Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells

Several proteins implicated in the pathogenesis of polycystic kidney disease (PKD) localize to cilia. Furthermore, cilia are malformed in mice with PKD with mutations in TgN737Rpw (encoding polaris). It is not known, however, whether ciliary dysfunction occurs or is relevant to cyst formation in PKD. Here, we show that polycystin-1 (PC1) and polycystin-2 (PC2), proteins respectively encoded by Pkd1 and Pkd2, mouse orthologs of genes mutated in human autosomal dominant PKD, co-distribute in the primary cilia of kidney epithelium. Cells isolated from transgenic mice that lack functional PC1 formed cilia but did not increase Ca(2+) influx in response to physiological fluid flow. Blocking antibodies directed against PC2 similarly abolished the flow response in wild-type cells as did inhibitors of the ryanodine receptor, whereas inhibitors of G-proteins, phospholipase C and InsP(3) receptors had no effect. These data suggest that PC1 and PC2 contribute to fluid-flow sensation by the primary cilium in renal epithelium and that they both function in the same mechanotransduction pathway. Loss or dysfunction of PC1 or PC2 may therefore lead to PKD owing to the inability of cells to sense mechanical cues that normally regulate tissue morphogenesis.     

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.     

Wnt proteins are lipid-modified and can act as stem cell growth factors

Wnt signalling is involved in numerous events in animal development, including the proliferation of stem cells and the specification of the neural crest. Wnt proteins are potentially important reagents in expanding specific cell types, but in contrast to other developmental signalling molecules such as hedgehog proteins and the bone morphogenetic proteins, Wnt proteins have never been isolated in an active form. Although Wnt proteins are secreted from cells, secretion is usually inefficient and previous attempts to characterize Wnt proteins have been hampered by their high degree of insolubility. Here we have isolated active Wnt molecules, including the product of the mouse Wnt3a gene. By mass spectrometry, we found the proteins to be palmitoylated on a conserved cysteine. Enzymatic removal of the palmitate or site-directed and natural mutations of the modified cysteine result in loss of activity, and indicate that the lipid is important for signalling. The purified Wnt3a protein induces self-renewal of haematopoietic stem cells, signifying its potential use in tissue engineering.     

Persistence of subalpine forest--meadow ecotones in the Gunnison Basin, Colorado

Forests of the southern Rocky Mountains are punctuated by persistent meadows called parks that are dominated by grasses and forbs. In an attempt to elucidate the maintenance of subalpine parks in the Gunnison Basin, Colorado, soil texture and tree morphology differences along 60-m transects spanning the forest-park ecotone were studied in 6 representative parks. Seedling survivorship, percent seed germination, and soil moisture available to plants were also studied along one of the transects in Willow Park. Soil analyses revealed 40% more silt and significantly less sand and clay in all 6 parks ( P P = 0.011), with 54% more water in forest than in park soils. Measures of growth rate obtained from tree height, dbh, and age were significantly higher nearer the ecotone ( P P = 0.002). These results suggest that stress of mature Engelmann spruce ( Picea engelmannii ) and lodgepole pine ( Pinus contorta ) is an unlikely explanation of park maintenance. P. engelmanii percent seed germination and seedling survivorship were significantly higher in the forest than in the park ( P < 0.001). This may be largely due to the more severe seedling microclimate observed in the park. Results indicate that limited seedling establishment is primarily responsible for maintenance of subalpine parks in the Gunnison Basin.     

行波：数学推理的元极导航

本书是《剑桥理论计算科学专论》丛书的第56卷。自从20世纪50年代起，自动化理论证明成为一个活跃的研究领域。在该领域中的研究人员开始着手处理类似人类的自动化推理。在20世纪60年代和70年代，人们对自动化理论证明的兴趣增加了，这是由于理论进展的驱动。例如归纳的开发以及对程序验证的兴趣增加。     

OPTIMAL MAINTENANCE AND REPLACEMENT OF EXTRACTION MACHINERY

This paper considers a problem of optimal preventive maintenance and replacement schedule of equipment devoted to extracting resources from known deposits. Typical examples are oil drills, mine shovels, etc. At most one replacement of the existing machinery by a new one is allowed. The problem is formulated as an optimal control problem subject to the state constraint that the remaining deposit at any given time is nonnegative. We show that the optimal preventive maintenance, production rates, and the replacement and salvage times of the existing machinery and the new one, if required, can be obtained by solving sequentially a series of free-end-point optimal control problems. Moreover, an algorithm based on this result is developed and used to solve two illustrative examples.     

Anti-apoptotic mechanisms of HIV: lessons and novel approaches to curing HIV

Past efforts at curing infection with the human immunodeficiency virus (HIV) have been blocked by the resistance of some infected cells to viral cytopathic effects and the associated development of a latent viral reservoir. Furthermore, current efforts to clear the viral reservoir by means of reactivating latent virus are hampered by the lack of cell death in the newly productively infected cells. The purpose of this review is to describe the many anti-apoptotic mechanisms of HIV, as well as the current limitations in the field. Only by understanding how infected cells avoid HIV-induced cell death can an effective strategy to kill infected cells be developed.     

Book reviews

This paper traces the relationship between the food committees of the Royal Society and government during the First World War, concentrating on the period up to the resignation of Lord Devonport as first Food Controller. It argues that, in the context of a radical public science discourse emanating from some sections of the scientific community and greatly increased contacts between scientists and government, the food scientists of the committees were moved to press for a formalization of the committees' role in food policy. The members constantly manoeuvred to achieve this aim, but also used a network of alternative channels into the heart of the policy process to get their findings translated into hard policy. In doing so, they explicitly rehearsed characteristic 'public science' arguments. In the institutional blur of wartime state-science relations, scientists often got close to the policy-making process. Post-War, the state swiftly moved to clarify the position: science was to be given more money, but was to be specifically blocked by new administrative arrangements embodied in the Haldane Report on the Machinery of Government from having any say in the core areas of general policy, the expert domain of the generalist policy-maker.