Ient B.,University of Southampton |
Edwards R.,University of Southampton |
Mould R.,University of Southampton |
Hannah M.,NIMR |
And 3 more authors.
Invertebrate Neuroscience | Year: 2012
Acute and chronic exposure of Caenorhabditis elegans to concentrations of ethanol in the range 250-350 mM elicits distinct behaviours. Previous genetic analysis highlights specific neurobiological substrates for these effects. However, ethanol may also elicit cellular stress responses which may contribute to the repertoire of ethanol-induced behaviours. Here, we have studied the effect of ethanol on an important arm of the cellular stress pathways, which emanates from the endoplasmic reticulum (ER) in response to several conditions including heat shock and chemical or genetic perturbations that lead to protein misfolding. HSP-4 is a heat shock protein and homologue of mammalian BiP. It is a pivotal upstream component of the ER stress response. Therefore, we used a C. elegans heat shock protein mutant, hsp-4, and a strain carrying a transcriptional reporter, Phsp-4::gfp, to test the role of the ER following chronic ethanol conditioning. We found no evidence for an overt ER response during acute or prolonged exposure to concentrations of ethanol that lead to defined ethanol-induced behaviours. Furthermore, whilst hsp-4 was strongly induced by tunicamycin, pre-exposure of C. elegans to low doses of tunicamycin followed by ethanol was not sufficient to induce an additive ER stress response. Behavioural analysis of an hsp-4 mutant indicated no difference compared to wild type in susceptibility to ethanol intoxication and withdrawal. There is a clear precedent for a significance of ER stress pathways particularly in clinical conditions associated with toxic or pathological effects of high doses of alcohol consumption. The concentrations of ethanol used in this C. elegans study equate to the highest blood alcohol levels measured in patients with chronic alcohol dependency. Taken together, these observations imply that the classic ER stress pathway in C. elegans is relatively refractory to induction by ethanol. © Springer-Verlag 2012.
Feldblum P.J.,Family Health International |
Lie C.-C.,Family Health International |
Weaver M.A.,Family Health International |
Van Damme L.,Family Health International |
And 6 more authors.
Sexually Transmitted Diseases | Year: 2010
Background: Analyzing pooled data from 4 recent microbicide trials, we aimed to determine characteristics of participants at higher risk of HIV and sexually transmitted infections (STIs), to inform targeted recruitment, preserved study power, and potentially smaller study sizes in future trials. Methods: We evaluated the relationships between participants? characteristics and the incidence of HIV, STIs, and reproductive tract infections (RTIs). We calculated incidence rates as the number of infection events divided by the person-years of observation. We applied Cox regression models to assess the relationships between baseline demographic, reproductive and behavioral factors and incident HIV, STIs and RTIs. Results: The pooled incidence rates for HIV, chlamydia, and gonorrhea were 2.1, 6.4 and 9.9 per 100 person-years, respectively. Proportions of participants with trichomoniasis, bacterial vaginosis (BV), and candidiasis were 0.06, 0.40, and 0.40, respectively. In final multivariable models, age and education were significantly (and inversely) associated with incident HIV; baseline chlamydia, baseline trichomoniasis, and younger age were associated with incident Chlamydia; and baseline gonorrhea infection, younger age, less education, nulliparous status, baseline chlamydia, and condom use for contraception were associated with incident gonorrhea. Three factors were associated with trichomoniasis: baseline trichomoniasis infection, baseline chlamydia, and baseline BV. CONCLUSIONS:: Only younger age was robustly associated with multiple STI outcomes in our multivariable analyses. Although there was little evidence of associations between baseline STIs and incident HIV, they were strongly associated with incident STIs. We found no evidence that measured baseline sexual behavior factors were associated with incident HIV or STIs. Copyright © 2010 American Sexually Transmitted Diseases Association All rights reserved.
Metzakopian E.,NIMR |
Lin W.,NIMR |
Salmon-Divon M.,European Bioinformatics Institute |
Salmon-Divon M.,Cancer Research Center |
And 7 more authors.
Development (Cambridge) | Year: 2012
The transcription factors Foxa1 and Foxa2 promote the specification of midbrain dopaminergic (mDA) neurons and the floor plate. Whether their role is direct has remained unclear as they also regulate the expression of Shh, which has similar roles. We characterized the Foxa2 cis-regulatory network by chromatin immunoprecipitation followed by high-throughput sequencing of mDA progenitors. This identified 9160 high-quality Foxa2 binding sites associated with 5409 genes, providing mechanistic insights into Foxa2-mediated positive and negative regulatory events. Foxa2 regulates directly and positively key determinants of mDA neurons, including Lmx1a, Lmx1b, Msx1 and Ferd3l, while negatively inhibiting transcription factors expressed in ventrolateral midbrain such as Helt, Tle4, Otx1, Sox1 and Tal2. Furthermore, Foxa2 negatively regulates extrinsic and intrinsic components of the Shh signaling pathway, possibly by binding to the same enhancer regions of co-regulated genes as Gli1. Foxa2 also regulates the expression of floor plate factors that control axon trajectories around the midline of the embryo, thereby contributing to the axon guidance function of the floor plate. Finally, this study identified multiple Foxa2-regulated enhancers that are active in the floor plate of the midbrain or along the length of the embryo in mouse and chick. This work represents the first comprehensive characterization of Foxa2 targets in mDA progenitors and provides a framework for elaborating gene regulatory networks in a functionally important progenitor population. © 2012. Published by The Company of Biologists Ltd.
