this study we used event......-related fMRI to study the brain activity caused by everyday material objects when they are perceived as signals. We found that comprehension of material signals activates bilaterally areas of the ventral stream and pars triangularis of the inferior frontal cortex, that is, areas traditionally associated...

Occupying, mediating and resignifying the city's image

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Didiana Prata

2017-12-01

Full Text Available The opening of the bike path on Avenida Paulista and the closing of vehicle lanes on Sundays for exclusive pedestrian use transformed the city’s iconic avenue into another space reframed for its temporary use. From this example of collective event, we will relate the experience of pedestrians or cyclists with the production of urban landscape images made with mobile devices, the mobile phone cameras. The main focus will be to understand how the aesthetic absorption of urban things comes through, via production, mediation and placement of images on social networks – specifically on Instagram – and to what extent overproduction of event driven pictures, and the aesthetics-oriented day-to-day routine allow for the production of new poetry and new bonds with the city.

LARP1 functions as a molecular switch for mTORC1-mediated translation of an essential class of mRNAs.

Science.gov (United States)

Hong, Sungki; Freeberg, Mallory A; Han, Ting; Kamath, Avani; Yao, Yao; Fukuda, Tomoko; Suzuki, Tsukasa; Kim, John K; Inoki, Ken

2017-06-26

The RNA binding protein, LARP1, has been proposed to function downstream of mTORC1 to regulate the translation of 5'TOP mRNAs such as those encoding ribosome proteins (RP). However, the roles of LARP1 in the translation of 5'TOP mRNAs are controversial and its regulatory roles in mTORC1-mediated translation remain unclear. Here we show that LARP1 is a direct substrate of mTORC1 and Akt/S6K1. Deep sequencing of LARP1-bound mRNAs reveal that non-phosphorylated LARP1 interacts with both 5' and 3'UTRs of RP mRNAs and inhibits their translation. Importantly, phosphorylation of LARP1 by mTORC1 and Akt/S6K1 dissociates it from 5'UTRs and relieves its inhibitory activity on RP mRNA translation. Concomitantly, phosphorylated LARP1 scaffolds mTORC1 on the 3'UTRs of translationally-competent RP mRNAs to facilitate mTORC1-dependent induction of translation initiation. Thus, in response to cellular mTOR activity, LARP1 serves as a phosphorylation-sensitive molecular switch for turning off or on RP mRNA translation and subsequent ribosome biogenesis.

Maize transformation technology development for commercial event generation

Science.gov (United States)

Que, Qiudeng; Elumalai, Sivamani; Li, Xianggan; Zhong, Heng; Nalapalli, Samson; Schweiner, Michael; Fei, Xiaoyin; Nuccio, Michael; Kelliher, Timothy; Gu, Weining; Chen, Zhongying; Chilton, Mary-Dell M.

2014-01-01

Maize is an important food and feed crop in many countries. It is also one of the most important target crops for the application of biotechnology. Currently, there are more biotech traits available on the market in maize than in any other crop. Generation of transgenic events is a crucial step in the development of biotech traits. For commercial applications, a high throughput transformation system producing a large number of high quality events in an elite genetic background is highly desirable. There has been tremendous progress in Agrobacterium-mediated maize transformation since the publication of the Ishida et al. (1996) paper and the technology has been widely adopted for transgenic event production by many labs around the world. We will review general efforts in establishing efficient maize transformation technologies useful for transgenic event production in trait research and development. The review will also discuss transformation systems used for generating commercial maize trait events currently on the market. As the number of traits is increasing steadily and two or more modes of action are used to control key pests, new tools are needed to efficiently transform vectors containing multiple trait genes. We will review general guidelines for assembling binary vectors for commercial transformation. Approaches to increase transformation efficiency and gene expression of large gene stack vectors will be discussed. Finally, recent studies of targeted genome modification and transgene insertion using different site-directed nuclease technologies will be reviewed. PMID:25140170

Maize transformation technology development for commercial event generation.

Science.gov (United States)

Que, Qiudeng; Elumalai, Sivamani; Li, Xianggan; Zhong, Heng; Nalapalli, Samson; Schweiner, Michael; Fei, Xiaoyin; Nuccio, Michael; Kelliher, Timothy; Gu, Weining; Chen, Zhongying; Chilton, Mary-Dell M

2014-01-01

Maize is an important food and feed crop in many countries. It is also one of the most important target crops for the application of biotechnology. Currently, there are more biotech traits available on the market in maize than in any other crop. Generation of transgenic events is a crucial step in the development of biotech traits. For commercial applications, a high throughput transformation system producing a large number of high quality events in an elite genetic background is highly desirable. There has been tremendous progress in Agrobacterium-mediated maize transformation since the publication of the Ishida et al. (1996) paper and the technology has been widely adopted for transgenic event production by many labs around the world. We will review general efforts in establishing efficient maize transformation technologies useful for transgenic event production in trait research and development. The review will also discuss transformation systems used for generating commercial maize trait events currently on the market. As the number of traits is increasing steadily and two or more modes of action are used to control key pests, new tools are needed to efficiently transform vectors containing multiple trait genes. We will review general guidelines for assembling binary vectors for commercial transformation. Approaches to increase transformation efficiency and gene expression of large gene stack vectors will be discussed. Finally, recent studies of targeted genome modification and transgene insertion using different site-directed nuclease technologies will be reviewed.

Molecular dynamics and docking simulation of a natural variant of Activated Protein C with impaired protease activity: implications for integrin-mediated antiseptic function.

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D'Ursi, Pasqualina; Orro, Alessandro; Morra, Giulia; Moscatelli, Marco; Trombetti, Gabriele; Milanesi, Luciano; Rovida, Ermanna

2015-01-01

Activated Protein C (APC) is a multifunctional serine protease, primarily known for its anticoagulant function in the coagulation system. Several studies have already elucidated its role in counteracting apoptosis and inflammation in cells, while significant effort is still ongoing for defining its involvement in sepsis. Earlier literature has shown that the antiseptic function of APC is mediated by its binding to leukocyte integrins, which is due to the presence of the integrin binding motif Arg-Gly-Asp at the N-terminus of the APC catalytic chain. Many natural mutants have been identified in patients with Protein C deficiency diagnosis including a variant of specificity pocket (Gly216Asp). In this work, we present a molecular model of the complex of APC with αVβ3 integrin obtained by protein-protein docking approach. A computational analysis of this variant is hereby presented, based on molecular dynamics and docking simulations, aiming at investigating the effects of the Gly216Asp mutation on the protein conformation and inferring its functional implications. Our study shows that such mutation is likely to impair the protease activity while preserving the overall protein fold. Moreover, superposition of the integrin binding motifs in wild-type and mutant forms suggests that the interaction with integrin can still occur and thus the mutant is likely to retain its antiseptic function related to the neutrophyl integrin binding. Therapeutic applications could result in this APC mutant which retains antiseptic function without anticoagulant side effects.

Mediation analysis with time varying exposures and mediators.

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VanderWeele, Tyler J; Tchetgen Tchetgen, Eric J

2017-06-01

In this paper we consider causal mediation analysis when exposures and mediators vary over time. We give non-parametric identification results, discuss parametric implementation, and also provide a weighting approach to direct and indirect effects based on combining the results of two marginal structural models. We also discuss how our results give rise to a causal interpretation of the effect estimates produced from longitudinal structural equation models. When there are time-varying confounders affected by prior exposure and mediator, natural direct and indirect effects are not identified. However, we define a randomized interventional analogue of natural direct and indirect effects that are identified in this setting. The formula that identifies these effects we refer to as the "mediational g-formula." When there is no mediation, the mediational g-formula reduces to Robins' regular g-formula for longitudinal data. When there are no time-varying confounders affected by prior exposure and mediator values, then the mediational g-formula reduces to a longitudinal version of Pearl's mediation formula. However, the mediational g-formula itself can accommodate both mediation and time-varying confounders and constitutes a general approach to mediation analysis with time-varying exposures and mediators.

Oxidative Mechanisms of Monocyte-Mediated Cytotoxicity

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Weiss, Stephen J.; Lobuglio, Albert F.; Kessler, Howard B.

1980-01-01

Human monocytes stimulated with phorbol myristate acetate were able to rapidly destroy autologous erythrocyte targets. Monocyte-mediated cytotoxicity was related to phorbol myristate acetate concentration and monocyte number. Purified preparations of lymphocytes were incapable of mediating erythrocyte lysis in this system. The ability of phorbol myristate acetate-stimulated monocytes to lyse erythrocyte targets was markedly impaired by catalase or superoxide dismutase but not by heat-inactivated enzymes or albumin. Despite a simultaneous requirement for superoxide anion and hydrogen peroxide in the cytotoxic event, a variety of hydroxyl radical and singlet oxygen scavengers did not effect cytolysis. However, tryptophan significantly inhibited cytotoxicity. The myeloperoxidase inhibitor cyanide enhanced erythrocyte destruction, whereas azide reduced it modestly. The inability of cyanide to reduce cytotoxicity coupled with the protective effect of superoxide dismutase suggests that cytotoxicity is independent of the classic myeloperoxidase system. We conclude that monocytes, stimulated with phorbol myristate acetate, generate superoxide anion and hydrogen peroxide, which together play an integral role in this cytotoxic mechanism.

GABA-mediated synchronization in the human neocortex: elevations in extracellular potassium and presynaptic mechanisms.

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Louvel, J; Papatheodoropoulos, C; Siniscalchi, A; Kurcewicz, I; Pumain, R; Devaux, B; Turak, B; Esposito, V; Villemeure, J G; Avoli, M

2001-01-01

Field potential and extracellular [K(+)] ([K(+)](o)) recordings were made in the human neocortex in an in vitro slice preparation to study the synchronous activity that occurs in the presence of 4-aminopyridine (50 microM) and ionotropic excitatory amino acid receptor antagonists. Under these experimental conditions, negative or negative-positive field potentials accompanied by rises in [K(+)](o) (up to 4.1 mM from a baseline of 3.25 mM) occurred spontaneously at intervals of 3-27 s. Both field potentials and [K(+)](o) elevations were largest at approximately 1000 microm from the pia. Similar events were induced by neocortical electrical stimuli. Application of medium containing low [Ca(2+)]/high [Mg(2+)] (n=3 slices), antagonism of the GABA(A) receptor (n=7) or mu-opioid receptor activation (n=4) abolished these events. Hence, they represented network, GABA-mediated potentials mainly reflecting the activation of type A receptors following GABA release from interneurons. The GABA(B) receptor agonist baclofen (10-100 microM, n=11) reduced and abolished the GABA-mediated potentials (ID(50)=18 microM). Baclofen effects were antagonized by the GABA(B) receptor antagonist CGP 35348 (0.1-1 mM, n=6; ID(50)=0.19 mM). CGP 38345 application to control medium increased the amplitude of the GABA-mediated potentials and the concomitant [K(+)](o) rises without modifying their rate of occurrence. The GABA-mediated potentials were not influenced by the broad-spectrum metabotropic glutamate agonist (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (100 microM, n=10), but decreased in rate with the group I receptor agonist (S)-3,5-dihydroxyphenylglycine (10-100 microM, n=9). Our data indicate that human neocortical networks challenged with 4-aminopyridine generate glutamatergic-independent, GABA-mediated potentials that are modulated by mu-opioid and GABA(B) receptors presumably located on interneuron terminals. These events are associated with [K(+)](o) elevations that may

Molecular and physiological responses of trees to waterlogging stress.

