288 research outputs found

    Diffusion, disorder and dynamics in the nuclear pore complex

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    Converging on the function of intrinsically disordered nucleoporins in the nuclear pore complex

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    Several biological mechanisms involve proteins or proteinaceous components that are intrinsically disordered. A case in point pertains to the nuclear pore complex (NPC), which regulates molecular transport between the nucleus and the cytoplasm. NPC functionality is dependent on unfolded domains rich in Phe-Gly (FG) repeats (i.e., FG-domains) that collectively act to promote or hinder cargo translocation. To a large extent, our understanding of FG-domain behavior is limited to in vitro investigations given the difficulty to resolve them directly in the NPC. Nevertheless, recent findings indicate a collective convergence towards rationalizing FG-domain function. This review aims to glean further insight into this fascinating problem by taking an objective look at the boundary conditions and contextual details underpinning FG-domain behavior in the NPC. Here, we treat the FG-domains as being commensurate with polymeric chains to address ambiguities such as for instance, how FG-domains tethered to the central channel of the NPC would behave differently as compared with their free-floating counterparts in solution. By bringing such fundamental questions to the fore, this review seeks to illuminate the importance of how such parameters can hold influence over the structure-function relation of intrinsically disordered proteins in the NPC and beyon

    From the trap to the basket: getting to the bottom of the nuclear pore complex

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    Nuclear pore complexes (NPCs) are large supramolecular assemblies that perforate the double-membraned nuclear envelope and serve as the sole gateways of molecular exchange between the cytoplasm and the nucleus in interphase cells. Combining novel specimen preparation regimes with innovative use of high-resolution scanning electron microscopy, Hans Ris produced in the late eighties stereo images of the NPC with unparalleled clarity and structural detail, thereby setting new standards in the field. Since that time, efforts undertaken to resolve the molecular structure and architecture, and the numerous interactions that occur between NPC proteins (nucleoporins), soluble transport receptors, and the small GTPase Ran, have led to a deeper understanding of the functional role of NPCs in nucleocytoplasmic transport. In spite of these breakthroughs, getting to the bottom of the actual cargo translocation mechanism through the NPC remains elusive and controversial. Here, we review recent insights into NPC function by correlating structural findings with biochemical data. By introducing new experimental and computational results, we reexamine how NPCs can discriminate between receptor-mediated and passive cargo to promote vectorial translocation in a highly regulated manner. Moreover, we comment on the importance and potential benefits of identifying and experimenting with individual key components implicated in the translocation mechanism. We conclude by dwelling on questions that we feel are pertinent to a more rational understanding of the physical aspects governing NPC mechanics. Last but not least, we substantiate these uncertainties by boldly suggesting a new direction in NPC research as a means to verify such novel concepts, for example, a de novo designed ‘minimalist' NP

    Towards reconciling structure and function in the nuclear pore complex

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    The spatial separation between the cytoplasm and the cell nucleus necessitates the continuous exchange of macromolecular cargo across the double-membraned nuclear envelope. Being the only passageway in and out of the nucleus, the nuclear pore complex (NPC) has the principal function of regulating the high throughput of nucleocytoplasmic transport in a highly selective manner so as to maintain cellular order and function. Here, we present a retrospective review of the evidence that has led to the current understanding of both NPC structure and function. Looking towards the future, we contemplate on how various outstanding effects and nanoscopic characteristics ought to be addressed, with the goal of reconciling structure and function into a single unified picture of the NP

    An Atlas on Global Water Cycle

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    What do climate models predict for the rainfall where you live? What about evaporation or runoff? Should your local community consider constructing new dams or do the existing water storages appear adequate? What about the availability of water for irrigation farming? Do the predictions differ between different climate models or do all the models basically predict the same changes in water availability where you live? These are all simple questions but it is surprisingly hard for an individual, whether they be a farmer, water resources engineer, teacher or interested citizen, to answer them. As researchers active in the field we could not answer the questions either. In fact, we had never seen a compilation of the rainfall, evaporation and runoff predictions made by all the different climate models. The Atlas contains maps and tables that document model predictions contributed by international climate modelling groups to the 2007 4th Assessment Report of the Intergovernmental Panel on Climate Change. The predictions are made available here via the wonders of the internet and ongoing cooperation by the international climate modelling community who routinely archive their results. The maps and tables in the Atlas document rainfall, evaporation and runoff estimates for the 20th century along with predictions of the same quantities at the end of the 21st century. Whatever your interest, we hope you find the Atlas as helpful as we do

    A general framework for understanding the response of the water cycle to global warming over land and ocean