Mbilinyi D.,NIMR |
Daniel M.L.,University of Bergen |
Lie G.T.,University of Bergen
BMC Health Services Research | Year: 2011
Background: Health worker motivation can potentially affect the provision of health services. The HIV pandemic has placed additional strain on health service provision through the extra burden of increased testing and counselling, treating opportunistic infections and providing antiretroviral treatment. The aim of this paper is to explore the challenges generated by HIV care and treatment and their impact on health worker motivation in Mbeya Region, Tanzania. Methods. Thirty in-depth interviews were conducted with health workers across the range of health care professions in health facilities in two high HIV-prevalence districts of Mbeya Region, Tanzania. A qualitative framework analysis was adopted for data analysis. Results: The negative impact of HIV-related challenges on health worker motivation was confirmed by this study. Training seminars and workshops related to HIV contributed to the shortage of health workers in the facilities. Lower status workers were frequently excluded from training and were more severely affected by the consequent increase in workload as seminars were usually attended by higher status professionals who controlled access. Constant and consistent complaints by clients have undermined health workers' expectations of trust and recognition. Health workers were forced to take responsibility for dealing with problems arising from organisational inefficiencies within the health system. Conclusion: HIV-related challenges undermine motivation among health workers in Mbeya, Tanzania with the burden falling most heavily on lower status workers. Strained relations between health workers and the community they serve, further undermine motivation of health workers. © 2011 Mbilinyi et al; licensee BioMed Central Ltd.
Nandha B.,NIMR |
Journal of Communicable Diseases | Year: 2011
Diethylcarbamazinecitrate (DEC) salt in conjunction with annual singledose mass drug administration (MDA) with DEC tablets can be considered as potential option to hasten the process of Lymphatic Filariasis (LF) elimination. Consumption of DEC tablet/salt by at least 80% of the endemic population is crucial in achieving elimination in five years. This study examines the determinants of rural-urban population movement and its implication on DEC fortified salt program to control LF. Data was collected through questionnaire from 150 each movers and non-movers from 10 randomly selected villages and also using Key informant (KI) interviews in Villupuram district in Tamil Nadu. Households with at least one family member engaged in movement at any point of time in the previous year, range from 24-43% in different villages. Knowledge on cause, control, ongoing LF elimination programs and compliance with DEC tablets (28.7%) and salt (30%) were significantly higher (p<0.05) among non-movers than movers (4.7% and 3.3%respectively). In order to achieve the goal of elimination of LF by 2020, measures need to be undertaken to ensure that the social mobilization activities and LF intervention programs need to cover the 24-43% of mobile population.
Nygard A.-B.,Copenhagen University |
Cirera S.,Copenhagen University |
Gilchrist M.J.,NIMR |
Gorodkin J.,Copenhagen University |
And 2 more authors.
BMC Research Notes | Year: 2010
Background. Since at least half of the genes in mammalian genomes are subjected to alternative splicing, alternative pre-mRNA splicing plays an important contribution to the complexity of the mammalian proteome. Expressed sequence tags (ESTs) provide evidence of a great number of possible alternative isoforms. With the EST resource for the domestic pig now containing more than one million porcine ESTs, it is possible to identify alternative splice forms of the individual transcripts in this species from the EST data with some confidence. Results. The pig EST data generated by the Sino-Danish Pig Genome project has been assembled with publicly available ESTs and made available in the PigEST database. Using the Distiller package 2,515 EST clusters with candidate alternative isoforms were identified in the EST data with high confidence. In agreement with general observations in human and mouse, we find putative splice variants in about 30% of the contigs with more than 50 ESTs. Based on the criteria that a minimum of two EST sequences confirmed each splice event, a list of 100 genes with the most distinct tissue-specific alternative splice events was generated from the list of candidates. To confirm the tissue specificity of the splice events, 10 genes with functional annotation were randomly selected from which 16 individual splice events were chosen for experimental verification by quantitative PCR (qPCR). Six genes were shown to have tissue specific alternatively spliced transcripts with expression patterns matching those of the EST data. The remaining four genes had tissue-restricted expression of alternative spliced transcripts. Five out of the 16 splice events that were experimentally verified were found to be putative pig specific. Conclusions. In accordance with human and rodent studies we estimate that approximately 30% of the porcine genes undergo alternative splicing. We found a good correlation between EST predicted tissue-specificity and experimentally validated splice events in different porcine tissue. This study indicates that a cluster size of around 50 ESTs is optimal for in silico detection of alternative splicing. Although based on a limited number of splice events, the study supports the notion that alternative splicing could have an important impact on species differentiation since 31% of the splice events studied appears to be species specific. © 2010 Fredholm et al; licensee BioMed Central Ltd.