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Kreuzwieser, Jürgen; Rennenberg, Heinz

2014-10-01

One major effect of global climate change will be altered precipitation patterns in many regions of the world. This will cause a higher probability of long-term waterlogging in winter/spring and flash floods in summer because of extreme rainfall events. Particularly, trees not adapted at their natural site to such waterlogging stress can be impaired. Despite the enormous economic, ecological and social importance of forest ecosystems, the effect of waterlogging on trees is far less understood than the effect on many crops or the model plant Arabidopsis. There is only a handful of studies available investigating the transcriptome and metabolome of waterlogged trees. Main physiological responses of trees to waterlogging include the stimulation of fermentative pathways and an accelerated glycolytic flux. Many energy-consuming, anabolic processes are slowed down to overcome the energy crisis mediated by waterlogging. A crucial feature of waterlogging tolerance is the steady supply of glycolysis with carbohydrates, particularly in the roots; stress-sensitive trees fail to maintain sufficient carbohydrate availability resulting in the dieback of the stressed tissues. The present review summarizes physiological and molecular features of waterlogging tolerance of trees; the focus is on carbon metabolism in both, leaves and roots of trees. © 2014 John Wiley & Sons Ltd.

The molecular origin and evolution of dim-light vision in mammals.

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Bickelmann, Constanze; Morrow, James M; Du, Jing; Schott, Ryan K; van Hazel, Ilke; Lim, Steve; Müller, Johannes; Chang, Belinda S W

2015-11-01

The nocturnal origin of mammals is a longstanding hypothesis that is considered instrumental for the evolution of endothermy, a potential key innovation in this successful clade. This hypothesis is primarily based on indirect anatomical inference from fossils. Here, we reconstruct the evolutionary history of rhodopsin--the vertebrate visual pigment mediating the first step in phototransduction at low-light levels--via codon-based model tests for selection, combined with gene resurrection methods that allow for the study of ancient proteins. Rhodopsin coding sequences were reconstructed for three key nodes: Amniota, Mammalia, and Theria. When expressed in vitro, all sequences generated stable visual pigments with λMAX values similar to the well-studied bovine rhodopsin. Retinal release rates of mammalian and therian ancestral rhodopsins, measured via fluorescence spectroscopy, were significantly slower than those of the amniote ancestor, indicating altered molecular function possibly related to nocturnality. Positive selection along the therian branch suggests adaptive evolution in rhodopsin concurrent with therian ecological diversification events during the Mesozoic that allowed for an exploration of the environment at varying light levels. © 2015 The Author(s). Evolution © 2015 The Society for the Study of Evolution.

Temporal dynamics of host molecular responses differentiate symptomatic and asymptomatic influenza a infection.

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Yongsheng Huang

2011-08-01

Full Text Available Exposure to influenza viruses is necessary, but not sufficient, for healthy human hosts to develop symptomatic illness. The host response is an important determinant of disease progression. In order to delineate host molecular responses that differentiate symptomatic and asymptomatic Influenza A infection, we inoculated 17 healthy adults with live influenza (H3N2/Wisconsin and examined changes in host peripheral blood gene expression at 16 timepoints over 132 hours. Here we present distinct transcriptional dynamics of host responses unique to asymptomatic and symptomatic infections. We show that symptomatic hosts invoke, simultaneously, multiple pattern recognition receptors-mediated antiviral and inflammatory responses that may relate to virus-induced oxidative stress. In contrast, asymptomatic subjects tightly regulate these responses and exhibit elevated expression of genes that function in antioxidant responses and cell-mediated responses. We reveal an ab initio molecular signature that strongly correlates to symptomatic clinical disease and biomarkers whose expression patterns best discriminate early from late phases of infection. Our results establish a temporal pattern of host molecular responses that differentiates symptomatic from asymptomatic infections and reveals an asymptomatic host-unique non-passive response signature, suggesting novel putative molecular targets for both prognostic assessment and ameliorative therapeutic intervention in seasonal and pandemic influenza.

Tear Mediators in Corneal Ectatic Disorders.

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Dorottya Pásztor

Full Text Available To compare the concentrations of 11 tear mediators in order to reveal the biochemical difference between pellucid marginal degeneration (PMD and keratoconus (KC.We have designed a cross-sectional study in which patients with corneal ectasia based on slit-lamp biomicroscopy and Pentacam HR (keratometry values (K1, K2, Kmax, astigmatism, minimal radius of curvature (Rmin, corneal thickness (Apex and Min, indices (surface variation, vertical asymmetry, keratoconus, central keratoconus, height asymmetry and decentration were enrolled. Eyes of keratoconic patients were similar to the PMD patients in age and severity (K2, Kmax and Rmin. Non-stimulated tear samples were collected from nine eyes of seven PMD patients, 55 eyes of 55 KC patients and 24 eyes of 24 healthy controls. The mediators' (interleukin -6, -10, chemokine ligand 5, -8, -10, matrix metalloproteinase (MMP -9, -13, tissue inhibitor of metalloproteinases (TIMP-1, tissue plasminogen activator, plasminogen activator inhibitor, nerve growth factor concentrations were measured using Cytometric Bead Array.MMP-9 was the only mediator which presented relevant variances between the two patient groups (p = 0.005. The ratios of MMP-9 and TIMP-1 were 2.45, 0.40 and 0.23 in PMD, KC and the controls, respectively.As far as we are aware, this is the first study that aims to reveal the biochemical differences between PMD and KC. Further studies of biomarkers to investigate the precise role of these mediators need to be defined, and it is important to confirm the observed changes in a larger study to gain further insights into the molecular alterations in PMD.

Can sports events affect suicidal behavior? A review of the literature and implications for prevention.

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Andriessen, Karl; Krysinska, Karolina

2009-01-01

Engagement in sports and physical activity, either actively as an athlete or in a passive way as a spectator, impacts interpersonal behavior and physical and mental health. The study reviews literature on the relationship between sports spectatorship and suicidal behavior to ascertain whether sports spectatorship has an impact on suicidal behavior, either increasing the risk or being a protective factor. The literature was searched via PubMed/MEDLINE and PsycINFO. Nine studies published between 1986 and 2006 were identified. The reviewed studies focused on the impact of sports events on the societal level, and analyzed data regarding national or local suicide rates. Their results indicate that sports events can have an impact on suicide mortality and morbidity, but this relationship seems to be mediated by age, gender, marital status, and alcohol consumption, as well as the process and outcome of the game (e.g., victory vs. defeat of the favored team). There is some evidence that sports events can reduce the rates of suicide on the societal level; however, there is a lack of studies exploring how sports spectatorship might influence levels of suicide risk in individuals and how mediating variables might operate on the individual level.

Molecular pathways underpinning ethanol-induced neurodegeneration

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Dan eGoldowitz*

2014-07-01

Full Text Available While genetics impacts the type and severity of damage following developmental ethanol exposure, little is currently known about the molecular pathways that mediate these effects. Traditionally, research in this area has used a candidate gene approach and evaluated effects on a gene-by-gene basis. Recent studies, however, have begun to use unbiased approaches and genetic reference populations to evaluate the roles of genotype and epigenetic modifications in phenotypic changes following developmental ethanol exposure, similar to studies that evaluated numerous alcohol-related phenotypes in adults. Here, we present work assessing the role of genetics and chromatin-based alterations in mediating ethanol-induced apoptosis in the developing nervous system. Utilizing the expanded family of BXD recombinant inbred mice, animals were exposed to ethanol at postnatal day 7 via subcutaneous injection (5.0 g/kg in 2 doses. Tissue was collected 7 hours after the initial ethanol treatment and analyzed by activated caspase-3 immunostaining to visualize dying cells in the cerebral cortex and hippocampus. In parallel, the levels of two histone modifications relevant to apoptosis, γH2AX and H3K14 acetylation, were examined in the cerebral cortex using protein blot analysis. Activated caspase-3 staining identified marked differences in cell death across brain regions between different mouse strains. Genetic analysis of ethanol susceptibility in the hippocampus led to the identification of a quantitative trait locus on chromosome 12, which mediates, at least in part, strain-specific differential vulnerability to ethanol-induced apoptosis. Furthermore, analysis of chromatin modifications in the cerebral cortex revealed a global increase in γH2AX levels following ethanol exposure, but did not show any change in H3K14 acetylation levels. Together, these findings provide new insights into the molecular mechanisms and genetic contributions underlying ethanol

The role of molecular pain biomarkers in temporomandibular joint internal derangement.

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Ernberg, M

2017-06-01

There is evidence that low-grade inflammation may be responsible for pain and development of degenerative changes in temporomandibular joint internal derangement. This article reviews the current knowledge of the molecular mechanisms behind TMJ internal derangements. A non-systematic search was carried out in PubMed, Embase and the Cochrane library for studies regarding pathophysiological mechanisms behind internal derangements focusing on pain-mediating inflammatory and cartilage-degrading molecules. Recent data suggest that release of cytokines may be the key event for pain and cartilage destruction in TMJ internal derangements. Cytokines promote the release of matrix metalloproteinases (MMPs), and due to hypoxia, vascular endothelial growth factor (VEGF) is released. This activates chondrocytes to produce MMPs and reduce their tissue inhibitors (TIMPs) as well as the recruitment of osteoclasts, ultimately leading to cartilage and bone resorption. Also, proteoglycans have an important role in this process. Several cytokines, MMPs, TIMPs and VEGF have been identified in higher concentrations in the TMJ synovial fluid of patients with painful internal derangements and shown to be associated with the degree of degeneration. Other molecules that show elevated levels include hyaluronic acid synthase, disintegrin and metalloproteinase with thrombospondin motifs (ADAMTs), aggrecan, fibromodulin, biglycan and lumican. Taken together, more or less pronounced inflammation of TMJ structures with release of cytokines, MMPs and other molecular markers that interact in a complex manner may be responsible for tissue degeneration in internal derangements. As internal derangements may be symptom-free, the degree of inflammation, but also other mechanisms, may be important for pain development. © 2017 John Wiley & Sons Ltd.

Serial killers: ordering caspase activation events in apoptosis.

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Slee, E A; Adrain, C; Martin, S J

1999-11-01

Caspases participate in the molecular control of apoptosis in several guises; as triggers of the death machinery, as regulatory elements within it, and ultimately as a subset of the effector elements of the machinery itself. The mammalian caspase family is steadily growing and currently contains 14 members. At present, it is unclear whether all of these proteases participate in apoptosis. Thus, current research in this area is focused upon establishing the repertoire and order of caspase activation events that occur during the signalling and demolition phases of cell death. Evidence is accumulating to suggest that proximal caspase activation events are typically initiated by molecules that promote caspase aggregation. As expected, distal caspase activation events are likely to be controlled by caspases activated earlier in the cascade. However, recent data has cast doubt upon the functional demarcation of caspases into signalling (upstream) and effector (downstream) roles based upon their prodomain lengths. In particular, caspase-3 may perform an important role in propagating the caspase cascade, in addition to its role as an effector caspase within the death programme. Here, we discuss the apoptosis-associated caspase cascade and the hierarchy of caspase activation events within it.

Evolution of egg coats: linking molecular biology and ecology.

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Shu, Longfei; Suter, Marc J-F; Räsänen, Katja

2015-08-01

One central goal of evolutionary biology is to explain how biological diversity emerges and is maintained in nature. Given the complexity of the phenotype and the multifaceted nature of inheritance, modern evolutionary ecological studies rely heavily on the use of molecular tools. Here, we show how molecular tools help to gain insight into the role of egg coats (i.e. the extracellular structures surrounding eggs and embryos) in evolutionary diversification. Egg coats are maternally derived structures that have many biological functions from mediating fertilization to protecting the embryo from environmental hazards. They show great molecular, structural and functional diversity across species, but intraspecific variability and the role of ecology in egg coat evolution have largely been overlooked. Given that much of the variation that influences egg coat function is ultimately determined by their molecular phenotype, cutting-edge molecular tools (e.g. proteomics, glycomics and transcriptomics), combined with functional assays, are needed for rigorous inferences on their evolutionary ecology. Here, we identify key research areas and highlight emerging molecular techniques that can increase our understanding of the role of egg coats in the evolution of biological diversity, from adaptation to speciation. © 2015 John Wiley & Sons Ltd.

Molecular interactions between tomato and the leaf mold pathogen Cladosporium fulvum.

