Targeted mutation of Cyln2 in the Williams syndrome critical region links CLIP-115 haploinsufficiency to neurodevelopmental abnormalities in mice

Williams syndrome is a neurodevelopmental disorder caused by the hemizygous deletion of 1.6 Mb on human chromosome 7q11.23. This region comprises the gene CYLN2, encoding CLIP-115, a microtubule-binding protein of 115 kD. Using a gene-targeting approach, we provide evidence that mice with haploinsufficiency for Cyln2 have features reminiscent of Williams syndrome, including mild growth deficiency, brain abnormalities, hippocampal dysfunction and particular deficits in motor coordination. Absence of CLIP-115 also leads to increased levels of CLIP-170 (a closely related cytoplasmic linker protein) and dynactin at the tips of growing microtubules. This protein redistribution may affect dynein motor regulation and, together with the loss of CLIP-115-specific functions, underlie neurological alterations in Williams syndrome.     

Occurrence, persistence, and expansion of saltcedar ( Tamarix spp.) populations in the Great Plains of Montana

Saltcedar ( Tamarix spp.), a shrub native to Eurasia, is associated with major alterations to wetland and riparian systems in the southwestern United States. Since the 1960s saltcedar has been naturalized in northern states of the U.S. where its growth potential and impacts are not well known. Here, we describe the occurrence, age, size, and relative cover of saltcedar populations in several river basins in central eastern Montana, USA, to identify potential patterns of spread across the region and changes in individual populations as they age. Stands were aged according to the oldest saltcedar individuals and were sampled for dominant plant cover and soil properties. Multiple introductions appear to have occurred in Montana, with the oldest stands occurring on the Bighorn River in southern Montana. Saltcedar absolute and relative cover and stand area increased significantly with stand age, while native tree and shrub relative cover remained low across all stand ages. These results suggest that saltcedar stands establish where woody natives are not abundant and that they persist and expand over time. Although soil salinity remained constant, soil pH decreased with saltcedar stand age, indicating a possible effect of organic matter inputs. An analysis of annual wood increment of saltcedar and sandbar willow (a native with analogous growth form) stems along a latitudinal gradient showed that stem growth of both species did not differ significantly among regions. Stem growth decreased inversely with elevation for both species while growth responses to elevation did not differ between species. Our results show an increase in number of populations and continued viability of these populations. Mechanisms of saltcedar increases in this region are yet to be determined. Anthropogenic influences, such as saltcedar plantings, watershed alterations (e.g., river flow control), and habitat disturbances (e.g., cattle grazing or habitat clearing) may facilitate its spread in similar climates of the Great Plains.     

Methyl-accepting chemotaxis proteins: a core sensing element in prokaryotes and archaea

Chemotaxis is the directed motility by means of which microbes sense chemical cues and relocate towards more favorable environments. Methyl-accepting chemotaxis proteins (MCPs) are the most common receptors in bacteria and archaea. They are arranged as trimers of dimers that, in turn, form hexagonal arrays in the cytoplasmic membrane or in the cytoplasm. Several different classes of MCPs have been identified according to their ligand binding region and membrane topology. MCPs have been further classified based on the length and sequence conservation of their cytoplasmic domains. Clusters of membrane-embedded MCPs often localize to the poles of the cell, whereas cytoplasmic MCPs can be targeted to the poles or distributed throughout the cell body. MCPs play an important role in cell survival, pathogenesis, and biodegradation. Bacterial adaptation to diverse environmental conditions promotes diversity among the MCPs. This review summarizes structure, classification, and structure–activity relationship of the known MCP receptors, with a brief overview of the signal transduction mechanisms in bacteria and archaea.     

Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection

Ebola virus (EboV) is a highly pathogenic enveloped virus that causes outbreaks of zoonotic infection in Africa. The clinical symptoms are manifestations of the massive production of pro-inflammatory cytokines in response to infection and in many outbreaks, mortality exceeds 75%. The unpredictable onset, ease of transmission, rapid progression of disease, high mortality and lack of effective vaccine or therapy have created a high level of public concern about EboV. Here we report the identification of a novel benzylpiperazine adamantane diamide-derived compound that inhibits EboV infection. Using mutant cell lines and informative derivatives of the lead compound, we show that the target of the inhibitor is the endosomal membrane protein Niemann-Pick C1 (NPC1). We find that NPC1 is essential for infection, that it binds to the virus glycoprotein (GP), and that antiviral compounds interfere with GP binding to NPC1. Combined with the results of previous studies of GP structure and function, our findings support a model of EboV infection in which cleavage of the GP1 subunit by endosomal cathepsin proteases removes heavily glycosylated domains to expose the amino-terminal domain, which is a ligand for NPC1 and regulates membrane fusion by the GP2 subunit. Thus, NPC1 is essential for EboV entry and a target for antiviral therapy.     

Initial genome sequencing and analysis of multiple myeloma

Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumour genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the data set. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-κB signalling was indicated by mutations in 11 members of the NF-κB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge.     

碳纤维表面处理及其复合材料界面优化的研究Ⅵ．碳纤维复合材料的界面结合

通过扭转动态力学、层间剪切强度（ＩＬＳＳ）、微量冲击、ＳＥＭ等研究发现，未处理碳纤维复合材料的界面结合强度已经弱到不能有效传递载荷的地步，而１００ｎｍ厚接技碳纤维复合材料却具有优良的整体性和ＩＬＳＳ，在冲击过程中有足够的弹性承载能力和一定的纤维拔出与界面脱粘可能，从而有较高的抗冲击性能。氧等离子处理纤维复合材料的界面结合过强，冲击时几乎没有纤维拔出和滑移，也就没有很高的杭冲击能力和ＩＬＳＳ。