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.     

Identifying distinct classes of bladder carcinoma using microarrays

Bladder cancer is a common malignant disease characterized by frequent recurrences. The stage of disease at diagnosis and the presence of surrounding carcinoma in situ are important in determining the disease course of an affected individual. Despite considerable effort, no accepted immunohistological or molecular markers have been identified to define clinically relevant subsets of bladder cancer. Here we report the identification of clinically relevant subclasses of bladder carcinoma using expression microarray analysis of 40 well characterized bladder tumors. Hierarchical cluster analysis identified three major stages, Ta, T1 and T2-4, with the Ta tumors further classified into subgroups. We built a 32-gene molecular classifier using a cross-validation approach that was able to classify benign and muscle-invasive tumors with close correlation to pathological staging in an independent test set of 68 tumors. The classifier provided new predictive information on disease progression in Ta tumors compared with conventional staging (P < 0.005). To delineate non-recurring Ta tumors from frequently recurring Ta tumors, we analyzed expression patterns in 31 tumors by applying a supervised learning classification methodology, which classified 75% of the samples correctly (P < 0.006). Furthermore, gene expression profiles characterizing each stage and subtype identified their biological properties, producing new potential targets for therapy.     

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.     

Loss of neuropathy target esterase in mice links organophosphate exposure to hyperactivity

Neuropathy target esterase (NTE) is involved in neural development and is the target for neurodegeneration induced by selected organophosphorus pesticides and chemical warfare agents. We generated mice with disruptions in Nte, the gene encoding NTE. Nte(-/-) mice die after embryonic day 8, and Nte(+/-) mice have lower activity of Nte in the brain and higher mortality when exposed to the Nte-inhibiting compound ethyl octylphosphonofluoridate (EOPF) than do wild-type mice. Nte(+/-) and wild-type mice treated with 1 mg per kg of body weight of EOPF have elevated motor activity, showing that even minor reduction of Nte activity leads to hyperactivity. These studies show that genetic or chemical reduction of Nte activity results in a neurological phenotype of hyperactivity in mammals and indicate that EOPF toxicity occurs directly through inhibition of Nte without the requirement for Nte gain of function or aging.     

A gravitationally lensed quasar with quadruple images separated by 14.62 arcseconds

Gravitational lensing is a powerful tool for the study of the distribution of dark matter in the Universe. The cold-dark-matter model of the formation of large-scale structures (that is, clusters of galaxies and even larger assemblies) predicts the existence of quasars gravitationally lensed by concentrations of dark matter so massive that the quasar images would be split by over 7 arcsec. Numerous searches for large-separation lensed quasars have, however, been unsuccessful. All of the roughly 70 lensed quasars known, including the first lensed quasar discovered, have smaller separations that can be explained in terms of galaxy-scale concentrations of baryonic matter. Although gravitationally lensed galaxies with large separations are known, quasars are more useful cosmological probes because of the simplicity of the resulting lens systems. Here we report the discovery of a lensed quasar, SDSS J1004 + 4112, which has a maximum separation between the components of 14.62 arcsec. Such a large separation means that the lensing object must be dominated by dark matter. Our results are fully consistent with theoretical expectations based on the cold-dark-matter model.     

An increased estimate of the merger rate of double neutron stars from observations of a highly relativistic system

The merger of close binary systems containing two neutron stars should produce a burst of gravitational waves, as predicted by the theory of general relativity. A reliable estimate of the double-neutron-star merger rate in the Galaxy is crucial in order to predict whether current gravity wave detectors will be successful in detecting such bursts. Present estimates of this rate are rather low, because we know of only a few double-neutron-star binaries with merger times less than the age of the Universe. Here we report the discovery of a 22-ms pulsar, PSR J0737-3039, which is a member of a highly relativistic double-neutron-star binary with an orbital period of 2.4 hours. This system will merge in about 85 Myr, a time much shorter than for any other known neutron-star binary. Together with the relatively low radio luminosity of PSR J0737-3039, this timescale implies an order-of-magnitude increase in the predicted merger rate for double-neutron-star systems in our Galaxy (and in the rest of the Universe).     

The bright optical afterglow of the nearby gamma-ray burst of 29 March 2003

Past studies of cosmological gamma-ray bursts (GRBs) have been hampered by their extreme distances, resulting in faint afterglows. A nearby GRB could potentially shed much light on the origin of these events, but GRBs with a redshift z 相似文献   

REE geochemistry of suspended sediments from the rivers around the Yellow Sea and provenance indicators

Rare earth element (REE) compositions of the suspended sediments from the rivers around the Yellow Sea were different in that Korean river sediments (Han, Keum and Yeongsan Rivers) yield stronger fractionations than Chinese river sediments (Changjiang, Huanghe and Yalujiang), shown by obvious enrichments of LREE (light rare earth element) relative to UCC (upper continental crust).Variations of source rock compositions in the drainage basins are responsible for the differences of REE compositions between the river sediments. REE fractionation parameters including (La/Yb)ucc and (Gd/Yb)ucc as well as the ratios of La/Sc and Th/Sc can be treated as proper proxies for identifying the Chinese river sediments from those Korean river matters, and furthermore, for studying the provenances and paleoenvironmental changes of the marginal seas of China.