Adherens junction protein nectin-4 is the epithelial receptor for measles virus

Measles virus is an aerosol-transmitted virus that affects more than 10 million children each year and accounts for approximately 120,000 deaths. Although it was long believed to replicate in the respiratory epithelium before disseminating, it was recently shown to infect initially macrophages and dendritic cells of the airways using signalling lymphocytic activation molecule family member 1 (SLAMF1; also called CD150) as a receptor. These cells then cross the respiratory epithelium and transport the infection to lymphatic organs where measles virus replicates vigorously. How and where the virus crosses back into the airways has remained unknown. On the basis of functional analyses of surface proteins preferentially expressed on virus-permissive human epithelial cell lines, here we identify nectin-4 (ref. 8; also called poliovirus-receptor-like-4 (PVRL4)) as a candidate host exit receptor. This adherens junction protein of the immunoglobulin superfamily interacts with the viral attachment protein with high affinity through its membrane-distal domain. Nectin-4 sustains measles virus entry and non-cytopathic lateral spread in well-differentiated primary human airway epithelial sheets infected basolaterally. It is downregulated in infected epithelial cells, including those of macaque tracheae. Although other viruses use receptors to enter hosts or transit through their epithelial barriers, we suggest that measles virus targets nectin-4 to emerge in the airways. Nectin-4 is a cellular marker of several types of cancer, which has implications for ongoing measles-virus-based clinical trials of oncolysis.     

Susceptibility loci for intracranial aneurysm in European and Japanese populations

Stroke is the world's third leading cause of death. One cause of stroke, intracranial aneurysm, affects approximately 2% of the population and accounts for 500,000 hemorrhagic strokes annually in mid-life (median age 50), most often resulting in death or severe neurological impairment. The pathogenesis of intracranial aneurysm is unknown, and because catastrophic hemorrhage is commonly the first sign of disease, early identification is essential. We carried out a multistage genome-wide association study (GWAS) of Finnish, Dutch and Japanese cohorts including over 2,100 intracranial aneurysm cases and 8,000 controls. Genome-wide genotyping of the European cohorts and replication studies in the Japanese cohort identified common SNPs on chromosomes 2q, 8q and 9p that show significant association with intracranial aneurysm with odds ratios 1.24-1.36. The loci on 2q and 8q are new, whereas the 9p locus was previously found to be associated with arterial diseases, including intracranial aneurysm. Associated SNPs on 8q likely act via SOX17, which is required for formation and maintenance of endothelial cells, suggesting a role in development and repair of the vasculature; CDKN2A at 9p may have a similar role. These findings have implications for the pathophysiology, diagnosis and therapy of intracranial aneurysm.     

黑洞、信息和弦论——全息的宇宙图景

自从1905年两个似乎格格不入的理论——相对论和量子力学引入以来，综合上述两个理论到量子场论和粒子现象的标准模型的尝试成为物理学的主流。本书就是80多年来对于上述的尝试的一个总结，同时也是对本领域的一个导论。     

Intestinal uptake of ouabain and digitoxin in the milkweed bug,Oncopeltus fasciatus

Summary The absorption of ouabain and digitoxin into the gut of the milkweed bug was studied by a tissue-accumulation technique. Uptake of both compounds obeyed diffusion kinetics, was Na⁺ sensitive, and for digitoxin, was concentrative.The authors express their appreciation to Dr.James A. Slater and Ms.Flavia O'Rourke, Biological Sciences Group, University of Connecticut, Storrs, Conn. (USA) for supplying milkweed bugs. This work was supported by the University of Maine Honors Program and the University of Maine Agricultural Experiment Station.     

Amphipols: polymeric surfactants for membrane biology research

Membrane proteins classically are handled in aqueous solutions as complexes with detergents. The dissociating character of detergents, combined with the need to maintain an excess of them, frequently results in more or less rapid inactivation of the protein under study. Over the past few years, we have endeavored to develop a novel family of surfactants, dubbed amphipols (APs). APs are amphiphilic polymers that bind to the transmembrane surface of the protein in a noncovalent but, in the absence of a competing surfactant, quasi-irreversible manner. Membrane proteins complexed by APs are in their native state, stable, and they remain water-soluble in the absence of detergent or free APs. An update is presented of the current knowledge about these compounds and their demonstrated or putative uses in membrane biology.     

Cell-specific mitotic defect and dyserythropoiesis associated with erythroid band 3 deficiency

Most eukaryotic cell types use a common program to regulate the process of cell division. During mitosis, successful partitioning of the genetic material depends on spatially coordinated chromosome movement and cell cleavage. Here we characterize a zebrafish mutant, retsina (ret), that exhibits an erythroid-specific defect in cell division with marked dyserythropoiesis similar to human congenital dyserythropoietic anemia. Erythroblasts from ret fish show binuclearity and undergo apoptosis due to a failure in the completion of chromosome segregation and cytokinesis. Through positional cloning, we show that the ret mutation is in a gene (slc4a1) encoding the anion exchanger 1 (also called band 3 and AE1), an erythroid-specific cytoskeletal protein. We further show an association between deficiency in Slc4a1 and mitotic defects in the mouse. Rescue experiments in ret zebrafish embryos expressing transgenic slc4a1 with a variety of mutations show that the requirement for band 3 in normal erythroid mitosis is mediated through its protein 4.1R-binding domains. Our report establishes an evolutionarily conserved role for band 3 in erythroid-specific cell division and illustrates the concept of cell-specific adaptation for mitosis.     

Non-classical receptive field mediates switch in a sensory neuron's frequency tuning

Animals have developed stereotyped communication calls to which specific sensory neurons are well tuned. These communication calls must be discriminated from environmental signals such as those produced by prey. Sensory systems might have evolved neural circuitry to encode both categories. In weakly electric fish, prey and communication signals differ in their spatial extent and frequency content. Here we show that stimuli of different spatial extents mimicking prey and communication signals cause a switch in the frequency tuning and spike-timing precision of electrosensory pyramidal neurons, resulting in the selective and optimal encoding of both stimulus categories. As in other sensory systems, pyramidal neurons respond only to stimuli located within a restricted region of space known as the classical receptive field (CRF). In some systems, stimulation outside the CRF but within a non-classical receptive field (nCRF) can modulate the neural response to CRF stimulation even though nCRF stimulation alone fails to elicit responses. We show that pyramidal neurons possess a nCRF and that it can modulate the response to CRF stimuli to induce this neurobiological switch in frequency tuning.