Nck adaptor proteins link nephrin to the actin cytoskeleton of kidney podocytes

The glomerular filtration barrier in the kidney is formed in part by a specialized intercellular junction known as the slit diaphragm, which connects adjacent actin-based foot processes of kidney epithelial cells (podocytes). Mutations affecting a number of slit diaphragm proteins, including nephrin (encoded by NPHS1), lead to renal disease owing to disruption of the filtration barrier and rearrangement of the actin cytoskeleton, although the molecular basis for this is unclear. Here we show that nephrin selectively binds the Src homology 2 (SH2)/SH3 domain-containing Nck adaptor proteins, which in turn control the podocyte cytoskeleton in vivo. The cytoplasmic tail of nephrin has multiple YDxV sites that form preferred binding motifs for the Nck SH2 domain once phosphorylated by Src-family kinases. We show that this Nck-nephrin interaction is required for nephrin-dependent actin reorganization. Selective deletion of Nck from podocytes of transgenic mice results in defects in the formation of foot processes and in congenital nephrotic syndrome. Together, these findings identify a physiological signalling pathway in which nephrin is linked through phosphotyrosine-based interactions to Nck adaptors, and thus to the underlying actin cytoskeleton in podocytes. Simple and widely expressed SH2/SH3 adaptor proteins can therefore direct the formation of a specialized cellular morphology in vivo.     

Smart Cities and M<Superscript>3</Superscript>: Rapid Research,Meaningful Metrics and Co-Design

The research described in this paper is undertaken under the banner of the smart city, a concept that captures the way urban spaces are re-made by the incursion of new technology. Much of smart is centred on converting everyday activities into data, and using this data to generate knowledge mediated by technology. Ordinary citizens, those that may have their lives impacted by the technology, usually are not properly involved in the ‘smartification’ process. Their perceptions, concerns and expectations should inform the conception and development of smart technologies at the same extent. How to engage general public with smart cities research is the central challenge for the Making Metrics Meaningful (MMM) project. Applying a rapid participatory method, ‘Imagine’ over a five-month period (March – July) the research sought to gain insights from the general public into novel forms of information system innovation. This brief paper describes the nature of the accelerated research undertaken and explores some of the themes which emerged in the analysis. Generic themes, beyond the remit of an explicit transport focus, are developed and pointers towards further research directions are discussed. Participatory methods, including engaging with self-selected transport users actively through both picture creation and programmatically specific musical ‘signatures’ as well as group discussion, were found to be effective in eliciting users’ own concerns, needs and ideas for novel information systems.     

基于数理模型的二手房买卖经纪模式仿真比较

为研究二手房买卖经纪模式对买方效用的影响,比较不同经纪模式下的买方效用,基于对现实二手房买卖过程及特点的分析,分别构建"单一经纪人"和"双经纪人"模式下的买方效用数理模型并进行求解,最后采用Matlab工具对这2种经纪模式下的买方效用及相关指标进行仿真比较。研究结果表明:1)与"双经纪人"模式相比,"单一经纪人"模式下的买方佣金激励程度小,但经纪人搜寻努力高且买方效用大;2)在其他条件不变的情况下,从买方效用的角度分析,二手房买卖过程中的买方应选择"单一经纪人"模式,以达到促进交易进程的目标。     

Turing and the Serendipitous Discovery of the Modern Computer

In the centenary year of Turing’s birth, a lot of good things are sure to be written about him. But it is hard to find something new to write about Turing. This is the biggest merit of this article: it shows how von Neumann’s architecture of the modern computer is a serendipitous consequence of the universal Turing machine, built to solve a logical problem.     

Immune suppression by neutrophils and granulocytic myeloid-derived suppressor cells: similarities and differences

Neutrophils are essential effector cells in the host defense against invading pathogens. Recently, novel neutrophil functions have emerged in addition to their classical anti-microbial role. One of these functions is the suppression of T cell responses. In this respect, neutrophils share similarities with granulocytic myeloid-derived suppressor cells (G-MDSCs). In this review, we will discuss the similarities and differences between neutrophils and G-MDSCs. Various types of G-MDSCs have been described, ranging from immature to mature cells shaping the immune response by different immune suppressive mechanisms. However, all types of G-MDSCs share distinct features of neutrophils, such as surface markers and morphology. We propose that G-MDSCs are heterogeneous and represent novel phenotypes of neutrophils, capable of suppressing the immune response. In this review, we will attempt to clarify the differences and similarities between neutrophils and G-MDSCs and attempt to facilitate further research.     

