TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function

Progressive kidney failure is a genetically and clinically heterogeneous group of disorders. Podocyte foot processes and the interposed glomerular slit diaphragm are essential components of the permeability barrier in the kidney. Mutations in genes encoding structural proteins of the podocyte lead to the development of proteinuria, resulting in progressive kidney failure and focal segmental glomerulosclerosis. Here, we show that the canonical transient receptor potential 6 (TRPC6) ion channel is expressed in podocytes and is a component of the glomerular slit diaphragm. We identified five families with autosomal dominant focal segmental glomerulosclerosis in which disease segregated with mutations in the gene TRPC6 on chromosome 11q. Two of the TRPC6 mutants had increased current amplitudes. These data show that TRPC6 channel activity at the slit diaphragm is essential for proper regulation of podocyte structure and function.     

The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease

The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (Abeta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Abeta-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.     

RGS2 regulates signal transduction in olfactory neurons by attenuating activation of adenylyl cyclase III

The heterotrimeric G-protein Gs couples cell-surface receptors to the activation of adenylyl cyclases and cyclic AMP production (reviewed in refs 1, 2). RGS proteins, which act as GTPase-activating proteins (GAPs) for the G-protein alpha-subunits alpha(i) and alpha(q), lack such activity for alpha(s) (refs 3-6). But several RGS proteins inhibit cAMP production by Gs-linked receptors. Here we report that RGS2 reduces cAMP production by odorant-stimulated olfactory epithelium membranes, in which the alpha(s) family member alpha(olf) links odorant receptors to adenylyl cyclase activation. Unexpectedly, RGS2 reduces odorant-elicited cAMP production, not by acting on alpha(olf) but by inhibiting the activity of adenylyl cyclase type III, the predominant adenylyl cyclase isoform in olfactory neurons. Furthermore, whole-cell voltage clamp recordings of odorant-stimulated olfactory neurons indicate that endogenous RGS2 negatively regulates odorant-evoked intracellular signalling. These results reveal a mechanism for controlling the activities of adenylyl cyclases, which probably contributes to the ability of olfactory neurons to discriminate odours.     

Mesozoic Alpine facies deposition as a result of past latitudinal plate motion

The fragmentation of Pangaea as a consequence of the opening of the Atlantic Ocean is documented in the Alpine-Mediterranean region by the onset of widespread pelagic sedimentation. Shallow-water sediments were replaced by mainly pelagic limestones in the Early Jurassic period, radiolarian cherts in the Middle-Late Jurassic period, and again pelagic limestones in the Late Jurassic-Cretaceous period. During initial extension, basin subsidence below the carbonate compensation depth (CCD) is thought to have triggered the transition from Early Jurassic limestones to Middle-Late Jurassic radiolarites. It has been proposed that the transition from radiolarites to limestones in the Late Jurassic period was due to an increase in calcareous nannoplankton abundance when the CCD was depressed below the ocean floor. But in modern oceans, sediments below the CCD are not necessarily radiolaritic. Here we present palaeomagnetic samples from the Jurassic-Cretaceous pelagic succession exposed in the Lombardian basin, Italy. On the basis of an analysis of our palaeolatitudinal data in a broader palaeogeographic context, we propose an alternative explanation for the above facies tripartition. We suggest that the Lombardian basin drifted initially towards, and subsequently away from, a near-equatorial upwelling zone of high biosiliceous productivity. Our tectonic model for the genesis of radiolarites adds an essential horizontal plate motion component to explanations involving only vertical variations of CCD relative to the ocean floor. It may explain the deposition of radiolarites throughout the Mediterranean and Middle Eastern region during the Jurassic period.     

带预制空心板的半刚性复合节点的弯矩和转动能力预测方法

对带预制空心板的复合梁-柱节点结构性能的研究目前是新颖且无暂行的可用来预测其弯矩和转动能力的计算方法．在本文中,在足尺度测试和参数分析的基础上,提出了预测该类型复合节点的弯矩和转动能力的设计公式．对所提计算方法和足尺度测试结果进行了对比,结果吻合良好．