2,607 research outputs found
The Social and Political Dimensions of the Ebola Response: Global Inequality, Climate Change, and Infectious Disease
The 2014 Ebola crisis has highlighted public-health vulnerabilities in Liberia, Sierra
Leone, and Guinea – countries ravaged by extreme poverty, deforestation and
mining-related disruption of livelihoods and ecosystems, and bloody civil wars in
the cases of Liberia and Sierra Leone. Ebola’s emergence and impact are grounded
in the legacy of colonialism and its creation of enduring inequalities within African
nations and globally, via neoliberalism and the Washington Consensus. Recent
experiences with new and emerging diseases such as SARS and various strains of
HN influenzas have demonstrated the effectiveness of a coordinated local and
global public health and education-oriented response to contain epidemics. To what
extent is international assistance to fight Ebola strengthening local public health and
medical capacity in a sustainable way, so that other emerging disease threats, which
are accelerating with climate change, may be met successfully? This chapter
considers the wide-ranging socio-political, medical, legal and environmental factors
that have contributed to the rapid spread of Ebola, with particular emphasis on the
politics of the global and public health response and the role of gender, social
inequality, colonialism and racism as they relate to the mobilization and
establishment of the public health infrastructure required to combat Ebola and other
emerging diseases in times of climate change
Hsp90 orchestrates transcriptional regulation by Hsf1 and cell wall remodelling by MAPK signalling during thermal adaptation in a pathogenic yeast
Acknowledgments We thank Rebecca Shapiro for creating CaLC1819, CaLC1855 and CaLC1875, Gillian Milne for help with EM, Aaron Mitchell for generously providing the transposon insertion mutant library, Jesus Pla for generously providing the hog1 hst7 mutant, and Cathy Collins for technical assistance.Peer reviewedPublisher PD
Anticipated impacts of achieving SDG targets on forests - a review
Sustainable development requires knowledge of trade-offs and synergies between environmental and non-environmental goals and targets. Understanding the ways in which positive progress in matters of development not directly concerned with the environment can affect the natural environment, whether for better or for worse, can allow policymakers and development agencies to avoid the negative impacts of their actions, while capitalising on mutually beneficial opportunities. Through a systematic review of the literature, we consider the impacts of UN Sustainable Development Goal (SDG) targets on forest ecosystems, and identify 63 targets associated with potentially beneficial, damaging or mixed (i.e. damaging and/or beneficial depending on context or location) impacts. Types of impact are not uniform within SDGs, nor necessarily within individual targets. Targets relating to energy and infrastructure are among the most damaging and best studied, while targets expected to potentially result in beneficial outcomes, typically associated with social progress and well-being, have been investigated to a much lesser degree, especially in the context of external interventions. Thirty-eight targets have some variation in the direction of their impacts (i.e. at least one record with mixed impacts, or two or more records with different directions), suggesting the potential to achieve beneficial over damaging impacts in many cases. We provide illustrative examples of a range of impacts and use our findings to provide recommendations for researchers, development agencies and policymakers
ruvA Mutants that resolve Holliday junctions but do not reverse replication forks
RuvAB and RuvABC complexes catalyze branch migration and resolution of Holliday junctions (HJs) respectively. In addition to their action in the last steps of homologous recombination, they process HJs made by replication fork reversal, a reaction which occurs at inactivated replication forks by the annealing of blocked leading and lagging strand ends. RuvAB was recently proposed to bind replication forks and directly catalyze their conversion into HJs. We report here the isolation and characterization of two separation-of-function ruvA mutants that resolve HJs, based on their capacity to promote conjugational recombination and recombinational repair of UV and mitomycin C lesions, but have lost the capacity to reverse forks. In vivo and in vitro evidence indicate that the ruvA mutations affect DNA binding and the stimulation of RuvB helicase activity. This work shows that RuvA's actions at forks and at HJs can be genetically separated, and that RuvA mutants compromised for fork reversal remain fully capable of homologous recombination
Increased S-nitrosylation and proteasomal degradation of caspase-3 during infection contribute to the persistence of adherent invasive escherichia coli (AIEC) in immune cells
Adherent invasive Escherichia coli (AIEC) have been implicated as a causative agent of Crohn's disease (CD) due to their isolation from the intestines of CD sufferers and their ability to persist in macrophages inducing granulomas. The rapid intracellular multiplication of AIEC sets it apart from other enteric pathogens such as Salmonella Typhimurium which after limited replication induce programmed cell death (PCD). Understanding the response of infected cells to the increased AIEC bacterial load and associated metabolic stress may offer insights into AIEC pathogenesis and its association with CD. Here we show that AIEC persistence within macrophages and dendritic cells is facilitated by increased proteasomal degradation of caspase-3. In addition S-nitrosylation of pro- and active forms of caspase-3, which can inhibit the enzymes activity, is increased in AIEC infected macrophages. This S-nitrosylated caspase-3 was seen to accumulate upon inhibition of the proteasome indicating an additional role for S-nitrosylation in inducing caspase-3 degradation in a manner independent of ubiquitination. In addition to the autophagic genetic defects that are linked to CD, this delay in apoptosis mediated in AIEC infected cells through increased degradation of caspase-3, may be an essential factor in its prolonged persistence in CD patients
The effectiveness of interventions to change six health behaviours: a review of reviews
Background: Several World Health Organisation reports over recent years have highlighted the high incidence of chronic diseases such as diabetes, coronary heart disease and cancer. Contributory factors include unhealthy diets, alcohol and tobacco use and sedentary lifestyles. This paper reports the findings of a review of reviews of behavioural change interventions to reduce unhealthy behaviours or promote healthy behaviours. We included six different health-related behaviours in the review: healthy eating, physical exercise, smoking, alcohol misuse, sexual risk taking (in young people) and illicit drug use. We excluded reviews which focussed on pharmacological treatments or those which required intensive treatments (e. g. for drug or alcohol dependency).