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Rivas, Susana; Thomas, Colwyn M

2005-01-01

The interaction between tomato and the leaf mold pathogen Cladosporium fulvum is controlled in a gene-for-gene manner. This interaction has provided useful insights to the molecular basis of recognition specificity in plant disease resistance (R) proteins, disease resistance (R) gene evolution, R-protein mediated signaling, and cellular responses to pathogen attack. Tomato Cf genes encode type I membrane-associated receptor-like proteins (RLPs) comprised predominantly of extracellular leucine-rich repeats (eLRRs) and which are anchored in the plasma membrane. Cf proteins recognize fungal avirulence (Avr) peptides secreted into the leaf apoplast during infection. A direct interaction of Cf proteins with their cognate Avr proteins has not been demonstrated and the molecular mechanism of Avr protein perception is not known. Following ligand perception Cf proteins trigger a hypersensitive response (HR) and the arrest of pathogen development. Cf proteins lack an obvious signaling domain, suggesting that defense response activation is mediated through interactions with other partners. Avr protein perception results in the rapid accumulation of active oxygen species (AOS), changes in cellular ion fluxes, activation of protein kinase cascades, changes in gene expression and, possibly, targeted protein degradation. Here we review our current understanding of Cf-mediated responses in resistance to C. fulvum.

Comparative mRNA and microRNA expression profiling of three genitourinary cancers reveals common hallmarks and cancer-specific molecular events.

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Xianxin Li

Full Text Available Genome-wide gene expression profile using deep sequencing technologies can drive the discovery of cancer biomarkers and therapeutic targets. Such efforts are often limited to profiling the expression signature of either mRNA or microRNA (miRNA in a single type of cancer.Here we provided an integrated analysis of the genome-wide mRNA and miRNA expression profiles of three different genitourinary cancers: carcinomas of the bladder, kidney and testis.Our results highlight the general or cancer-specific roles of several genes and miRNAs that may serve as candidate oncogenes or suppressors of tumor development. Further comparative analyses at the systems level revealed that significant aberrations of the cell adhesion process, p53 signaling, calcium signaling, the ECM-receptor and cell cycle pathways, the DNA repair and replication processes and the immune and inflammatory response processes were the common hallmarks of human cancers. Gene sets showing testicular cancer-specific deregulation patterns were mainly implicated in processes related to male reproductive function, and general disruptions of multiple metabolic pathways and processes related to cell migration were the characteristic molecular events for renal and bladder cancer, respectively. Furthermore, we also demonstrated that tumors with the same histological origins and genes with similar functions tended to group together in a clustering analysis. By assessing the correlation between the expression of each miRNA and its targets, we determined that deregulation of 'key' miRNAs may result in the global aberration of one or more pathways or processes as a whole.This systematic analysis deciphered the molecular phenotypes of three genitourinary cancers and investigated their variations at the miRNA level simultaneously. Our results provided a valuable source for future studies and highlighted some promising genes, miRNAs, pathways and processes that may be useful for diagnostic or

Covariate measurement error correction methods in mediation analysis with failure time data.

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Zhao, Shanshan; Prentice, Ross L

2014-12-01

Mediation analysis is important for understanding the mechanisms whereby one variable causes changes in another. Measurement error could obscure the ability of the potential mediator to explain such changes. This article focuses on developing correction methods for measurement error in the mediator with failure time outcomes. We consider a broad definition of measurement error, including technical error, and error associated with temporal variation. The underlying model with the "true" mediator is assumed to be of the Cox proportional hazards model form. The induced hazard ratio for the observed mediator no longer has a simple form independent of the baseline hazard function, due to the conditioning event. We propose a mean-variance regression calibration approach and a follow-up time regression calibration approach, to approximate the partial likelihood for the induced hazard function. Both methods demonstrate value in assessing mediation effects in simulation studies. These methods are generalized to multiple biomarkers and to both case-cohort and nested case-control sampling designs. We apply these correction methods to the Women's Health Initiative hormone therapy trials to understand the mediation effect of several serum sex hormone measures on the relationship between postmenopausal hormone therapy and breast cancer risk. © 2014, The International Biometric Society.

Behavioral control blunts reactions to contemporaneous and future adverse events: Medial prefrontal cortex plasticity and a corticostriatal network

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Steven F. Maier

2015-01-01

Full Text Available It has been known for many years that the ability to exert behavioral control over an adverse event blunts the behavioral and neurochemical impact of the event. More recently, it has become clear that the experience of behavioral control over adverse events also produces enduring changes that reduce the effects of subsequent negative events, even if they are uncontrollable and quite different from the original event controlled. This review focuses on the mechanism by which control both limits the impact of the stressor being experienced and produces enduring, trans-situational “immunization”. The evidence will suggest that control is detected by a corticostriatal circuit involving the ventral medial prefrontal cortex (mPFC and the posterior dorsomedial striatum (DMS. Once control is detected, other mPFC neurons that project to stress-responsive brainstem (dorsal raphe nucleus, DRN and limbic (amygdala structures exert top–down inhibitory control over the activation of these structures that is produced by the adverse event. These structures, such as the DRN and amygdala, in turn regulate the proximate mediators of the behavioral and physiological responses produced by adverse events, and so control blunts these responses. Importantly, the joint occurrence of control and adverse events seems to produce enduring plastic changes in the top–down inhibitory mPFC system such that this system is now activated by later adverse events even if they are uncontrollable, thereby reducing the impact of these events. Other issues are discussed that include a whether other processes such as safety signals and exercise, that lead to resistance/resilience, also use the mPFC circuitry or do so in other ways; b whether control has similar effects and neural mediation in humans, and c the relationship of this work to clinical phenomena.

Memory for past public events depends on retrieval frequency but not memory age in Alzheimer's disease.

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Müller, Stephan; Mychajliw, Christian; Hautzinger, Martin; Fallgatter, Andreas J; Saur, Ralf; Leyhe, Thomas

2014-01-01

Alzheimer's disease (AD) is characterized by retrograde memory deficits primarily caused by dysfunction of the hippocampal complex. Unresolved questions exist concerning the time course of hippocampal involvement in conscious recollection of declarative knowledge, as reports of temporal gradients of retrograde amnesia have been inconclusive. The aim of this study was to examine whether the extent and severity of retrograde amnesia is mediated by retrieval frequency or, in contrast, whether it depends on the age of the memory according to the assumptions of the main current theories of memory formation. We compared recall of past public events in patients with AD and healthy control (HC) individuals using the Historic Events Test (HET). The HET assesses knowledge about famous public events of the past 60 years divided into four time segments and consists of subjective memory rating, dating accuracy, and contextual memory tasks. Although memory for public events was impaired in AD patients, there was a strong effect of retrieval frequency across all time segments and both groups. As AD and HC groups derived similar benefits from greater retrieval frequency, cortical structures other than the hippocampal complex may mediate memory retrieval. These findings suggest that more frequently retrieved events and facts become more independent of the hippocampal complex and thus better protected against early damage of AD. This could explain why cognitive activity may delay the onset of memory decline in persons who develop AD.

Early cell adhesion events differ between osteoporotic and non-osteoporotic osteoblasts.

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Perinpanayagam, H; Zaharias, R; Stanford, C; Brand, R; Keller, J; Schneider, G

2001-11-01

In osteoporosis, the regenerative capacity of bone is compromised, which may involve altered osteoblast (OB) activity. This could be attributed to an inappropriate synthesis and assembly of an extracellular matrix (ECM), altered cell adhesion to the ECM, or be due to inappropriate downstream activation of adhesion-mediated signaling cascades through proteins such as focal adhesion kinase (FAK). The purpose of our study was to compare early adhesion-mediated events using previously described and characterized clinically derived OBs obtained from human patients undergoing major joint arthroplasty for osteoporosis or osteoarthritis. The presence or absence of osteoporosis was established with a radiographic index. Using light microscopy and crystal violet staining, we show that OB cells derived from sites of osteoporosis do not attach and spread as well as non-osteoporotic (OP) OB cells. OP cells initially have a more rounded morphology, and show significantly less (P attachment to serum-coated tissue culture plastic over a 24 h time period. Immunofluorescent labeling after 24 h of attachment showed that OP OB focal adhesions (FAs) and stress fibers were less defined, and that the OP cells were smaller and had a more motile phenotype. When normalized protein lysates were Western blotted for phosphotyrosine (PY) a band corresponding to pp125FAK was identified. FAK tyrosine phosphorylation was evident at 6 h in both the OP and non-OP OBs, but decreased or was absent through 24 h in OP OBs. These results suggest early adhesion-mediated events, such as cell adhesion, attachment, and FAK signaling via PY may be altered in OP OBs.

Survival under stress: molecular mechanisms of metabolic rate ...

African Journals Online (AJOL)

Studies in my laboratory are analysing the molecular mechanisms and regulatory events that underlie transitions to and from hypometabolic states In systems including anoxia-tolerant turtles and molluscs, estivating snails and toads, hibernating small mammals, and freeze tolerant frogs and insects. Our newest research ...

Hippocampal and ventral medial prefrontal activation during retrieval-mediated learning supports novel inference.

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Zeithamova, Dagmar; Dominick, April L; Preston, Alison R

2012-07-12

Memory enables flexible use of past experience to inform new behaviors. Although leading theories hypothesize that this fundamental flexibility results from the formation of integrated memory networks relating multiple experiences, the neural mechanisms that support memory integration are not well understood. Here, we demonstrate that retrieval-mediated learning, whereby prior event details are reinstated during encoding of related experiences, supports participants' ability to infer relationships between distinct events that share content. Furthermore, we show that activation changes in a functionally coupled hippocampal and ventral medial prefrontal cortical circuit track the formation of integrated memories and successful inferential memory performance. These findings characterize the respective roles of these regions in retrieval-mediated learning processes that support relational memory network formation and inferential memory in the human brain. More broadly, these data reveal fundamental mechanisms through which memory representations are constructed into prospectively useful formats. Copyright © 2012 Elsevier Inc. All rights reserved.

Overview of the biology of extreme events

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Gutschick, V. P.; Bassirirad, H.

2008-12-01

Extreme events have, variously, meteorological origins as in heat waves or precipitation extremes, or biological origins as in pest and disease eruptions (or tectonic, earth-orbital, or impact-body origins). Despite growing recognition that these events are changing in frequency and intensity, a universal model of ecological responses to these events is slow to emerge. Extreme events, negative and positive, contrast with normal events in terms of their effects on the physiology, ecology, and evolution of organisms, hence also on water, carbon, and nutrient cycles. They structure biogeographic ranges and biomes, almost surely more than mean values often used to define biogeography. They are challenging to study for obvious reasons of field-readiness but also because they are defined by sequences of driving variables such as temperature, not point events. As sequences, their statistics (return times, for example) are challenging to develop, as also from the involvement of multiple environmental variables. These statistics are not captured well by climate models. They are expected to change with climate and land-use change but our predictive capacity is currently limited. A number of tools for description and analysis of extreme events are available, if not widely applied to date. Extremes for organisms are defined by their fitness effects on those organisms, and are specific to genotypes, making them major agents of natural selection. There is evidence that effects of extreme events may be concentrated in an extended recovery phase. We review selected events covering ranges of time and magnitude, from Snowball Earth to leaf functional loss in weather events. A number of events, such as the 2003 European heat wave, evidence effects on water and carbon cycles over large regions. Rising CO2 is the recent extreme of note, for its climatic effects and consequences for growing seasons, transpiration, etc., but also directly in its action as a substrate of photosynthesis

Protection of HepG2 cells against acrolein toxicity by 2-cyano-3,12-dioxooleana-1,9-dien-28-imidazolide via glutathione-mediated mechanism.

