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81.
Classic infectious disease theory assumes that transmission depends on either the global density of the parasite (for directly
transmitted diseases) or its global frequency (for sexually transmitted diseases). One important implication of this dichotomy
is that parasite-driven host extinction is only predicted under frequency-dependent transmission. However, transmission is
fundamentally a local process between individuals that is determined by their and/or their vector’s behaviour. We examine
the implications of local transmission processes to the likelihood of disease-driven host extinction. Local density-dependent
transmission can lead to parasite-driven extinction, but extinction is more likely under local frequency-dependent transmission
and much more likely when there is active local searching behaviour. Density-dependent directly transmitted diseases spread
locally can therefore lead to deterministic host extinction, but locally frequency-dependent passive vector-borne diseases
are more likely to cause extinctions. However, it is active searching behaviour either by a vector or between sexual partners
that is most likely to cause the host to go extinct. Our work emphasises that local processes are essential in determining
parasite-driven extinctions, and the role of parasites in the extinction of rare species may have been underplayed due to
the classic assumption of global density-dependent transmission. 相似文献
82.
Space-time modeling of small area data is often used in epidemiology for mapping chronic disease rates and by government statistical agencies for producing local estimates of, for example, unemployment or crime rates. Although there is typically a general temporal trend, which affects all areas similarly, abrupt changes may occur in a particular area, e.g. due to emergence of localized predictors/risk factor(s) or impact of a new policy. Detection of areas with "unusual" temporal patterns is therefore important as a screening tool for further investigations. In this paper, we propose BaySTDetect, a novel detection method for short-time series of small area data using Bayesian model choice between two competing space-time models. The first model is a multiplicative decomposition of the area effect and the temporal effect, assuming one common temporal pattern across the whole study region. The second model estimates the time trends independently for each area. For each area, the posterior probability of belonging to the common trend model is calculated, which is then used to classify the local time trend as unusual or not. Crucial to any detection method, we provide a Bayesian estimate of the false discovery rate (FDR). A comprehensive simulation study has demonstrated the consistent good performance of BaySTDetect in detecting various realistic departure patterns in addition to estimating well the FDR. The proposed method is applied retrospectively to mortality data on chronic obstructive pulmonary disease (COPD) in England and Wales between 1990 and 1997 (a) to test a hypothesis that a government policy increased the diagnosis of COPD and (b) to perform surveillance. While results showed no evidence supporting the hypothesis regarding the policy, an identified unusual district (Tower Hamlets in inner London) was later recognized to have higher than national rates of hospital readmission and mortality due to COPD by the National Health Service, which initiated various local enhanced services to tackle the problem. Our method would have led to an early detection of this local health issue. 相似文献
83.
Intrinsically disordered proteins that acquire their three dimensional structures only upon binding to their targets are very important in cellular signal regulation. While experimental studies have been made on the structures of both bound (structured) and unbound (disordered) states, less is known about the actual folding-binding transition. Coarse grained simulations using native-centric (i.e. Gō) potentials have been particularly useful in addressing this problem, given the large search space for IDP binding, but have well-known deficiencies in reproducing the unfolded state structure and dynamics. Here, we investigate the interaction of HIF1α with CBP using a hierarchy of coarse-grained models, in each case matching the binding affinity at 300 K to the experimental value. Starting from a pure Gō-like model based on the native structure of the complex we go on to consider a more realistic model of helix propensity in the HIF1α, and finally the effect of non-native interactions between binding partners. We find structural disorder (i.e."fuzziness") in the bound state of HIF1α in all models which is supported by the results of atomistic simulations. Correcting the over-stabilized helices in the unbound state gives rise to a more cooperative folding-binding transition (destabilizing partially bound intermediates). Adding non-native contacts lowers the free energy barrier for binding to an almost barrierless scenario, leading to higher binding/unbinding rates relative to the other models, in better agreement with the near diffusion-limited binding rates measured experimentally. Transition state structures for the three models are highly disordered, supporting a fly-casting mechanism for binding. 相似文献
84.
Persistent elevation of the intracellular free Ca(2+) concentration [Ca(2+)](i) is neurotoxic and therefore it is important to understand how it affects downstream components of the Ca(2+) signaling pathway. The response of calmodulin (CaM) and alphaCa(2+)/CaM-dependent protein kinase II (alphaCaMKII), to intracellular Ca(2+) overload in hippocampal neurons is studied by confocal imaging of fluorescently tagged proteins. Transient and persistent redistribution of CaM and alphaCaMKII together is seen from the cytosol to dendritic and somatic punctae. Typical persistent redistribution occurs following a lag of 138+/-(S.E.M.) 12 s and is complete at 460+/-(S.E.M.) 34 s (n=18), lack of Thr(286)-autophosphorylation of alphaCaMKII however promotes the formation of early transient punctae (peak at 40 s). In contrast, the T286D-mimick of phospho-Thr(286)-alphaCaMKII forms punctae with a delay >10 min, indicating that Thr(286)-autophosphorylation is antagonistic to CaMKII clustering. A two-state model is proposed in which phospho-Thr(286)-alphaCaMKII, formed immediately upon Ca(2+) stimulation, is primarily responsible for target interactions and memory functions of alphaCaMKII. However, a distinct clustering form denoted alphaCaMKII(c), generated upon persistent intracellular free Ca(2+) elevation, is deposited in the punctae which are made of self-interacting CaM/CaMKII complexes. Punctate deposition disables both the interactions and the activity of CaMKII. 相似文献
85.