BMC Biology | Year: 2015
James Briscoe has a BSc in Microbiology and Virology (from the University of Warwick, UK) and a PhD in Molecular and Cellular Biology (from the Imperial Cancer Research Fund, London, now Cancer Research UK). He started working on the development of the neural tube in the lab of Tom Jessel as a postdoctoral fellow, establishing that there was graded sonic hedgehog signaling in the ventral neural tube. He is currently a group leader and Head of Division in Developmental Biology at the MRC National Institute for Medical Research (which will become part of the Francis Crick Institute in April 2015). He is working to understand the molecular and cellular mechanisms of graded signaling in the vertebrate neural tube. We interviewed him about the development of ideas on morphogenetic gradients and his own work on modeling the development of the neural tube for our series on modeling in biology. © 2015 Briscoe.
PubMed | NIMR
Type: Journal Article | Journal: Development (Cambridge, England) | Year: 2012
The transcription factors Foxa1 and Foxa2 promote the specification of midbrain dopaminergic (mDA) neurons and the floor plate. Whether their role is direct has remained unclear as they also regulate the expression of Shh, which has similar roles. We characterized the Foxa2 cis-regulatory network by chromatin immunoprecipitation followed by high-throughput sequencing of mDA progenitors. This identified 9160 high-quality Foxa2 binding sites associated with 5409 genes, providing mechanistic insights into Foxa2-mediated positive and negative regulatory events. Foxa2 regulates directly and positively key determinants of mDA neurons, including Lmx1a, Lmx1b, Msx1 and Ferd3l, while negatively inhibiting transcription factors expressed in ventrolateral midbrain such as Helt, Tle4, Otx1, Sox1 and Tal2. Furthermore, Foxa2 negatively regulates extrinsic and intrinsic components of the Shh signaling pathway, possibly by binding to the same enhancer regions of co-regulated genes as Gli1. Foxa2 also regulates the expression of floor plate factors that control axon trajectories around the midline of the embryo, thereby contributing to the axon guidance function of the floor plate. Finally, this study identified multiple Foxa2-regulated enhancers that are active in the floor plate of the midbrain or along the length of the embryo in mouse and chick. This work represents the first comprehensive characterization of Foxa2 targets in mDA progenitors and provides a framework for elaborating gene regulatory networks in a functionally important progenitor population.
PubMed | NIMR, University of Cincinnati and Ottawa Hospital Research Institute
Type: Journal Article | Journal: Development (Cambridge, England) | Year: 2015
Midbrain dopamine neuronal progenitors develop into heterogeneous subgroups of neurons, such as substantia nigra pars compacta, ventral tegmental area and retrorubal field, that regulate motor control, motivated and addictive behaviours. The development of midbrain dopamine neurons has been extensively studied, and these studies indicate that complex cross-regulatory interactions between extrinsic and intrinsic molecules regulate a precise temporal and spatial programme of neurogenesis in midbrain dopamine progenitors. To elucidate direct molecular interactions between multiple regulatory factors during neuronal differentiation in mice, we characterised genome-wide binding sites of the forkhead/winged helix transcription factor Foxa1, which functions redundantly with Foxa2 to regulate the differentiation of mDA neurons. Interestingly, our studies identified a rostral brain floor plate Neurog2 enhancer that requires direct input from Otx2, Foxa1, Foxa2 and an E-box transcription factor for its transcriptional activity. Furthermore, the chromatin remodelling factor Smarca1 was shown to function downstream of Foxa1 and Foxa2 to regulate differentiation from immature to mature midbrain dopaminergic neurons. Our genome-wide Foxa1-bound cis-regulatory sequences from ChIP-Seq and Foxa1/2 candidate target genes from RNA-Seq analyses of embryonic midbrain dopamine cells also provide an excellent resource for probing mechanistic insights into gene regulatory networks involved in the differentiation of midbrain dopamine neurons.
News Article | February 20, 2017
Visitors look at vehicles on display during the International Defence Exhibition and Conference (IDEX) in Abu Dhabi, United Arab Emirates February 19, 2017. REUTERS/Stringer ABU DHABI (Reuters) - The United Arab Emirates (UAE) awarded 4.5 billion dirhams ($1.2 billion) in military procurement deals on Sunday, part of a total of 20 billion dirhams worth of purchases it expects to make at an arms fair this week, a spokesman for the expo said. The deals awarded to local and international companies on Sunday included a 2 billion dirham award to the UAE's NIMR Automotive, part of Tawazun Holdings, for the supply of 400 armored vehicles to the UAE Armed Forces, Rashid al Shamsi, a spokesman for the International Defence Exhibition (Idex), said. "We expect (to award) more than 20 billion dirhams in contracts by the end of Idex," he said. Over 1,200 companies are participating at Idex, the region's largest defense expo.