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Shah, Halley; Speen, Adam M; Saunders, Christina; Brooke, Elizabeth A S; Nallasamy, Palanisamy; Zhu, Hong; Li, Y Robert; Jia, Zhenquan

2015-10-01

Acrolein is an environmental toxicant, mainly found in smoke released from incomplete combustion of organic matter. Several studies showed that exposure to acrolein can lead to liver damage. The mechanisms involved in acrolein-induced hepatocellular toxicity, however, are not completely understood. This study examined the cytotoxic mechanisms of acrolein on HepG2 cells. Acrolein at pathophysiological concentrations was shown to cause apoptotic cell death and an increase in levels of protein carbonyl and thiobarbituric acid reactive acid substances. Acrolein also rapidly depleted intracellular glutathione (GSH), GSH-linked glutathione-S-transferases, and aldose reductase, three critical cellular defenses that detoxify reactive aldehydes. Results further showed that depletion of cellular GSH by acrolein preceded the loss of cell viability. To further determine the role of cellular GSH in acrolein-mediated cytotoxicity, buthionine sulfoximine (BSO) was used to inhibit cellular GSH biosynthesis. It was observed that depletion of cellular GSH by BSO led to a marked potentiation of acrolein-mediated cytotoxicity in HepG2 cells. To further assess the contribution of these events to acrolein-induced cytotoxicity, triterpenoid compound 2-cyano-3,12-dioxooleana-1,9-dien-28-imidazolide (CDDO-Im) was used for induction of GSH. Induction of GSH by CDDO-Im afforded cytoprotection against acrolein toxicity in HepG2 cells. Furthermore, BSO significantly inhibited CDDO-Im-mediated induction in cellular GSH levels and also reversed cytoprotective effects of CDDO-Im in HepG2 cells. These results suggest that GSH is a predominant mechanism underlying acrolein-induced cytotoxicity as well as CDDO-Im-mediated cytoprotection. This study may provide understanding on the molecular action of acrolein which may be important to develop novel strategies for the prevention of acrolein-mediated toxicity. © 2014 by the Society for Experimental Biology and Medicine.

Event-by-event jet quenching

Energy Technology Data Exchange (ETDEWEB)

Fries, R.J.; Rodriguez, R.; Ramirez, E.

2010-08-14

High momentum jets and hadrons can be used as probes for the quark gluon plasma (QGP) formed in nuclear collisions at high energies. We investigate the influence of fluctuations in the fireball on jet quenching observables by comparing propagation of light quarks and gluons through averaged, smooth QGP fireballs with event-by-event jet quenching using realistic inhomogeneous fireballs. We find that the transverse momentum and impact parameter dependence of the nuclear modification factor R{sub AA} can be fit well in an event-by-event quenching scenario within experimental errors. However the transport coefficient {cflx q} extracted from fits to the measured nuclear modification factor R{sub AA} in averaged fireballs underestimates the value from event-by-event calculations by up to 50%. On the other hand, after adjusting {cflx q} to fit R{sub AA} in the event-by-event analysis we find residual deviations in the azimuthal asymmetry v{sub 2} and in two-particle correlations, that provide a possible faint signature for a spatial tomography of the fireball. We discuss a correlation function that is a measure for spatial inhomogeneities in a collision and can be constrained from data.

Event-by-event jet quenching

Energy Technology Data Exchange (ETDEWEB)

Rodriguez, R. [Cyclotron Institute and Physics Department, Texas A and M University, College Station, TX 77843 (United States); Fries, R.J., E-mail: rjfries@comp.tamu.ed [Cyclotron Institute and Physics Department, Texas A and M University, College Station, TX 77843 (United States); RIKEN/BNL Research Center, Brookhaven National Laboratory, Upton, NY 11973 (United States); Ramirez, E. [Physics Department, University of Texas El Paso, El Paso, TX 79968 (United States)

2010-09-27

High momentum jets and hadrons can be used as probes for the quark gluon plasma (QGP) formed in nuclear collisions at high energies. We investigate the influence of fluctuations in the fireball on jet quenching observables by comparing propagation of light quarks and gluons through averaged, smooth QGP fireballs with event-by-event jet quenching using realistic inhomogeneous fireballs. We find that the transverse momentum and impact parameter dependence of the nuclear modification factor R{sub AA} can be fit well in an event-by-event quenching scenario within experimental errors. However the transport coefficient q extracted from fits to the measured nuclear modification factor R{sub AA} in averaged fireballs underestimates the value from event-by-event calculations by up to 50%. On the other hand, after adjusting q to fit R{sub AA} in the event-by-event analysis we find residual deviations in the azimuthal asymmetry v{sub 2} and in two-particle correlations, that provide a possible faint signature for a spatial tomography of the fireball. We discuss a correlation function that is a measure for spatial inhomogeneities in a collision and can be constrained from data.

Dysregulation of RNA Mediated Gene Expression in Motor Neuron Diseases.

Science.gov (United States)

Gonçalves, Inês do Carmo G; Rehorst, Wiebke A; Kye, Min Jeong

2016-01-01

Recent findings indicate an important role for RNA-mediated gene expression in motor neuron diseases, including ALS (amyotrophic lateral sclerosis) and SMA (spinal muscular atrophy). ALS, also known as Lou Gehrig's disease, is an adult-onset progressive neurodegenerative disorder, whereby SMA or "children's Lou Gehrig's disease" is considered a pediatric neurodevelopmental disorder. Despite the difference in genetic causes, both ALS and SMA share common phenotypes; dysfunction/loss of motor neurons that eventually leads to muscle weakness and atrophy. With advanced techniques in molecular genetics and cell biology, current data suggest that these two distinct motor neuron diseases share more than phenotypes; ALS and SMA have similar cellular pathological mechanisms including mitochondrial dysfunction, oxidative stress and dysregulation in RNA-mediated gene expression. Here, we will discuss the current findings on these two diseases with specific focus on RNA-mediated gene regulation including miRNA expression, pre-mRNA processing and RNA binding proteins.

Mitochondrial protection impairs BET bromodomain inhibitor-mediated cell death and provides rationale for combination therapeutic strategies.

Science.gov (United States)

Lasorsa, E; Smonksey, M; Kirk, J S; Rosario, S; Hernandez-Ilizaliturri, F J; Ellis, L

2015-12-10

Inhibitors of the bromodomain and extraterminal domain family (BETI) have recently entered phase I clinical trials. In patients with advanced leukemia's, potent antileukemia activity was displayed with minimum dose-limiting toxicity. In preclinical models of hematological malignancies, including aggressive B-cell lymphomas, BETI induced cell-cycle arrest and apoptosis. However, the underlying cell death mechanisms are still not well understood. Dissecting the mechanisms required by BETI to mediate cell death would provide strong direction on how to best utilize BETI to treat patients with aggressive hematological malignancies. Herein, we provide understanding of the molecular mechanisms underlying BETI-mediated cell death using I-BET762. Induction of cell death occurred in primary murine and human B-cell lymphomas through apoptosis. Genetic dissection using Eμ-myc B-cell lymphoma compound mutants demonstrated that I-BET762-induced apoptosis does not require the p53 pathway. Furthermore, deletion of Apaf1, and thus the absence of a functional apoptosome, is associated with a delayed drug response but do not provide long-term resistance. Prolonged treatment of this model in fact fails to suppress the therapeutic efficacy of the drug and is associated with biochemical features of autophagy. However, lack of mitochondrial permeability completely inhibited I-BET762-mediated tumor cell death, indicating mitochondrial damage as key events for its activity. Combination of I-BET762 with BH3-only mimetics ABT-263 or obatoclax, restored sensitivity to I-BET762 lymphoma killing; however, success was determined by expression of Bcl-2 family antiapoptotic proteins. Our study provides critical insight for clinical decisions regarding the appropriate strategy for using BETI as a single agent or in combination to treat patients with aggressive B-cell lymphomas.

Malleable machines in transcription regulation: the mediator complex.

Directory of Open Access Journals (Sweden)

Agnes Tóth-Petróczy

2008-12-01

Full Text Available The Mediator complex provides an interface between gene-specific regulatory proteins and the general transcription machinery including RNA polymerase II (RNAP II. The complex has a modular architecture (Head, Middle, and Tail and cryoelectron microscopy analysis suggested that it undergoes dramatic conformational changes upon interactions with activators and RNAP II. These rearrangements have been proposed to play a role in the assembly of the preinitiation complex and also to contribute to the regulatory mechanism of Mediator. In analogy to many regulatory and transcriptional proteins, we reasoned that Mediator might also utilize intrinsically disordered regions (IDRs to facilitate structural transitions and transmit transcriptional signals. Indeed, a high prevalence of IDRs was found in various subunits of Mediator from both Saccharomyces cerevisiae and Homo sapiens, especially in the Tail and the Middle modules. The level of disorder increases from yeast to man, although in both organisms it significantly exceeds that of multiprotein complexes of a similar size. IDRs can contribute to Mediator's function in three different ways: they can individually serve as target sites for multiple partners having distinctive structures; they can act as malleable linkers connecting globular domains that impart modular functionality on the complex; and they can also facilitate assembly and disassembly of complexes in response to regulatory signals. Short segments of IDRs, termed molecular recognition features (MoRFs distinguished by a high protein-protein interaction propensity, were identified in 16 and 19 subunits of the yeast and human Mediator, respectively. In Saccharomyces cerevisiae, the functional roles of 11 MoRFs have been experimentally verified, and those in the Med8/Med18/Med20 and Med7/Med21 complexes were structurally confirmed. Although the Saccharomyces cerevisiae and Homo sapiens Mediator sequences are only weakly conserved, the

Molecular profiling of synchronous and metachronous cancers of the pancreas reveal molecular mimicry between samples from the same patient.

Science.gov (United States)

Talbott, Vanessa A; Yeo, Charles J; Brody, Jonathan R; Witkiewicz, Agnieszka K

2012-07-01

Pancreatic ductal adenocarcinoma (PDA) is rarely a survivable disease. In rare cases, separate synchronous tumors are discovered at the time of resection, while in others, patients present with a metachronous cancer after prior surgical resection. Studying molecular markers of synchronous and metachronous lesions may aid to clarify the biology of this often deadly disease. Two patients presented with synchronous tumors (each one with a tumor in the pancreatic head/neck and the other in the tail, designated patients A and B). An additional patient (patient C) underwent an R0 resection for PDA of the head and recurred 1.5 y later with PDA in the tail. Genomic DNA was laser capture microdissected (LCM) from the tumor and molecular analysis was performed. K-ras status and loss of heterozygosity (LOH) were determined from multiple specimens for each case. All samples from each patient harbored identical K-ras mutations. In patient A, the tumor at the head of the pancreas had more clonal genetic instability as reflected by LOH analysis over multiple LCM samples. Patient B had more genetic instability in the tail lesion compared with the neck. Patient C had virtually the identical molecular profile in both tumors, supporting the notion that both tumors were related. We conclude that the synchronous and metachronous tumors likely are initiated from identical precursor lesions and/or events (i.e., K-ras mutations). Future studies will need to investigate if these tumors will respond similarly to adjuvant therapies targeted against the clonal molecular events in the tumor. Copyright © 2012 Elsevier Inc. All rights reserved.

Contribution of microglia-mediated neuroinflammation to retinal degenerative diseases.

Science.gov (United States)

Madeira, Maria H; Boia, Raquel; Santos, Paulo F; Ambrósio, António F; Santiago, Ana R

2015-01-01

Retinal degenerative diseases are major causes of vision loss and blindness worldwide and are characterized by chronic and progressive neuronal loss. One common feature of retinal degenerative diseases and brain neurodegenerative diseases is chronic neuroinflammation. There is growing evidence that retinal microglia, as in the brain, become activated in the course of retinal degenerative diseases, having a pivotal role in the initiation and propagation of the neurodegenerative process. A better understanding of the events elicited and mediated by retinal microglia will contribute to the clarification of disease etiology and might open new avenues for potential therapeutic interventions. This review aims at giving an overview of the roles of microglia-mediated neuroinflammation in major retinal degenerative diseases like glaucoma, age-related macular degeneration, and diabetic retinopathy.

Impulsivity and suicidality: the mediating role of painful and provocative experiences.

