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.     

Internalization of polypeptide hormones and receptor recycling

Conclusion The insulin receptor is an integral protein of the plasma membrane of the cell. It is composed of two subunits: an subunit, which binds the hormone, and a subunit which is a tyrosine specific protein kinase capable of undergoing autophosphorylation. These independent subunits are synthesized by way of a higher molecular weight single chain precursor and thus are the product of a single gene^{29, 49, 85} localized to chromosome 19^{29, 91}. Assuming that the insulin receptor is synthesized in the same fashion as other integral membrane glycoproteins, then the nucleus, the rough endoplasmic reticulum, and the Golgi apparatus are involved in its biosynthesis. Further, there must be some form of transport of the mature receptor subunits to the plasma membrane where they are inserted.By contrast, the endocytotic route involves coated pits, coated vesicles, large clear vesicles or endosomes, multivesicular bodies and other lysosomal forms. In addition, it is possible that some other as yet unidentified organelle is involved in recycling (fig. 8). At the present time, with respect to the insulin receptor, the biosynthetic pathway and the endocytotic pathway appear to be separate. Further, it does not appear that either pathway, i. e. synthesis or endocytosis, exerts a regulatory function over the other.     

Inland thinning of West Antarctic Ice Sheet steered along subglacial rifts

Current ice loss from the West Antarctic Ice Sheet (WAIS) accounts for about ten per cent of observed global sea-level rise. Losses are dominated by dynamic thinning, in which forcings by oceanic or atmospheric perturbations to the ice margin lead to an accelerated thinning of ice along the coastline. Although central to improving projections of future ice-sheet contributions to global sea-level rise, the incorporation of dynamic thinning into models has been restricted by lack of knowledge of basal topography and subglacial geology so that the rate and ultimate extent of potential WAIS retreat remains difficult to quantify. Here we report the discovery of a subglacial basin under Ferrigno Ice Stream up to 1.5?kilometres deep that connects the ice-sheet interior to the Bellingshausen Sea margin, and whose existence profoundly affects ice loss. We use a suite of ice-penetrating radar, magnetic and gravity measurements to propose a rift origin for the basin in association with the wider development of the West Antarctic rift system. The Ferrigno rift, overdeepened by glacial erosion, is a conduit which fed a major palaeo-ice stream on the adjacent continental shelf during glacial maxima. The palaeo-ice stream, in turn, eroded the 'Belgica' trough, which today routes warm open-ocean water back to the ice front to reinforce dynamic thinning. We show that dynamic thinning from both the Bellingshausen and Amundsen Sea region is being steered back to the ice-sheet interior along rift basins. We conclude that rift basins that cut across the WAIS margin can rapidly transmit coastally perturbed change inland, thereby promoting ice-sheet instability.     

Predicting the signs of forecast errors

The signs of forecast errors can be predicted using the difference between individuals' forecasts and the average of earlier forecasts of the same variable. It is possible to improve forecasts without worsening any. It is difficult to reconcile this result with the rational expectations hypothesis because the average of earlier forecasts is in the information set of the forecasters. Copyright © 2009 John Wiley & Sons, Ltd.     

Silicon carbide resonant tuning fork for microsensing applications in high temperature and high G shock environments

We present the fabrication and testing of a silicon carbide(SiC)balanced mass double-ended tuning fork that survives harsh environments without compromising the device strain sensitivity and resolution bandwidth.The device features a material stack that survives corrosive environments and enables high-temperature operation.To perform high-temperature testing,a specialized setup was constructed that allows the tuning fork to be characterized using traditional silicon electronics.The tuning fork has been operated at 600 ℃ in the presence of dry steam for short durations.This tuning fork has also been tested to 64 000 G using a hard-launch,soft-catch shock implemented with a light gas gun.However,the device still has a strain sensitivity of 66 Hz/με and strain resolution of 0.045 με in a 10 kHz bandwidth.As such,this balanced-mass double-ended tuning fork can be used to create a variety of different sensors including strain gauges,accelerometers,gyroscopes,and pressure transducers.Given the adaptable fabrication process flow,this device could be useful to micro-electro-mechanical systems(MEMS) designers creating sensors for a variety of different applications.     

De novo mutations revealed by whole-exome sequencing are strongly associated with autism

Multiple studies have confirmed the contribution of rare de novo copy number variations to the risk for autism spectrum disorders. But whereas de novo single nucleotide variants have been identified in affected individuals, their contribution to risk has yet to be clarified. Specifically, the frequency and distribution of these mutations have not been well characterized in matched unaffected controls, and such data are vital to the interpretation of de novo coding mutations observed in probands. Here we show, using whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sibling pairs, that highly disruptive (nonsense and splice-site) de novo mutations in brain-expressed genes are associated with autism spectrum disorders and carry large effects. On the basis of mutation rates in unaffected individuals, we demonstrate that multiple independent de novo single nucleotide variants in the same gene among unrelated probands reliably identifies risk alleles, providing a clear path forward for gene discovery. Among a total of 279 identified de novo coding mutations, there is a single instance in probands, and none in siblings, in which two independent nonsense variants disrupt the same gene, SCN2A (sodium channel, voltage-gated, type II, α subunit), a result that is highly unlikely by chance.     

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.