ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway

The rare diseases ataxia-telangiectasia (AT), caused by mutations in the ATM gene, and Nijmegen breakage syndrome (NBS), with mutations in the p95/nbs1 gene, share a variety of phenotypic abnormalities such as chromosomal instability, radiation sensitivity and defects in cell-cycle checkpoints in response to ionizing radiation. The ATM gene encodes a protein kinase that is activated by ionizing radiation or radiomimetic drugs, whereas p95/nbs1 is part of a protein complex that is involved in responses to DNA double-strand breaks. Here, because of the similarities between AT and NBS, we evaluated the functional interactions between ATM and p95/nbs1. Activation of the ATM kinase by ionizing radiation and induction of ATM-dependent responses in NBS cells indicated that p95/nbs1 may not be required for signalling to ATM after ionizing radiation. However, p95/nbs1 was phosphorylated on serine 343 in an ATM-dependent manner in vitro and in vivo after ionizing radiation. A p95/nbs1 construct mutated at the ATM phosphorylation site abrogated an S-phase checkpoint induced by ionizing radiation in normal cells and failed to compensate for this functional deficiency in NBS cells. These observations link ATM and p95/nbs1 in a common signalling pathway and provide an explanation for phenotypic similarities in these two diseases.     

Direct imaging of the pores and cages of three-dimensional mesoporous materials

Mesostructured composite materials, with features ranging from 20 to 500 A in size, are obtained by the kinetically controlled competitive assembly of organic and inorganic species into nanostructured domains. Short-range order is limited, and long-range order is determined by weak forces such as van der Waals or hydrogen-bonding. Three-dimensional mesoporous materials obtained by removing the organic phase are of particular interest for applications such as catalysis and chemical sensing or separation, for which structural features such as cavity shape, connectivity and ordered bimodal porosity are critical. But atomic-scale structural characterization by the usual diffraction techniques is challenging for these partially ordered materials because of the difficulty in obtaining large (> 10 microm) single crystals, and because large repeat spacings cause diffraction intensities to fall off rapidly with scattering angle so that only limited small-angle data are available. Here we present a general approach for the direct determination of three-dimensional mesoporous structures by electron microscopy. The structure solutions are obtained uniquely without pre-assumed models or parametrization. We report high-resolution details of cage and pore structures of periodically ordered mesoporous materials, which reveal a highly ordered dual micro- and mesoscale pore structure.     

A homochiral metal-organic porous material for enantioselective separation and catalysis

Inorganic zeolites are used for many practical applications that exploit the microporosity intrinsic to their crystal structures. Organic analogues, which are assembled from modular organic building blocks linked through non-covalent interactions, are of interest for similar applications. These range from catalysis, separation and sensor technology to optoelectronics, with enantioselective separation and catalysis being especially important for the chemical and pharmaceutical industries. The modular construction of these analogues allows flexible and rational design, as both the architecture and chemical functionality of the micropores can, in principle, be precisely controlled. Porous organic solids with large voids and high framework stability have been produced, and investigations into the range of accessible pore functionalities have been initiated. For example, catalytically active organic zeolite analogues are known, as are chiral metal-organic open-framework materials. However, the latter are only available as racemic mixtures, or lack the degree of framework stability or void space that is required for practical applications. Here we report the synthesis of a homochiral metal-organic porous material that allows the enantioselective inclusion of metal complexes in its pores and catalyses a transesterification reaction in an enantioselective manner. Our synthesis strategy, which uses enantiopure metal-organic clusters as secondary building blocks, should be readily applicable to chemically modified cluster components and thus provide access to a wide range of porous organic materials suitable for enantioselective separation and catalysis.     

Design of a 3-tier smart middleware system for ubiquitous sensor networks

As ubiquitous sensor networks (USN) technologies and its middleware are still at its early stages, the system of the USN relies on the middleware and applications. The past sensor networks are assumed to be designed for specific applications, having data communication protocols tightly coupled to applications. To avoid these problems, several kinds of USN middleware have been researched and developed. However, most middleware of USN are still restricted by its own infrastructure so far. This paper proposes appropriate 3 tier Smart Middleware System (3SMS) for USN.     