Science.gov (United States)

Bender, Theodore W; Gordon, Kathryn H; Bresin, Konrad; Joiner, Thomas E

2011-03-01

Multiple studies have reported a link between high levels of impulsivity and suicidal behavior. Joiner's (2005) explanation for this link is that impulsive individuals have a greater tendency to experience painful and provocative events that habituate them to fear and pain, which leads to an acquired capability for engaging in suicidal behavior. Study 1 tested Joiner's (2005) hypothesis in a sample of 182 undergraduate students who completed self-report questionnaires on impulsivity, frequency of painful and provocative events, and acquired capability for suicide. In addition to self-report, pain tolerance (an aspect of acquired capability for suicide) was measured with a pressure algometer. Study 2 sought to replicate our findings from Study 1 in a sample of 516 clinical outpatients using a multi-faceted measure of impulsivity. Consistent with prediction, product of coefficients tests for mediation (MacKinnon et al., 2002) revealed that impulsivity has an indirect relationship with acquired capability for suicidal behavior, and that this relationship is mediated by painful and provocative events. Data from our studies are cross-sectional in nature, which does not allow for conclusions about the temporal ordering of our variables. In addition, self-report was used to measure most variables. Future research may benefit from a longitudinal design and the inclusion of other modes of assessment (e.g., behavioral measures of impulsivity). Our findings suggest that the link between impulsivity and suicidal behavior occurs because impulsive people tend to have a greater capability for suicidal behavior, which they have acquired through experiencing painful and provocative events. Copyright © 2010 Elsevier B.V. All rights reserved.

Interventional Effects for Mediation Analysis with Multiple Mediators.

Science.gov (United States)

Vansteelandt, Stijn; Daniel, Rhian M

2017-03-01

The mediation formula for the identification of natural (in)direct effects has facilitated mediation analyses that better respect the nature of the data, with greater consideration of the need for confounding control. The default assumptions on which it relies are strong, however. In particular, they are known to be violated when confounders of the mediator-outcome association are affected by the exposure. This complicates extensions of counterfactual-based mediation analysis to settings that involve repeatedly measured mediators, or multiple correlated mediators. VanderWeele, Vansteelandt, and Robins introduced so-called interventional (in)direct effects. These can be identified under much weaker conditions than natural (in)direct effects, but have the drawback of not adding up to the total effect. In this article, we adapt their proposal to achieve an exact decomposition of the total effect, and extend it to the multiple mediator setting. Interestingly, the proposed effects capture the path-specific effects of an exposure on an outcome that are mediated by distinct mediators, even when-as often-the structural dependence between the multiple mediators is unknown, for instance, when the direction of the causal effects between the mediators is unknown, or there may be unmeasured common causes of the mediators.

Caenorhabditis elegans as a Model to Study the Molecular and Genetic Mechanisms of Drug Addiction

Science.gov (United States)

Engleman, Eric A.; Katner, Simon N.; Neal-Beliveau, Bethany S.

2016-01-01

Drug addiction takes a massive toll on society. Novel animal models are needed to test new treatments and understand the basic mechanisms underlying addiction. Rodent models have identified the neurocircuitry involved in addictive behavior and indicate that rodents possess some of the same neurobiologic mechanisms that mediate addiction in humans. Recent studies indicate that addiction is mechanistically and phylogenetically ancient and many mechanisms that underlie human addiction are also present in invertebrates. The nematode Caenorhabditis elegans has conserved neurobiologic systems with powerful molecular and genetic tools and a rapid rate of development that enables cost-effective translational discovery. Emerging evidence suggests that C. elegans is an excellent model to identify molecular mechanisms that mediate drug-induced behavior and potential targets for medications development for various addictive compounds. C. elegans emit many behaviors that can be easily quantitated including some that involve interactions with the environment. Ethanol (EtOH) is the best-studied drug-of-abuse in C. elegans and at least 50 different genes/targets have been identified as mediating EtOH’s effects and polymorphisms in some orthologs in humans are associated with alcohol use disorders. C. elegans has also been shown to display dopamine and cholinergic system–dependent attraction to nicotine and demonstrate preference for cues previously associated with nicotine. Cocaine and methamphetamine have been found to produce dopamine-dependent reward-like behaviors in C. elegans. These behavioral tests in combination with genetic/molecular manipulations have led to the identification of dozens of target genes/systems in C. elegans that mediate drug effects. The one target/gene identified as essential for drug-induced behavioral responses across all drugs of abuse was the cat-2 gene coding for tyrosine hydroxylase, which is consistent with the role of dopamine

Caenorhabditis elegans as a Model to Study the Molecular and Genetic Mechanisms of Drug Addiction.

Science.gov (United States)

Engleman, Eric A; Katner, Simon N; Neal-Beliveau, Bethany S

2016-01-01

Drug addiction takes a massive toll on society. Novel animal models are needed to test new treatments and understand the basic mechanisms underlying addiction. Rodent models have identified the neurocircuitry involved in addictive behavior and indicate that rodents possess some of the same neurobiologic mechanisms that mediate addiction in humans. Recent studies indicate that addiction is mechanistically and phylogenetically ancient and many mechanisms that underlie human addiction are also present in invertebrates. The nematode Caenorhabditis elegans has conserved neurobiologic systems with powerful molecular and genetic tools and a rapid rate of development that enables cost-effective translational discovery. Emerging evidence suggests that C. elegans is an excellent model to identify molecular mechanisms that mediate drug-induced behavior and potential targets for medications development for various addictive compounds. C. elegans emit many behaviors that can be easily quantitated including some that involve interactions with the environment. Ethanol (EtOH) is the best-studied drug-of-abuse in C. elegans and at least 50 different genes/targets have been identified as mediating EtOH's effects and polymorphisms in some orthologs in humans are associated with alcohol use disorders. C. elegans has also been shown to display dopamine and cholinergic system-dependent attraction to nicotine and demonstrate preference for cues previously associated with nicotine. Cocaine and methamphetamine have been found to produce dopamine-dependent reward-like behaviors in C. elegans. These behavioral tests in combination with genetic/molecular manipulations have led to the identification of dozens of target genes/systems in C. elegans that mediate drug effects. The one target/gene identified as essential for drug-induced behavioral responses across all drugs of abuse was the cat-2 gene coding for tyrosine hydroxylase, which is consistent with the role of dopamine neurotransmission

Tipping the Balance: Hepatotoxicity and the Four Apical Key Events of Hepatic Steatosis

Science.gov (United States)

Adverse outcome pathways (AOPs) are descriptive biological sequences that start from a molecular initiating event (MIE) and end with an adverse health outcome. AOPs provide biological context for high throughput chemical testing and further prioritize environmental health risk r...

Molecular Mechanisms Behind the Chemopreventive Effects of Anthocyanidins

Directory of Open Access Journals (Sweden)

De-Xing Hou

2004-01-01

Full Text Available Anthocyanins are polyphenolic ring-based flavonoids, and are widespread in fruits and vegetables of red-blue color. Epidemiological investigations and animal experiments have indicated that anthocyanins may contribute to cancer chemoprevention. The studies on the mechanism have been done recently at molecular level. This review summarizes current molecular bases for anthocyanidins on several key steps involved in cancer chemoprevention: (i inhibition of anthocyanidins in cell transformation through targeting mitogen-activated protein kinase (MAPK pathway and activator protein 1 (AP-1 factor; (ii suppression of anthocyanidins in inflammation and carcinogenesis through targeting nuclear factor kappa B (NF-κB pathway and cyclooxygenase 2 (COX-2 gene; (iii apoptotic induction of cancer cells by anthocyanidins through reactive oxygen species (ROS / c-Jun NH2-terminal kinase (JNK-mediated caspase activation. These data provide a first molecular view of anthocyanidins contributing to cancer chemoprevention.

Visions of a Semantic Molecular Future

OpenAIRE

Murray-Rust, Peter; Brooks, Brian; Bolton, Charlotte

2011-01-01

Booklet handout distributed at the VSMF Symposium held at the Unilever Centre on 2011-01-17 The event looks forward. Scholarship (universities, research, teaching, publishing) has been slow to take up the opportunities of this digital century. This is an opportunity to identify and build the future. EPSRC (Pathways to Impact Award). Unilever plc (Unilever Centre for Molecular Science Informatics)

Visions of a Semantic Molecular Future

OpenAIRE

Murray-Rust, Peter

2011-01-01

Additional booklet insert distributed at the VSMF Symposium held at the Unilever Centre on 2011-01-17 The event looks forward. Scholarship (universities, research, teaching, publishing) has been slow to take up the opportunities of this digital century. This is an opportunity to identify and build the future. EPSRC (Pathways to Impact award). Unilever plc (Unilever Centre for Molecular Science Informatics)

Herp regulates Hrd1-mediated ubiquitylation in a ubiquitin-like domain-dependent manner

DEFF Research Database (Denmark)

Kny, Melanie; Standera, Sybille; Hartmann-Petersen, Rasmus

2011-01-01

in ER-associated protein degradation (ERAD) and interacts directly with the ubiquitin ligase Hrd1, which is found in high molecular mass complexes of the ER membrane. Here we present the first evidence that Herp regulates Hrd1-mediated ubiquitylation in a ubiquitin-like (UBL) domain-dependent manner. We...

In silico simulations of tunneling barrier measurements for molecular orbital-mediated junctions: A molecular orbital theory approach to scanning tunneling microscopy

Energy Technology Data Exchange (ETDEWEB)

Terryn, Raymond J.; Sriraman, Krishnan; Olson, Joel A., E-mail: jolson@fit.edu; Baum, J. Clayton, E-mail: cbaum@fit.edu [Department of Chemistry, Florida Institute of Technology, 150 West University Boulevard, Melbourne, Florida 32901 (United States); Novak, Mark J. [Department of Chemistry and Applied Biological Sciences, South Dakota School of Mines and Technology, 501 E. Saint Joseph Street, Rapid City, South Dakota 57701 (United States)

2016-09-15

A new simulator for scanning tunneling microscopy (STM) is presented based on the linear combination of atomic orbitals molecular orbital (LCAO-MO) approximation for the effective tunneling Hamiltonian, which leads to the convolution integral when applied to the tip interaction with the sample. This approach intrinsically includes the structure of the STM tip. Through this mechanical emulation and the tip-inclusive convolution model, dI/dz images for molecular orbitals (which are closely associated with apparent barrier height, ϕ{sub ap}) are reported for the first time. For molecular adsorbates whose experimental topographic images correspond well to isolated-molecule quantum chemistry calculations, the simulator makes accurate predictions, as illustrated by various cases. Distortions in these images due to the tip are shown to be in accord with those observed experimentally and predicted by other ab initio considerations of tip structure. Simulations of the tunneling current dI/dz images are in strong agreement with experiment. The theoretical framework provides a solid foundation which may be applied to LCAO cluster models of adsorbate–substrate systems, and is extendable to emulate several aspects of functional STM operation.

In silico simulations of tunneling barrier measurements for molecular orbital-mediated junctions: A molecular orbital theory approach to scanning tunneling microscopy

International Nuclear Information System (INIS)

Terryn, Raymond J.; Sriraman, Krishnan; Olson, Joel A.; Baum, J. Clayton; Novak, Mark J.

2016-01-01

A new simulator for scanning tunneling microscopy (STM) is presented based on the linear combination of atomic orbitals molecular orbital (LCAO-MO) approximation for the effective tunneling Hamiltonian, which leads to the convolution integral when applied to the tip interaction with the sample. This approach intrinsically includes the structure of the STM tip. Through this mechanical emulation and the tip-inclusive convolution model, dI/dz images for molecular orbitals (which are closely associated with apparent barrier height, ϕ_a_p) are reported for the first time. For molecular adsorbates whose experimental topographic images correspond well to isolated-molecule quantum chemistry calculations, the simulator makes accurate predictions, as illustrated by various cases. Distortions in these images due to the tip are shown to be in accord with those observed experimentally and predicted by other ab initio considerations of tip structure. Simulations of the tunneling current dI/dz images are in strong agreement with experiment. The theoretical framework provides a solid foundation which may be applied to LCAO cluster models of adsorbate–substrate systems, and is extendable to emulate several aspects of functional STM operation.

