Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans

Remodeling of the cytoskeleton is central to the modulation of cell shape and migration. Filamin A, encoded by the gene FLNA, is a widely expressed protein that regulates re-organization of the actin cytoskeleton by interacting with integrins, transmembrane receptor complexes and second messengers. We identified localized mutations in FLNA that conserve the reading frame and lead to a broad range of congenital malformations, affecting craniofacial structures, skeleton, brain, viscera and urogenital tract, in four X-linked human disorders: otopalatodigital syndrome types 1 (OPD1; OMIM 311300) and 2 (OPD2; OMIM 304120), frontometaphyseal dysplasia (FMD; OMIM 305620) and Melnick-Needles syndrome (MNS; OMIM 309350). Several mutations are recurrent, and all are clustered into four regions of the gene: the actin-binding domain and rod domain repeats 3, 10 and 14/15. Our findings contrast with previous observations that loss of function of FLNA is embryonic lethal in males but manifests in females as a localized neuronal migration disorder, called periventricular nodular heterotopia (PVNH; refs. 3-6). The patterns of mutation, X-chromosome inactivation and phenotypic manifestations in the newly described mutations indicate that they have gain-of-function effects, implicating filamin A in signaling pathways that mediate organogenesis in multiple systems during embryonic development.     

Common deletion polymorphisms in the human genome

The locations and properties of common deletion variants in the human genome are largely unknown. We describe a systematic method for using dense SNP genotype data to discover deletions and its application to data from the International HapMap Consortium to characterize and catalogue segregating deletion variants across the human genome. We identified 541 deletion variants (94% novel) ranging from 1 kb to 745 kb in size; 278 of these variants were observed in multiple, unrelated individuals, 120 in the homozygous state. The coding exons of ten expressed genes were found to be commonly deleted, including multiple genes with roles in sex steroid metabolism, olfaction and drug response. These common deletion polymorphisms typically represent ancestral mutations that are in linkage disequilibrium with nearby SNPs, meaning that their association to disease can often be evaluated in the course of SNP-based whole-genome association studies.     

Possible tropical lakes on Titan from observations of dark terrain

Titan has clouds, rain and lakes--like Earth--but composed of methane rather than water. Unlike Earth, most of the condensable methane (the equivalent of 5?m depth globally averaged) lies in the atmosphere. Liquid detected on the surface (about 2?m deep) has been found by radar images only poleward of 50° latitude, while dune fields pervade the tropics. General circulation models explain this dichotomy, predicting that methane efficiently migrates to the poles from these lower latitudes. Here we report an analysis of near-infrared spectral images of the region between 20°?N and 20°?S latitude. The data reveal that the lowest fluxes in seven wavelength bands that probe Titan's surface occur in an oval region of about 60?×?40?km(2), which has been observed repeatedly since 2004. Radiative transfer analyses demonstrate that the resulting spectrum is consistent with a black surface, indicative of liquid methane on the surface. Enduring low-latitude lakes are best explained as supplied by subterranean sources (within the last 10,000 years), which may be responsible for Titan's methane, the continual photochemical depletion of which furnishes Titan's organic chemistry.     

Co-operative Inquiry: Changing Interprofessional Practice

Recent government guidance concerning the welfare of children emphasizes the necessity for change in interprofessional practice. This paper examines how co-operative inquiry enabled a diverse professional group to inquire into how change can be promoted in complex practice systems. It considers the influence of external stakeholders, highlights the consequent tension between task and process, and addresses the implications for the role of facilitators.     

N-P基本引理的严密化、标准化研究——兼评国内某些教材对此定理的引述与证明

我国目前所引述的Neyman-Pearson基本引理(下简称N-P引理),可谓是五花八门、应有尽有.就其证明的严密性而言,要么只给出了一致最大功效检验(下简记UMPT)函数的非随机化检验形式,要么仅局限于其充分性的证明.文章从N-P引理的本质特征出发,把φ的随机化检验形式,和引理的充要条件的证明统一在一起,因而形式更为完美,证明更加严谨,并且还给出了它直观的图像表示和扩大了检验函数的集类φ.     

Inhibition of protein misfolding and aggregation by natural phenolic compounds

Protein misfolding and aggregation into fibrillar deposits is a common feature of a large group of degenerative diseases affecting the central nervous system or peripheral organs, termed protein misfolding disorders (PMDs). Despite their established toxic nature, clinical trials aiming to reduce misfolded aggregates have been unsuccessful in treating or curing PMDs. An interesting possibility for disease intervention is the regular intake of natural food or herbal extracts, which contain active molecules that inhibit aggregation or induce the disassembly of misfolded aggregates. Among natural compounds, phenolic molecules are of particular interest, since most have dual activity as amyloid aggregation inhibitors and antioxidants. In this article, we review many phenolic natural compounds which have been reported in diverse model systems to have the potential to delay or prevent the development of various PMDs, including Alzheimer’s and Parkinson’s diseases, prion diseases, amyotrophic lateral sclerosis, systemic amyloidosis, and type 2 diabetes. The lower toxicity of natural compounds compared to synthetic chemical molecules suggest that they could serve as a good starting point to discover protein misfolding inhibitors that might be useful for the treatment of various incurable diseases.     

Sex ratios of the white-tailed antelope ground squirrel (Ammospermophilus leucurus), Indian Wells Valley, San Bernardino County, California

We studied the white-tailed antelope ground squirrel during spring and summer 2006 to determine young-of-the-year and adult sex ratios in the Indian Wells Valley, San Bernardino County, California. We calculated a young-of-the-year sex ratio of 1.45:1 (female to male), whereas the adult sex ratio was approximately 1:1. Our young-ofthe-year sex ratio was greater than the 1.1:1 (female to male) natal sex ratio previously reported. Differences between young-of-the-year and adult sex ratios may represent low female young-of-the-year survivorship in the Indian Wells Valley.