Methods: The Cochrane Library, Database of Abstracts of Reviews of Effectiveness (DARE) and several Ovid databases were searched for systematic reviews of interventions for the six behaviours (updated search 2008). Two reviewers applied the inclusion criteria, extracted data and assessed the quality of the reviews. The results were discussed in a narrative synthesis.
Results: We included 103 reviews published between 1995 and 2008. The focus of interventions varied, but those targeting specific individuals were generally designed to change an existing behaviour (e. g. cigarette smoking, alcohol misuse), whilst those aimed at the general population or groups such as school children were designed to promote positive behaviours (e. g. healthy eating). Almost 50% (n = 48) of the reviews focussed on smoking (either prevention or cessation). Interventions that were most effective across a range of health behaviours included physician advice or individual counselling, and workplace- and school-based activities. Mass media campaigns and legislative interventions also showed small to moderate effects in changing health behaviours. Generally, the evidence related to short-term effects rather than sustained/longer-term impact and there was a relative lack of evidence on how best to address inequalities.
Conclusions: Despite limitations of the review of reviews approach, it is encouraging that there are interventions that are effective in achieving behavioural change. Further emphasis in both primary studies and secondary analysis (e.g. systematic reviews) should be placed on assessing the differential effectiveness of interventions across different population subgroups to ensure that health inequalities are addressed.</p
Core temperatures during major abdominal surgery in patients warmed with new circulating-water garment, forced-air warming, or carbon-fiber resistive-heating system
Cooperation of local motions in the Hsp90 molecular chaperone ATPase mechanism
The Hsp90 chaperone is a central node of protein homeostasis activating a large number of diverse client proteins. Hsp90 functions as a molecular clamp that closes and opens in response to the binding and hydrolysis of ATP. Crystallographic studies define distinct conformational states of the mechanistic core implying structural changes that have not yet been observed in solution. Here, we engineered one-nanometer fluorescence probes based on photo-induced electron transfer into yeast Hsp90 to observe these motions. We found that the ATPase activity of the chaperone was reflected in the kinetics of specific structural rearrangements at remote positions that acted cooperatively. Nanosecond single-molecule fluorescence fluctuation analysis uncovered that critical structural elements that undergo rearrangement are mobile on a sub-millisecond time scale. We identified a two-step mechanism for lid closure over the nucleotide-binding pocket. The activating co-chaperone Aha1 mobilizes the lid of apo Hsp90, suggesting an early role in the catalytic cycle
The structure-function relationship of oncogenic LMTK3
Elucidating signaling driven by lemur tyrosine kinase 3 (LMTK3) could help drug development. Here, we solve the crystal structure of LMTK3 kinase domain to 2.1Å resolution, determine its consensus motif and phosphoproteome, unveiling in vitro and in vivo LMTK3 substrates. Via high-throughput homogeneous time-resolved fluorescence screen coupled with biochemical, cellular, and biophysical assays, we identify a potent LMTK3 small-molecule inhibitor (C28). Functional and mechanistic studies reveal LMTK3 is a heat shock protein 90 (HSP90) client protein, requiring HSP90 for folding and stability, while C28 promotes proteasome-mediated degradation of LMTK3. Pharmacologic inhibition of LMTK3 decreases proliferation of cancer cell lines in the NCI-60 panel, with a concomitant increase in apoptosis in breast cancer cells, recapitulating effects of LMTK3 gene silencing. Furthermore, LMTK3 inhibition reduces growth of xenograft and transgenic breast cancer mouse models without displaying systemic toxicity at effective doses. Our data reinforce LMTK3 as a druggable target for cancer therap
Drugs prescribed by general practitioners according to age, gender and socioeconomic status after adjustment for multimorbidity level
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