Diversity of IL-17-producing T lymphocytes

Interleukin (IL)-17 is a pro-inflammatory cytokine that plays critical roles in host defense against extracellular bacteria and fungi and also in the pathogenesis of autoimmune diseases. While CD4+ TCRαβ+ T helper (Th) 17 cells are the best-described cellular source of IL-17, many innate-like T cells are in fact potent producers of IL-17. Given the increasing interest in therapeutic modulation of the IL-17 axis, it is crucial to better understand the cellular origins of IL-17 in various infection and diseases settings. While the diverse population of IL-17-producing T cells share many common characteristics, notable differences also exist. In this review, we discuss the heterogeneity of IL-17-producing T cell types focusing on their development, regulation, and function.     

Mapping mammalian synaptic connectivity

Mapping mammalian synaptic connectivity has long been an important goal of neuroscientists since it is considered crucial for explaining human perception and behavior. Yet, despite enormous efforts, the overwhelming complexity of the neural circuitry and the lack of appropriate techniques to unravel it have limited the success of efforts to map connectivity. However, recent technological advances designed to overcome the limitations of conventional methods for connectivity mapping may bring about a turning point. Here, we address the promises and pitfalls of these new mapping technologies.     

A renormalization group approach to crowd psychology and inter-group coupling in social many-body systems

By adopting majority rule within a renormalization group approach, we can show that the strength of inter-group interaction in a social system either grows or shrinks monotonically with increasing group size, depending on the initial coupling strength of individuals in the group. This contrasts with the findings of previous studies in which the strength of the interaction grows with group size regardless of the initial strength. Our approach clearly demonstrates that the phenomena of crowd psychology, such as an extreme anti-reaction between different ethnic or ideological groups, could be a consequence of the many-particle nature of social systems when the initial strength of the interaction is larger than a critical value. The effect of neutral opinion holders is critically examined using the spin-one Ising model. The critical size of the population of neutral opinion holders, that can prevent crowd polarization, depends on the block spin rule.     

Forecasting Hourly Peak Call Volume for a Rural Electric Cooperative Call Center

This research forecasts peak call volume of a centralized after‐hours call center for rural electric cooperatives to help the call center determine staffing levels. A Gaussian copula is used to capture the dependence among non‐normal distributions. Using a centralized call center reduces costs by approximately 75% compared to having individual call centers at each cooperative. Adding cooperatives to the centralized call center is projected to further decrease costs per member. An out‐of‐sample forecasting exercise after the call center expanded validated the model's forecast that additional cooperatives could be added without a proportional increase in the peak number of calls. Copyright © 2011 John Wiley & Sons, Ltd.     

Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration

RNA exosomes are multi-subunit complexes conserved throughout evolution and are emerging as the major cellular machinery for processing, surveillance and turnover of a diverse spectrum of coding and noncoding RNA substrates essential for viability. By exome sequencing, we discovered recessive mutations in EXOSC3 (encoding exosome component 3) in four siblings with infantile spinal motor neuron disease, cerebellar atrophy, progressive microcephaly and profound global developmental delay, consistent with pontocerebellar hypoplasia type 1 (PCH1; MIM 607596). We identified mutations in EXOSC3 in an additional 8 of 12 families with PCH1. Morpholino knockdown of exosc3 in zebrafish embryos caused embryonic maldevelopment, resulting in small brain size and poor motility, reminiscent of human clinical features, and these defects were largely rescued by co-injection with wild-type but not mutant exosc3 mRNA. These findings represent the first example of an RNA exosome core component gene that is responsible for a human disease and further implicate dysregulation of RNA processing in cerebellar and spinal motor neuron maldevelopment and degeneration.