Estimation of causal mediation effects for a dichotomous outcome in multiple-mediator models using the mediation formula.

Science.gov (United States)

Wang, Wei; Nelson, Suchitra; Albert, Jeffrey M

2013-10-30

Mediators are intermediate variables in the causal pathway between an exposure and an outcome. Mediation analysis investigates the extent to which exposure effects occur through these variables, thus revealing causal mechanisms. In this paper, we consider the estimation of the mediation effect when the outcome is binary and multiple mediators of different types exist. We give a precise definition of the total mediation effect as well as decomposed mediation effects through individual or sets of mediators using the potential outcomes framework. We formulate a model of joint distribution (probit-normal) using continuous latent variables for any binary mediators to account for correlations among multiple mediators. A mediation formula approach is proposed to estimate the total mediation effect and decomposed mediation effects based on this parametric model. Estimation of mediation effects through individual or subsets of mediators requires an assumption involving the joint distribution of multiple counterfactuals. We conduct a simulation study that demonstrates low bias of mediation effect estimators for two-mediator models with various combinations of mediator types. The results also show that the power to detect a nonzero total mediation effect increases as the correlation coefficient between two mediators increases, whereas power for individual mediation effects reaches a maximum when the mediators are uncorrelated. We illustrate our approach by applying it to a retrospective cohort study of dental caries in adolescents with low and high socioeconomic status. Sensitivity analysis is performed to assess the robustness of conclusions regarding mediation effects when the assumption of no unmeasured mediator-outcome confounders is violated. Copyright © 2013 John Wiley & Sons, Ltd.

Estimation of Causal Mediation Effects for a Dichotomous Outcome in Multiple-Mediator Models using the Mediation Formula

Science.gov (United States)

Nelson, Suchitra; Albert, Jeffrey M.

2013-01-01

Mediators are intermediate variables in the causal pathway between an exposure and an outcome. Mediation analysis investigates the extent to which exposure effects occur through these variables, thus revealing causal mechanisms. In this paper, we consider the estimation of the mediation effect when the outcome is binary and multiple mediators of different types exist. We give a precise definition of the total mediation effect as well as decomposed mediation effects through individual or sets of mediators using the potential outcomes framework. We formulate a model of joint distribution (probit-normal) using continuous latent variables for any binary mediators to account for correlations among multiple mediators. A mediation formula approach is proposed to estimate the total mediation effect and decomposed mediation effects based on this parametric model. Estimation of mediation effects through individual or subsets of mediators requires an assumption involving the joint distribution of multiple counterfactuals. We conduct a simulation study that demonstrates low bias of mediation effect estimators for two-mediator models with various combinations of mediator types. The results also show that the power to detect a non-zero total mediation effect increases as the correlation coefficient between two mediators increases, while power for individual mediation effects reaches a maximum when the mediators are uncorrelated. We illustrate our approach by applying it to a retrospective cohort study of dental caries in adolescents with low and high socioeconomic status. Sensitivity analysis is performed to assess the robustness of conclusions regarding mediation effects when the assumption of no unmeasured mediator-outcome confounders is violated. PMID:23650048

Spider Transcriptomes Identify Ancient Large-Scale Gene Duplication Event Potentially Important in Silk Gland Evolution.

Science.gov (United States)

Clarke, Thomas H; Garb, Jessica E; Hayashi, Cheryl Y; Arensburger, Peter; Ayoub, Nadia A

2015-06-08

The evolution of specialized tissues with novel functions, such as the silk synthesizing glands in spiders, is likely an influential driver of adaptive success. Large-scale gene duplication events and subsequent paralog divergence are thought to be required for generating evolutionary novelty. Such an event has been proposed for spiders, but not tested. We de novo assembled transcriptomes from three cobweb weaving spider species. Based on phylogenetic analyses of gene families with representatives from each of the three species, we found numerous duplication events indicative of a whole genome or segmental duplication. We estimated the age of the gene duplications relative to several speciation events within spiders and arachnids and found that the duplications likely occurred after the divergence of scorpions (order Scorpionida) and spiders (order Araneae), but before the divergence of the spider suborders Mygalomorphae and Araneomorphae, near the evolutionary origin of spider silk glands. Transcripts that are expressed exclusively or primarily within black widow silk glands are more likely to have a paralog descended from the ancient duplication event and have elevated amino acid replacement rates compared with other transcripts. Thus, an ancient large-scale gene duplication event within the spider lineage was likely an important source of molecular novelty during the evolution of silk gland-specific expression. This duplication event may have provided genetic material for subsequent silk gland diversification in the true spiders (Araneomorphae). © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Conductance and thermopower in molecular nanojunctions

Science.gov (United States)

Sen, Arijit

2013-02-01

Electronic transport through short channels in a molecular junction is an intricate quantum scattering problem [1]. To garner insight on how the structure and the electrical properties of a nanoscale junction are correlated is thus of both fundamental and technological interest [1-3]. As observed experimentally in the last couple of years by several independent research groups [4-5], a two-terminal molecular junction comprising of a simple alkane chain with varying length can exhibit high as well as low conductance. However, what causes the simultaneous unveiling of multiple conductances remained largely obscure. We have recently demonstrated [6] that the binary conductance in these heterostructures is due mainly to two distinct electrode orientations that control the electrode-molecule coupling as well as the tunneling strength through quantum interference following diversity in the electrode band structures. Our detailed analysis on the transmission spectra indicates that even a single-molecule nanojunction can potentially serve as a realistic double-quantum-dot kind of system to yield tunable Fano resonance, as often desired for nanoscale switching. In this talk, I intend to give a brief account of molecular electronics and its future applications along with the challenges and possibilities in the current perspective. A few deliberations may as well include how the inter-dot tunneling strength may affect the non-equilibrium charge transport and thermoelectricity in a myriad of molecular junctions based on different molecular conformations and electrode structures. Finally, I shall try to touch upon the effect of electron-phonon interaction on the nanoscale charge transport, and also, the phonon-mediated thermal transport in molecular nanodevices.

Evolution of disorder in Mediator complex and its functional relevance.

Science.gov (United States)

Nagulapalli, Malini; Maji, Sourobh; Dwivedi, Nidhi; Dahiya, Pradeep; Thakur, Jitendra K

2016-02-29

Mediator, an important component of eukaryotic transcriptional machinery, is a huge multisubunit complex. Though the complex is known to be conserved across all the eukaryotic kingdoms, the evolutionary topology of its subunits has never been studied. In this study, we profiled disorder in the Mediator subunits of 146 eukaryotes belonging to three kingdoms viz., metazoans, plants and fungi, and attempted to find correlation between the evolution of Mediator complex and its disorder. Our analysis suggests that disorder in Mediator complex have played a crucial role in the evolutionary diversification of complexity of eukaryotic organisms. Conserved intrinsic disordered regions (IDRs) were identified in only six subunits in the three kingdoms whereas unique patterns of IDRs were identified in other Mediator subunits. Acquisition of novel molecular recognition features (MoRFs) through evolution of new subunits or through elongation of the existing subunits was evident in metazoans and plants. A new concept of 'junction-MoRF' has been introduced. Evolutionary link between CBP and Med15 has been provided which explain the evolution of extended-IDR in CBP from Med15 KIX-IDR junction-MoRF suggesting role of junction-MoRF in evolution and modulation of protein-protein interaction repertoire. This study can be informative and helpful in understanding the conserved and flexible nature of Mediator complex across eukaryotic kingdoms. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Causal mediation analysis with multiple causally non-ordered mediators.

Science.gov (United States)

Taguri, Masataka; Featherstone, John; Cheng, Jing

2018-01-01

In many health studies, researchers are interested in estimating the treatment effects on the outcome around and through an intermediate variable. Such causal mediation analyses aim to understand the mechanisms that explain the treatment effect. Although multiple mediators are often involved in real studies, most of the literature considered mediation analyses with one mediator at a time. In this article, we consider mediation analyses when there are causally non-ordered multiple mediators. Even if the mediators do not affect each other, the sum of two indirect effects through the two mediators considered separately may diverge from the joint natural indirect effect when there are additive interactions between the effects of the two mediators on the outcome. Therefore, we derive an equation for the joint natural indirect effect based on the individual mediation effects and their interactive effect, which helps us understand how the mediation effect works through the two mediators and relative contributions of the mediators and their interaction. We also discuss an extension for three mediators. The proposed method is illustrated using data from a randomized trial on the prevention of dental caries.

Data Mining FAERS to Analyze Molecular Targets of Drugs Highly Associated with Stevens-Johnson Syndrome.

Science.gov (United States)

Burkhart, Keith K; Abernethy, Darrell; Jackson, David

2015-06-01

Drug features that are associated with Stevens-Johnson syndrome (SJS) have not been fully characterized. A molecular target analysis of the drugs associated with SJS in the FDA Adverse Event Reporting System (FAERS) may contribute to mechanistic insights into SJS pathophysiology. The publicly available version of FAERS was analyzed to identify disproportionality among the molecular targets, metabolizing enzymes, and transporters for drugs associated with SJS. The FAERS in-house version was also analyzed for an internal comparison of the drugs most highly associated with SJS. Cyclooxygenases 1 and 2, carbonic anhydrase 2, and sodium channel 2 alpha were identified as disproportionately associated with SJS. Cytochrome P450 (CYPs) 3A4 and 2C9 are disproportionately represented as metabolizing enzymes of the drugs associated with SJS adverse event reports. Multidrug resistance protein 1 (MRP-1), organic anion transporter 1 (OAT1), and PEPT2 were also identified and are highly associated with the transport of these drugs. A detailed review of the molecular targets identifies important roles for these targets in immune response. The association with CYP metabolizing enzymes suggests that reactive metabolites and oxidative stress may have a contributory role. Drug transporters may enhance intracellular tissue concentrations and also have vital physiologic roles that impact keratinocyte proliferation and survival. Data mining FAERS may be used to hypothesize mechanisms for adverse drug events by identifying molecular targets that are highly associated with drug-induced adverse events. The information gained may contribute to systems biology disease models.

Molecular cloning and characterization of the porcine prostaglandin transporter (SLCO2A1: evaluation of its role in F4 mediated neonatal diarrhoea

Directory of Open Access Journals (Sweden)

Cox Eric

2009-10-01

Full Text Available Abstract Background Because prostaglandins are involved in many (pathophysiological processes, SLCO2A1 was already characterized in several species in an attempt to unravel specific processes/deficiencies. Here, we describe the molecular cloning and characterization of the porcine ortholog in order to evaluate its possible involvement in F4 enterotoxigenic E. coli mediated neonatal diarrhoea, based on a positional candidate gene approach study. Results Porcine SLCO2A1 is organized in 14 exons, containing an open reading frame of 1935 bp, encoding a 12-transmembrane organic anion cell surface transporter of 644 aa. The -388 to -5 upstream region comprises a (CpG48 island containing a number of conserved promoter elements, including a TATA box. A potential alternative promoter region was found in the conserved -973 to -700 upstream region. No consensus polyadenylation signal was discovered in the 3' UTR. Repeat sequences were found in 15% of all the non coding sequences. As expected for a multifunctional protein, a wide tissue distribution was observed. mRNA expression was found in the adrenal gland, bladder, caecum, colon (centripetal coil/centrifugal coil, diaphragm, duodenum, gallbladder, heart, ileum, jejunum, kidney, liver, longissimus dorsi muscle, lung, lymph node, mesenterium, rectum, spleen, stomach, tongue and ureter, but not in the aorta, oesophagus and pancreas. The promoter region and the exons (including the splice sites of SLCO2A1 were resequenced in 5 F4ab/ac receptor positive and 5 F4ab/ac receptor negative pigs. Two silent and 2 missense (both S → L at position 360 and 633 mutations were found, but none was associated with the F4ab/ac receptor phenotype. In addition, no phenotype associated differential mRNA expression or alternative/abberant splicing/polyadenylation was found in the jejunum. Conclusion The molecular cloning and characterization of porcine SLCO2A1 not only contributes to the already existing knowledge about the

VEGFR1-mediated pericyte ablation links VEGF and PlGF to cancer-associated retinopathy

DEFF Research Database (Denmark)

Cao, Renhai; Xue, Yuan; Hedlund, Eva-Maria

2010-01-01

. Moreover, blockade of VEGFR1 but not VEGFR2 significantly restores pericyte saturation in mature retinal vessels. Our findings link VEGF and PlGF to cancer-associated retinopathy, reveal the molecular mechanisms of VEGFR1 ligand-mediated retinopathy, and define VEGFR1 as an important target......, and adenoviral vectors ablates pericytes from the mature retinal vasculature through the VEGF receptor 1 (VEGFR1)-mediated signaling pathway, leading to increased vascular leakage. In contrast, we demonstrate VEGF receptor 2 (VEGFR2) is primarily expressed in nonvascular photoreceptors and ganglion cells...