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    Climate models project increases in globally averaged atmospheric specific humidity that are close to the Clausius"Clapeyron (CC) value of around 7%K-1 whilst projections for mean annual global precipitation (P) and evaporation (E) are somewhat muted at around 2%K-1. Such global projections are useful summaries but do not provide guidance at local (grid box) scales where impacts occur. To bridge that gap in spatial scale, previous research has shown that the "wet get wetter and dry get drier" relation, Δ(P -E)αP -E, follows CC scaling when the projected changes are averaged over latitudinal zones. Much of the research on projected climate impacts has been based on an implicit assumption that this CC relation also holds at local (grid box) scales but this has not previously been examined. In this paper we find that the simple latitudinal average CC scaling relation does not hold at local (grid box) scales over either ocean or land. This means that in terms of P -E, the climate models do not project that the "wet get wetter and dry get drier" at the local scales that are relevant for agricultural, ecological and hydrologic impacts. In an attempt to develop a simple framework for local-scale analysis we found that the climate model output shows a remarkably close relation to the long-standing Budyko framework of catchment hydrology. We subsequently use the Budyko curve and find that the local-scale changes in P -E projected by climate models are dominated by changes in P while the changes in net irradiance at the surface due to greenhouse forcing are small and only play a minor role in changing the mean annual P -E in the climate model projections. To further understand the apparently small changes in net irradiance we also examine projections of key surface energy balance terms. In terms of global averages, we find that the climate model projections are dominated by changes in only three terms of the surface energy balance: (1) an increase in the incoming long-wave irradiance, and the respective responses (2) in outgoing longwave irradiance and (3) in the evaporative flux, with the latter change being much smaller than the former two terms and mostly restricted to the oceans. The small fraction of the realised surface forcing that is partitioned into E explains why the hydrologic sensitivity (2%K-1) is so much smaller than CC scaling (7%K -1). Much public and scientific perception about changes in the water cycle has been based on the notion that temperature enhances E. That notion is partly true but has proved an unfortunate starting point because it has led to misleading conclusions about the impacts of climate change on the water cycle. A better general understanding of the potential impacts of climate change on water availability that are projected by climate models will surely be gained by starting with the notion that the greater the enhancement of E, the less the surface temperature increase (and vice versa). That latter notion is based on the conservation of energy and is an underlying basis of climate model projections

    Solvation forces in confined molecular liquids

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    Ph.DDOCTOR OF PHILOSOPH

    The Bi-Functional Organization of Human Basement Membranes

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    The current basement membrane (BM) model proposes a single-layered extracellular matrix (ECM) sheet that is predominantly composed of laminins, collagen IVs and proteoglycans. The present data show that BM proteins and their domains are asymmetrically organized providing human BMs with side-specific properties: A) isolated human BMs roll up in a side-specific pattern, with the epithelial side facing outward and the stromal side inward. The rolling is independent of the curvature of the tissue from which the BMs were isolated. B) The epithelial side of BMs is twice as stiff as the stromal side, and C) epithelial cells adhere to the epithelial side of BMs only. Side-selective cell adhesion was also confirmed for BMs from mice and from chick embryos. We propose that the bi-functional organization of BMs is an inherent property of BMs and helps build the basic tissue architecture of metazoans with alternating epithelial and connective tissue layers

    Simple biophysics underpins collective conformations of the intrinsically disordered proteins of the Nuclear Pore Complex

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    Nuclear Pore Complexes (NPCs) are key cellular transporter that control nucleocytoplasmic transport in eukaryotic cells, but its transport mechanism is still not understood. The centerpiece of NPC transport is the assembly of intrinsically disordered polypeptides, known as FG nucleoporins, lining its passageway. Their conformations and collective dynamics during transport are difficult to assess in vivo. In vitro investigations provide partially conflicting results, lending support to different models of transport, which invoke various conformational transitions of the FG nucleoporins induced by the cargo-carrying transport proteins. We show that the spatial organization of FG nucleoporin assemblies with the transport proteins can be understood within a first principles biophysical model with a minimal number of key physical variables, such as the average protein interaction strengths and spatial densities. These results address some of the outstanding controversies and suggest how molecularly divergent NPCs in different species can perform essentially the same function

    An environmental scan of academic pediatric emergency medicine at Canadian medical schools: Identifying variability across Canada

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    Objective To complement our environmental scan of academic emergency medicine departments, we conducted a similar environmental scan of the academic pediatric emergency medicine programs offered by the Canadian medical schools.Methods We developed an 88-question form, which was distributed to pediatric academic leaders at each medical school. The responses were validated via email to ensure that the questions were answered completely and consistently.Results Fourteen of the 17 Canadian medical schools have some type of pediatric emergency medicine academic program. None of the pediatric emergency medicine units have full departmental status, while nine are divisions, two are sections, and three have no status. Canadian academic pediatric emergency medicine is practised at 13 major teaching hospitals and one specialized pediatric emergency department. There are 394 pediatric emergency medicine faculty members, including 13 full professors and 64 associate professors. Eight sites regularly take pediatric undergraduate clinical clerks, and all 14 provide resident education. Fellowship training is offered at 10 sites, with five offering advanced pediatric emergency medicine fellowship training. Half of the sites have at least one physician with a Master\u27s degree in education, totalling 18 faculty members across Canada. There are 31 clinical researchers with salary support at nine universities. Eleven sites have published peer-reviewed papers (n=423) in the past five years, ranging from two to 102 per site. Annual academic budgets range from 10,000 to 2,607,515.Conclusions This comprehensive review of academic activities in pediatric emergency medicine across Canada identifies the variability across the country, including the recognition of sites above and below the national average, which may prompt change at individual sites. Sharing these academic practices may inspire sites to provide more support to teachers, educators, and researchers
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