Cluster Differences Unfolding for Two-Way Two-Mode Preference Rating Data

Classification and spatial methods can be used in conjunction to represent the individual information of similar preferences by means of groups. In the context of latent class models and using Simulated Annealing, the cluster-unfolding model for two-way two-mode preference rating data has been shown to be superior to a two-step approach of first deriving the clusters and then unfolding the classes. However, the high computational cost makes the procedure only suitable for small or medium-sized data sets, and the hypothesis of independent and normally distributed preference data may also be too restrictive in many practical situations. Therefore, an alternating least squares procedure is proposed, in which the individuals and the objects are partitioned into clusters, while at the same time the cluster centers are represented by unfolding. An enhanced Simulated Annealing algorithm in the least squares framework is also proposed in order to address the local optimum problem. Real and artificial data sets are analyzed to illustrate the performance of the model.     

RPA regulates telomerase action by providing Est1p access to chromosome ends

Replication protein A (RPA) is a highly conserved single-stranded DNA-binding protein involved in DNA replication, recombination and repair. We show here that RPA is present at the telomeres of the budding yeast Saccharomyces cerevisiae, with a maximal association in S phase. A truncation of the N-terminal region of Rfa2p (associated with the rfa2Delta40 mutated allele) results in severe telomere shortening caused by a defect in the in vivo regulation of telomerase activity. Cells carrying rfa2Delta40 show impaired binding of the protein Est1p, which is required for telomerase action. In addition, normal telomere length can be restored by expressing a Cdc13-Est1p hybrid protein. These findings indicate that RPA activates telomerase by loading Est1p onto telomeres during S phase. We propose a model of in vivo telomerase action that involves synergistic action of RPA and Cdc13p at the G-rich 3' overhang of telomeric DNA.     

Determination of electron orbital magnetic moments in carbon nanotubes

The remarkable transport properties of carbon nanotubes (CNTs) are determined by their unusual electronic structure. The electronic states of a carbon nanotube form one-dimensional electron and hole sub-bands, which, in general, are separated by an energy gap. States near the energy gap are predicted to have an orbital magnetic moment, mu(orb), that is much larger than the Bohr magneton (the magnetic moment of an electron due to its spin). This large moment is due to the motion of electrons around the circumference of the nanotube, and is thought to play a role in the magnetic susceptibility of CNTs and the magnetoresistance observed in large multiwalled CNTs. But the coupling between magnetic field and the electronic states of individual nanotubes remains to be quantified experimentally. Here we report electrical measurements of relatively small diameter (2-5 nm) individual CNTs in the presence of an axial magnetic field. We observe field-induced energy shifts of electronic states and the associated changes in sub-band structure, which enable us to confirm quantitatively the predicted values for mu(orb).     

Niche lability in the evolution of a Caribbean lizard community

Niche conservatism--the tendency for closely related species to be ecologically similar--is widespread. However, most studies compare closely related taxa that occur in allopatry; in sympatry, the stabilizing forces that promote niche conservatism, and thus inhibit niche shifts, may be countered by natural selection favouring ecological divergence to minimize the intensity of interspecific interactions. Consequently, the relative importance of niche conservatism versus niche divergence in determining community structure has received little attention. Here, we examine a tropical lizard community in which species have a long evolutionary history of ecological interaction. We find that evolutionary divergence overcomes niche conservatism: closely related species are no more ecologically similar than expected by random divergence and some distantly related species are ecologically similar, leading to a community in which the relationship between ecological similarity and phylogenetic relatedness is very weak. Despite this lack of niche conservatism, the ecological structuring of the community has a phylogenetic component: niche complementarity only occurs among distantly related species, which suggests that the strength of ecological interactions among species may be related to phylogeny, but it is not necessarily the most closely related species that interact most strongly.