Mediatization

DEFF Research Database (Denmark)

Hjarvard, Stig

2017-01-01

Mediatization research shares media effects studies' ambition of answering the difficult questions with regard to whether and how media matter and influence contemporary culture and society. The two approaches nevertheless differ fundamentally in that mediatization research seeks answers...... to these general questions by distinguishing between two concepts: mediation and mediatization. The media effects tradition generally considers the effects of the media to be a result of individuals being exposed to media content, i.e. effects are seen as an outcome of mediated communication. Mediatization...... research is concerned with long-term structural changes involving media, culture, and society, i.e. the influences of the media are understood in relation to how media are implicated in social and cultural changes and how these processes come to create new conditions for human communication and interaction...

Proteomic analysis of cAMP-mediated signaling during differentiation of 3 T3-L1 preadipocytes

DEFF Research Database (Denmark)

Borkowski, Kamil; Wrzesinski, Krzysztow; Rogowska-Wrzesinska, Adelina

2014-01-01

Initiation of adipocyte differentiation is promoted by the synergistic action of insulin/insulin-like growth factor, glucocorticoids, and agents activating cAMP-dependent signaling. The action of cAMP is mediated via PKA and Epac, where at least part of the PKA function relates to strong repression...... a comprehensive evaluation of Epac-mediated processes and their interplay with PKA during the initiation of 3 T3-L1 preadipocyte differentiation using a combination of proteomics, molecular approaches, and bioinformatics. Proteomic analyses revealed 7 proteins specifically regulated in response to Epac activation......-dependent signaling thereby adding a novel facet to our understanding of cAMP-mediated potentiation of adipocyte differentiation....

Scavenger receptor-mediated endocytosis by sinusoidal cells in rat bone marrow

International Nuclear Information System (INIS)

Geoffroy, J.S.

1987-01-01

Endocytosis of serum albumin by sinusoidal endothelial cells in rat bone marrow was investigated initially at the ultrastructural level with subsequent biochemical investigation of the specificity mediating this event. Bovine serum albumin adsorbed to 20nm colloidal gold particles (AuBSA) was chosen as the electron microscopic probe. Morphological data strongly suggested that a receptor was involved in uptake of AuBSA. Confirmation of receptor involvement in the uptake of AuBSA by marrow sinusoidal endothelial cells was achieved utilizing an in situ isolated hind limb perfusion protocol in conjunction with unlabeled, radiolabeled, and radio-/colloidal gold labeled probes. The major findings of competition and saturation experiments were: (1) endocytosis of AuBSA was mediated by a receptor for modified/treated serum albumin; (2) endocytosis of formaldehyde-treated serum albumin was mediated by a binding site which may be the same or closely related to the site responsible for the uptake of AuBSA; and (3) endocytosis of native untreated albumin was not mediated by receptor and probably represents fluid-phase pinocitosis

RESPONSE OF JAPANESE MEDAKA TO 17B-ESTRADIOL: A TIME COURSE OF ENDOCRINE-MEDIATED EFFECTS

Science.gov (United States)

Estrogenic compounds have been measured in the aquatic environment in concentrations subsequently found to affect reproduction and development in fish. Further investigations have described several endocrine-mediated events that indicate exposure of organisms to estrogens and/or ...

Molecular helpers wanted... Call for volunteers!

CERN Multimedia

2008-01-01

The Task Force in charge of the organization of the LHC Inauguration is looking for 40 volunteers to support the team of molecular cooks directed by international chef Ettore Bocchia. The "molecular" volunteers will help in the preparation of liquid nitrogen ice-cream. Your help is requested from 12h to 18h on October 21st. Your participation in a general rehearsal on October 20th is also required - (the time of the rehearsal will be communicated at a later moment). Dress code: black pants and shoes, long sleeved white shirt. Do not miss this opportunity to take part in an extraordinary event! For further information and to enrol, contact: mailto:Catherine.Brandt@cern.ch

Imidazoline and imidazolidine nitroxides as controlling agents in nitroxide-mediated pseudoliving radical polymerization

Science.gov (United States)

Edeleva, M. V.; Marque, S. R. A.; Bagryanskaya, E. G.

2018-04-01

Controlled, or pseudoliving, radical polymerization provides unique opportunities for the synthesis of structurally diverse polymers with a narrow molecular-weight distribution. These reactions occur under relatively mild conditions with broad tolerance to functional groups in the monomers. The nitroxide-mediated pseudoliving radical polymerization is of particular interest for the synthesis of polymers for biomedical applications. This review briefly describes one of the mechanisms of controlled radical polymerization. The studies dealing with the use of imidazoline and imidazolidine nitroxides as controlling agents for nitroxide-mediated pseudoliving radical polymerization of various monomers are summarized and analyzed. The publications addressing the key steps of the controlled radical polymerization in the presence of imidazoline and imidazolidine nitroxides and new approaches to nitroxide-mediated polymerization based on protonation of both nitroxides and monomers are considered. The bibliography includes 154 references.

Event Index - a LHCb Event Search System

CERN Document Server

INSPIRE-00392208; Kazeev, Nikita; Redkin, Artem

2015-12-23

LHC experiments generate up to $10^{12}$ events per year. This paper describes Event Index - an event search system. Event Index's primary function is quickly selecting subsets of events from a combination of conditions, such as the estimated decay channel or stripping lines output. Event Index is essentially Apache Lucene optimized for read-only indexes distributed over independent shards on independent nodes.

Molecular modeling of human neutral sphingomyelinase provides insight into its molecular interactions.

Science.gov (United States)

Dinesh; Goswami, Angshumala; Suresh, Panneer Selvam; Thirunavukkarasu, Chinnasamy; Weiergräber, Oliver H; Kumar, Muthuvel Suresh

2011-01-01

The neutral sphingomyelinase (N-SMase) is considered a major candidate for mediating the stress-induced production of ceramide, and it plays an important role in cell-cycle arrest, apoptosis, inflammation, and eukaryotic stress responses. Recent studies have identified a small region at the very N-terminus of the 55 kDa tumour necrosis factor receptor (TNF-R55), designated the neutral sphingomyelinase activating domain (NSD) that is responsible for the TNF-induced activation of N-SMase. There is no direct association between TNF-R55 NSD and N-SMase; instead, a protein named factor associated with N-SMase activation (FAN) has been reported to couple the TNF-R55 NSD to N-SMase. Since the three-dimensional fold of N-SMase is still unknown, we have modeled the structure using the protein fold recognition and threading method. Moreover, we propose models for the TNF-R55 NSD as well as the FAN protein in order to study the structural basis of N-SMase activation and regulation. Protein-protein interaction studies suggest that FAN is crucially involved in mediating TNF-induced activation of the N-SMase pathway, which in turn regulates mitogenic and proinflammatory responses. Inhibition of N-SMase may lead to reduction of ceramide levels and hence may provide a novel therapeutic strategy for inflammation and autoimmune diseases. Molecular dynamics (MD) simulations were performed to check the stability of the predicted model and protein-protein complex; indeed, stable RMS deviations were obtained throughout the simulation. Furthermore, in silico docking of low molecular mass ligands into the active site of N-SMase suggests that His135, Glu48, Asp177, and Asn179 residues play crucial roles in this interaction. Based on our results, these ligands are proposed to be potent and selective N-SMase inhibitors, which may ultimately prove useful as lead compounds for drug development.

DNA-mediated gene transfer into ataxia-telangiectasia cells

International Nuclear Information System (INIS)

Crescenzi, M.; Pulciani, S.; Carbonari, M.; Tedesco, L.; Russo, G.; Gaetano, C.; Fiorilli, M.

1986-01-01

The complete description of the genetic lesion(s) underlying the AT mutation might, therefore, highlight not only a DNA-repair pathwa, but also an important aspect of the physiology of lymphocytes. DNA-mediated gene transfer into eukaryotic cells has proved a powerful tool for the molecular cloning of certain mammalian genes. The possibility to clone a given gene using this technology depends, basically, on the availability of a selectable marker associated with the expression of the transfected gene in the recipient cell. Recently, a human DNA repair gene has been cloned in CHO mutant cells by taking advantage of the increased resistance to ultraviolet radiation of the transformants. As a preliminary step toward the molecular cloning of the AT gene(s), the authors have attempted to confer radioresistance to AT cells by transfection with normal human DNA

Search for Gauge Mediated Supersymmetry in the gamma gamma missing ET Channel

Energy Technology Data Exchange (ETDEWEB)

Kesisoglou, Stilianos Isaak [Brown Univ., Providence, RI (United States)

2005-05-01

We present results on a search for Gauge Mediated Supersymmetry in the di-photon final state using Run II data collected by the D0 Experiment at the Fermilab Tevatron Collider. We discuss event selection, Standard Model backgrounds, and the lower limits on the lightest neutralino and chargino masses resulted from this analysis.

Intercultural Mediation

OpenAIRE

Dragos Marian Radulescu; Denisa Mitrut

2012-01-01

The Intercultural Mediator facilitates exchanges between people of different socio-cultural backgrounds and acts as a bridge between immigrants and national and local associations, health organizations, services and offices in order to foster integration of every single individual. As the use mediation increases, mediators are more likely to be involved in cross-cultural mediation, but only the best mediators have the opportunity to mediate cross border business disputes or international poli...

Event segmentation ability uniquely predicts event memory.

Science.gov (United States)

Sargent, Jesse Q; Zacks, Jeffrey M; Hambrick, David Z; Zacks, Rose T; Kurby, Christopher A; Bailey, Heather R; Eisenberg, Michelle L; Beck, Taylor M

2013-11-01

Memory for everyday events plays a central role in tasks of daily living, autobiographical memory, and planning. Event memory depends in part on segmenting ongoing activity into meaningful units. This study examined the relationship between event segmentation and memory in a lifespan sample to answer the following question: Is the ability to segment activity into meaningful events a unique predictor of subsequent memory, or is the relationship between event perception and memory accounted for by general cognitive abilities? Two hundred and eight adults ranging from 20 to 79years old segmented movies of everyday events and attempted to remember the events afterwards. They also completed psychometric ability tests and tests measuring script knowledge for everyday events. Event segmentation and script knowledge both explained unique variance in event memory above and beyond the psychometric measures, and did so as strongly in older as in younger adults. These results suggest that event segmentation is a basic cognitive mechanism, important for memory across the lifespan. Copyright © 2013 Elsevier B.V. All rights reserved.

Spillover-mediated feedforward-inhibition functionally segregates interneuron activity

Science.gov (United States)

Coddington, Luke T.; Rudolph, Stephanie; Lune, Patrick Vande; Overstreet-Wadiche, Linda; Wadiche, Jacques I.