Best D Sahlender DA Walther N Peden AA Adams IR 《Development (Cambridge, England)》2008,135(8):1415-1425
In mammals, the supporting cell lineage in an embryonic gonad communicates the sex-determining decision to various sexually dimorphic cell types in the developing embryo, including the germ cells. However, the molecular nature of the sex-determining signals that pass from the supporting cells to the germ cells is not well understood. We have identified a conserved transmembrane protein, Sdmg1, owing to its male-specific expression in mouse embryonic gonads. Sdmg1 is expressed in the Sertoli cells of embryonic testes from 12.5 dpc, and in granulosa cells of growing follicles in adult ovaries. In Sertoli cells, Sdmg1 is localised to endosomes, and knock-down of Sdmg1 in Sertoli cell lines causes mis-localisation of the secretory SNARE Stx2 and defects in membrane trafficking. Upregulation of Sdmg1 appears to be part of a larger programme of changes to membrane trafficking pathways in embryonic Sertoli cells, and perturbing secretion in male embryonic gonads in organ culture causes male-to-female germ cell sex reversal. These data suggest that changes that occur in the cell biology of embryonic Sertoli cells may facilitate the communication of male sex-determining decisions to the germ cells during embryonic development. 相似文献
86.
Isakson BE Best AK Duling BR 《American journal of physiology. Heart and circulatory physiology》2008,294(6):H2898-H2904
Although much physiology in resistance vessels has been attributed to the cytoplasmic connection between endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), little is known of the protein expression between the two cell types. In an attempt to identify the proteins between ECs and VSMCs, mouse cremaster arterioles were stained with phalloidin-Alexa 594 and viewed on a confocal microscope that resolved "actin bridges" within the internal elastic lamina between ECs and VSMCs. To determine the incidence of protein, the pixel intensity from the antibodies on actin bridges were compared with the pixel intensity from antibodies within ECs or VSMCs. N-cadherin, desmin, connexin (Cx)40, and Cx43 and phosphorylated Cx43 at serine-368 were identified on actin bridges, but NG2, CD31, and Cx45 were not evident. Cx37 expression was more variable than the other connexins examined. Using this method on rat mesentery, we confirm the previously published predominance of Cx37 and Cx40 at the myoendothelial junction that was determined using electron microscopy. We conclude that this new method represents an important screening mechanism in which to rapidly test for protein expression between ECs and VSMCs and possibly a first-step in quantifying protein expression at the myoendothelial junction. 相似文献
87.
Terrière E Sharman M Donaghey C Herrmann L Lonie J Strachan M Dougall N Best J Ebmeier KP Pimlott S Patterson J Wyper D 《Neurochemical research》2008,33(4):643-651
Five patients with Alzheimer’s disease and five healthy volunteers were examined by SPECT with the nicotinic receptor ligand
123I-5-IA-85380. Patients were scanned before and after 6 weeks of treatment with donepezil. Quantification by regions of interest
was reliable and the optimal normalisation procedure used cerebellar ratios. We found relative reductions in 5-IA binding
capacity in patients in thalamus, frontal and central regions of interest of approximately one standard deviation unit (Cohen’s
d = 1). Reductions in binding after treatment with the acetylcholinesterase inhibitor donepezil of the same magnitude occurred
in the brain stem. The study was clearly too small to confirm group differences, but it suggests that 5-IA can be used to
examine both group differences and treatment effects in patients with Alzheimer’s disease.
Special issue article in honor of George Fink. 相似文献
88.
89.
90.
Benjamin S. Halpern Catherine Longo Julia S. Stewart Lowndes Benjamin D. Best Melanie Frazier Steven K. Katona Kristin M. Kleisner Andrew A. Rosenberg Courtney Scarborough Elizabeth R. Selig 《PloS one》2015,10(3)
International and regional policies aimed at managing ocean ecosystem health need quantitative and comprehensive indices to synthesize information from a variety of sources, consistently measure progress, and communicate with key constituencies and the public. Here we present the second annual global assessment of the Ocean Health Index, reporting current scores and annual changes since 2012, recalculated using updated methods and data based on the best available science, for 221 coastal countries and territories. The Index measures performance of ten societal goals for healthy oceans on a quantitative scale of increasing health from 0 to 100, and combines these scores into a single Index score, for each country and globally. The global Index score improved one point (from 67 to 68), while many country-level Index and goal scores had larger changes. Per-country Index scores ranged from 41–95 and, on average, improved by 0.06 points (range -8 to +12). Globally, average scores increased for individual goals by as much as 6.5 points (coastal economies) and decreased by as much as 1.2 points (natural products). Annual updates of the Index, even when not all input data have been updated, provide valuable information to scientists, policy makers, and resource managers because patterns and trends can emerge from the data that have been updated. Changes of even a few points indicate potential successes (when scores increase) that merit recognition, or concerns (when scores decrease) that may require mitigative action, with changes of more than 10–20 points representing large shifts that deserve greater attention. Goal scores showed remarkably little covariance across regions, indicating low redundancy in the Index, such that each goal delivers information about a different facet of ocean health. Together these scores provide a snapshot of global ocean health and suggest where countries have made progress and where a need for further improvement exists. 相似文献