2013-01-01

Summary Neurotransmitter spillover represents a form of neural transmission not restricted to morphologically defined synaptic connections. Communication between climbing fibers (CFs) and molecular layer interneurons (MLIs) in the cerebellum is mediated exclusively by glutamate spillover. Here, we show how CF stimulation functionally segregates MLIs based on their location relative to glutamate release. Excitation of MLIs that reside within the domain of spillover diffusion coordinates inhibition of MLIs outside the diffusion limit. CF excitation of MLIs is dependent on extrasynaptic NMDA receptors that enhance the spatial and temporal spread of CF signaling. Activity mediated by functionally segregated MLIs converges onto neighboring Purkinje cells (PCs) to generate a long-lasting biphasic change in inhibition. These data demonstrate how glutamate release from single CFs modulates excitability of neighboring PCs, thus expanding the influence of CFs on cerebellar cortical activity in a manner not predicted by anatomical connectivity. PMID:23707614

DNAzyme-Based Logic Gate-Mediated DNA Self-Assembly.

Science.gov (United States)

Zhang, Cheng; Yang, Jing; Jiang, Shuoxing; Liu, Yan; Yan, Hao

2016-01-13

Controlling DNA self-assembly processes using rationally designed logic gates is a major goal of DNA-based nanotechnology and programming. Such controls could facilitate the hierarchical engineering of complex nanopatterns responding to various molecular triggers or inputs. Here, we demonstrate the use of a series of DNAzyme-based logic gates to control DNA tile self-assembly onto a prescribed DNA origami frame. Logic systems such as "YES," "OR," "AND," and "logic switch" are implemented based on DNAzyme-mediated tile recognition with the DNA origami frame. DNAzyme is designed to play two roles: (1) as an intermediate messenger to motivate downstream reactions and (2) as a final trigger to report fluorescent signals, enabling information relay between the DNA origami-framed tile assembly and fluorescent signaling. The results of this study demonstrate the plausibility of DNAzyme-mediated hierarchical self-assembly and provide new tools for generating dynamic and responsive self-assembly systems.

Hairpin-induced tRNA-mediated (HITME) recombination in HIV-1

NARCIS (Netherlands)

Konstantinova, Pavlina; de Haan, Peter; Das, Atze T.; Berkhout, Ben

2006-01-01

Recombination due to template switching during reverse transcription is a major source of genetic variability in retroviruses. In the present study we forced a recombination event in human immunodeficiency virus type 1 (HIV-1) by electroporation of T cells with DNA from a molecular HIV-1 clone that

Mediator can regulate mitotic entry and direct periodic transcription in fission yeast.

Science.gov (United States)

Banyai, Gabor; Lopez, Marcela Davila; Szilagyi, Zsolt; Gustafsson, Claes M

2014-11-01

Cdk8 is required for correct timing of mitotic progression in fission yeast. How the activity of Cdk8 is regulated is unclear, since the kinase is not activated by T-loop phosphorylation and its partner, CycC, does not oscillate. Cdk8 is, however, a component of the multiprotein Mediator complex, a conserved coregulator of eukaryotic transcription that is connected to a number of intracellular signaling pathways. We demonstrate here that other Mediator components regulate the activity of Cdk8 in vivo and thereby direct the timing of mitotic entry. Deletion of Mediator components Med12 and Med13 leads to higher cellular Cdk8 protein levels, premature phosphorylation of the Cdk8 target Fkh2, and earlier entry into mitosis. We also demonstrate that Mediator is recruited to clusters of mitotic genes in a periodic fashion and that the complex is required for the transcription of these genes. We suggest that Mediator functions as a hub for coordinated regulation of mitotic progression and cell cycle-dependent transcription. The many signaling pathways and activator proteins shown to function via Mediator may influence the timing of these cell cycle events. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Mediation analysis with multiple versions of the mediator.

Science.gov (United States)

Vanderweele, Tyler J

2012-05-01

The causal inference literature has provided definitions of direct and indirect effects based on counterfactuals that generalize the approach found in the social science literature. However, these definitions presuppose well-defined hypothetical interventions on the mediator. In many settings, there may be multiple ways to fix the mediator to a particular value, and these various hypothetical interventions may have very different implications for the outcome of interest. In this paper, we consider mediation analysis when multiple versions of the mediator are present. Specifically, we consider the problem of attempting to decompose a total effect of an exposure on an outcome into the portion through the intermediate and the portion through other pathways. We consider the setting in which there are multiple versions of the mediator but the investigator has access only to data on the particular measurement, not information on which version of the mediator may have brought that value about. We show that the quantity that is estimated as a natural indirect effect using only the available data does indeed have an interpretation as a particular type of mediated effect; however, the quantity estimated as a natural direct effect, in fact, captures both a true direct effect and an effect of the exposure on the outcome mediated through the effect of the version of the mediator that is not captured by the mediator measurement. The results are illustrated using 2 examples from the literature, one in which the versions of the mediator are unknown and another in which the mediator itself has been dichotomized.

Mediators of Physical Activity on Neurocognitive Function: A Review at Multiple Levels of Analysis.

Science.gov (United States)

Stillman, Chelsea M; Cohen, Jamie; Lehman, Morgan E; Erickson, Kirk I

2016-01-01

Physical activity (PA) is known to maintain and improve neurocognitive health. However, there is still a poor understanding of the mechanisms by which PA exerts its effects on the brain and cognition in humans. Many of the most widely discussed mechanisms of PA are molecular and cellular and arise from animal models. While information about basic cellular and molecular mechanisms is an important foundation from which to build our understanding of how PA promotes cognitive health in humans, there are other pathways that could play a role in this relationship. For example, PA-induced changes to cellular and molecular pathways likely initiate changes to macroscopic properties of the brain and/or to behavior that in turn influence cognition. The present review uses a more macroscopic lens to identify potential brain and behavioral/socioemotional mediators of the association between PA and cognitive function. We first summarize what is known regarding cellular and molecular mechanisms, and then devote the remainder of the review to discussing evidence for brain systems and behavioral/socioemotional pathways by which PA influences cognition. It is our hope that discussing mechanisms at multiple levels of analysis will stimulate the field to examine both brain and behavioral mediators. Doing so is important, as it could lead to a more complete characterization of the processes by which PA influences neurocognitive function, as well as a greater variety of targets for modifying neurocognitive function in clinical contexts.

Mediators of Physical Activity on Neurocognitive Function: A Review at Multiple Levels of Analysis

Directory of Open Access Journals (Sweden)

Chelsea M. Stillman

2016-12-01

Full Text Available Physical activity (PA is known to maintain and improve neurocognitive health. However, there is still a poor understanding of the mechanisms by which PA exerts its effects on the brain and cognition in humans. Many of the most widely discussed mechanisms of PA are molecular and cellular and arise from animal models. While information about basic cellular and molecular mechanisms is an important foundation from which to build our understanding of how PA promotes cognitive health in humans, there are other pathways that could play a role in this relationship. For example, PA-induced changes to cellular and molecular pathways likely initiate changes to macroscopic properties of the brain and/or to behavior that in turn influence cognition. The present review uses a more macroscopic lens to identify potential brain and behavioral/socioemotional mediators of the association between PA and cognitive function. We first summarize what is known regarding cellular and molecular mechanisms, and then devote the remainder of the review to discussing evidence for brain systems and behavioral/socioemotional pathways by which PA influences cognition. It is our hope that discussing mechanisms at multiple levels of analysis will stimulate the field to examine both brain and behavioral mediators. Doing so is important, as it could lead to a more complete characterization of the processes by which PA influences neurocognitive function, as well as a greater variety of targets for modifying neurocognitive function in clinical contexts.

Molecular mechanism of sarcopenia and cachexia: recent research advances.

Science.gov (United States)

Sakuma, Kunihiro; Aoi, Wataru; Yamaguchi, Akihiko

2017-06-01

Skeletal muscle provides a fundamental basis for human function, enabling locomotion and respiration. Muscle loss occurs as a consequence of several chronic diseases (cachexia) and normal aging (sarcopenia). Although many negative regulators (atrogin-1, muscle ring finger-1, nuclear factor-kappaB (NF-κB), myostatin, etc.) have been proposed to enhance protein degradation during both sarcopenia and cachexia, the adaptation of these mediators markedly differs within both conditions. Sarcopenia and cachectic muscles have been demonstrated to be abundant in myostatin-linked molecules. The ubiquitin-proteasome system (UPS) is activated during rapid atrophy model (cancer cachexia), but few mediators of the UPS change during sarcopenia. NF-κB signaling is activated in cachectic, but not in sarcopenic, muscle. Recent studies have indicated the age-related defect of autophagy signaling in skeletal muscle, whereas autophagic activation occurs in cachectic muscle. This review provides recent research advances dealing with molecular mediators modulating muscle mass in both sarcopenia and cachexia.

Key mediators of intracellular amino acids signaling to mTORC1 activation.

Science.gov (United States)

Duan, Yehui; Li, Fengna; Tan, Kunrong; Liu, Hongnan; Li, Yinghui; Liu, Yingying; Kong, Xiangfeng; Tang, Yulong; Wu, Guoyao; Yin, Yulong

2015-05-01

Mammalian target of rapamycin complex 1 (mTORC1) is activated by amino acids to promote cell growth via protein synthesis. Specifically, Ras-related guanosine triphosphatases (Rag GTPases) are activated by amino acids, and then translocate mTORC1 to the surface of late endosomes and lysosomes. Ras homolog enriched in brain (Rheb) resides on this surface and directly activates mTORC1. Apart from the presence of intracellular amino acids, Rag GTPases and Rheb, other mediators involved in intracellular amino acid signaling to mTORC1 activation include human vacuolar sorting protein-34 (hVps34) and mitogen-activating protein kinase kinase kinase kinase-3 (MAP4K3). Those molecular links between mTORC1 and its mediators form a complicate signaling network that controls cellular growth, proliferation, and metabolism. Moreover, it is speculated that amino acid signaling to mTORC1 may start from the lysosomal lumen. In this review, we discussed the function of these mediators in mTORC1 pathway and how these mediators are regulated by amino acids in details.

Early life traumatic stressors and the mediating role of PTSD in incident HIV infection among US men, comparisons by sexual orientation and race/ethnicity: results from the NESARC, 2004-2005.

Science.gov (United States)

Reisner, Sari L; Falb, Kathryn L; Mimiaga, Matthew J

2011-08-01

Stressful life events in childhood during critical periods of development have long-term psychological and neurobiological sequelae, which may affect risk for HIV infection across the life course. Data were from a nationally representative sample of 13,274 US men (National Epidemiologic Survey on Alcohol and Related Conditions, 2004-2005). Weighted multivariable logistic regression models examined (1) the association of childhood violent events before age 18 on 12-month incident HIV infection and (2) whether posttraumatic stress disorder (PTSD) diagnosis (clinical interview) mediated the association between early life events and HIV. Overall, the 12-month HIV incidence was incident HIV infection (aOR = 5.75; 95% CI: 4.76 to 6.95). There was evidence that PTSD partially mediated the relationship between early life events and HIV (aOR = 1.14; 95% CI: 1.02 to 1.28). Experiencing early life violent family stressors was associated with HIV infection among men. Early life events and HIV infection were mediated by PTSD, which has implications for understanding disparities in HIV infection. Interventions are urgently needed that address the long-term sequelae of childhood violence.

Public gaming: eSport and event marketing in the experience economy

OpenAIRE

Borowy, Michael

2012-01-01

This thesis situates organized competitive digital gaming (eSport) in the context of historical sport, the rise of the computer and video games industry, event marketing, and the experience economy. It argues that the oftentimes misattributed origins of eSport in truth first took place during the early 1980s in arcades, when the various criteria for sport, including public contest, a structured framework for victory and defeat, mediatization and promotion, professionalization, record-keeping,...

Impact of pEGFP mediated ING4 gene on growth of glioma U251 ...

African Journals Online (AJOL)

Jane

2011-06-22

Jun 22, 2011 ... Full Length Research Paper. Impact of pEGFP mediated ING4 gene on growth of glioma U251 cells and its potential molecular mechanism. Yuefei Deng*, Bingxi Lei and Yiying Zhao. Department of Neurosurgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.