Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis

Thoracic aortic aneurysms and dissections are a main feature of connective tissue disorders, such as Marfan syndrome and Loeys-Dietz syndrome. We delineated a new syndrome presenting with aneurysms, dissections and tortuosity throughout the arterial tree in association with mild craniofacial features and skeletal and cutaneous anomalies. In contrast with other aneurysm syndromes, most of these affected individuals presented with early-onset osteoarthritis. We mapped the genetic locus to chromosome 15q22.2-24.2 and show that the disease is caused by mutations in SMAD3. This gene encodes a member of the TGF-β pathway that is essential for TGF-β signal transmission. SMAD3 mutations lead to increased aortic expression of several key players in the TGF-β pathway, including SMAD3. Molecular diagnosis will allow early and reliable identification of cases and relatives at risk for major cardiovascular complications. Our findings endorse the TGF-β pathway as the primary pharmacological target for the development of new treatments for aortic aneurysms and osteoarthritis.     

Fras1 deficiency results in cryptophthalmos,renal agenesis and blebbed phenotype in mice

Loss of tight association between epidermis and dermis underlies several blistering disorders and is frequently caused by impaired function of extracellular matrix (ECM) proteins. Here we describe a new protein in mouse, Fras1, that is specifically detected in a linear fashion underlying the epidermis and the basal surface of other epithelia in embryos. Loss of Fras1 function results in the formation of subepidermal hemorrhagic blisters as well as unilateral or bilateral renal agenesis during mouse embryogenesis. Postnatally, homozygous Fras1 mutants have fusion of the eyelids and digits and unilateral renal agenesis or dysplasia. The defects observed in Fras1-/- mice phenocopy those of the existing bl (blebbed) mouse mutants, which have been considered a model for the human genetic disorder Fraser syndrome. We show that bl/bl homozygous embryos are devoid of Fras1 protein, consistent with the finding that Fras1 is mutated in these mice. In sum, our data suggest that perturbations in the composition of the extracellular space underlying epithelia could account for the onset of the blebbed phenotype in mouse and Fraser syndrome manifestation in human.     

Predicting Stock Return Volatility: Can We Benefit from Regression Models for Return Intervals?

We study the performance of recently developed linear regression models for interval data when it comes to forecasting the uncertainty surrounding future stock returns. These interval data models use easy‐to‐compute daily return intervals during the modeling, estimation and forecasting stage. They have to stand up to comparable point‐data models of the well‐known capital asset pricing model type—which employ single daily returns based on successive closing prices and might allow for GARCH effects—in a comprehensive out‐of‐sample forecasting competition. The latter comprises roughly 1000 daily observations on all 30 stocks that constitute the DAX, Germany's main stock index, for a period covering both the calm market phase before and the more turbulent times during the recent financial crisis. The interval data models clearly outperform simple random walk benchmarks as well as the point‐data competitors in the great majority of cases. This result does not only hold when one‐day‐ahead forecasts of the conditional variance are considered, but is even more evident when the focus is on forecasting the width or the exact location of the next day's return interval. Regression models based on interval arithmetic thus prove to be a promising alternative to established point‐data volatility forecasting tools. Copyright ©2015 John Wiley & Sons, Ltd.     

A laser frequency comb that enables radial velocity measurements with a precision of 1 cm s(-1)

Searches for extrasolar planets using the periodic Doppler shift of stellar spectral lines have recently achieved a precision of 60 cm s(-1) (ref. 1), which is sufficient to find a 5-Earth-mass planet in a Mercury-like orbit around a Sun-like star. To find a 1-Earth-mass planet in an Earth-like orbit, a precision of approximately 5 cm s(-1) is necessary. The combination of a laser frequency comb with a Fabry-Pérot filtering cavity has been suggested as a promising approach to achieve such Doppler shift resolution via improved spectrograph wavelength calibration, with recent encouraging results. Here we report the fabrication of such a filtered laser comb with up to 40-GHz (approximately 1-A) line spacing, generated from a 1-GHz repetition-rate source, without compromising long-term stability, reproducibility or spectral resolution. This wide-line-spacing comb, or 'astro-comb', is well matched to the resolving power of high-resolution astrophysical spectrographs. The astro-comb should allow a precision as high as 1 cm s(-1) in astronomical radial velocity measurements.     

有机硫对维多利亚褐煤液化的催化作用之穆斯堡尔研究

我们以Morwell和Coolungoolun两种维多利亚褐煤进行实验,对铁和锡在煤的液化中的催化作用进行了比较,发现锡对低硫的Morwell煤较为有效,而铁则更适合于高硫的Coolungoolun煤。对液化余渣的穆斯堡尔分析的结果,使我们可以用低硫煤中元素态锡的形成以及在高硫煤中磁黄铁矿（Fe_(0.92)S）的形成来对观察到的现象作出解释。硫的损耗数据表明,磁黄铁矿的存在使得煤中的硫转化为气相的量增加了。     

Recursive estimation and forecasting of non-stationary time series

The paper presents a unified, fully recursive approach to the modelling and forecasting of non-stationary time-series. The basic time-series model, which is based on the well-known ‘component’ or ‘structuraL’ form, is formulated in state-space terms. A novel spectral decomposition procedure, based on the exploitation of recursive smoothing algorithms, is then utilized to simplify the procedures of model identification and estimation. Finally, the fully recursive formulation allows for conventional or self-adaptive implementation of state-space forecasting and seasonal adjustment. Although the paper is restricted to the consideration of univariate time series, the basic approach can be extended to handle explanatory variables or full multivariable (vector) series.     

Inconsistent idealizations and inferentialism about scientific representation

Inferentialists about scientific representation hold that an apparatus's representing a target system consists in the apparatus allowing “surrogative inferences” about the target. I argue that a serious problem for inferentialism arises from the fact that many scientific theories and models contain internal inconsistencies. Inferentialism, left unamended, implies that inconsistent scientific models have unlimited representational power, since an inconsistency permits any conclusion to be inferred. I consider a number of ways that inferentialists can respond to this challenge before suggesting my own solution. I develop an analogy to exploitable glitches in a game. Even though inconsistent representational apparatuses may in some sense allow for contradictions to be generated within them, doing so violates the intended function of the apparatus's parts and hence violates representational “gameplay”.     

Spatial proximity of translocation-prone gene loci in human lymphomas

Cancer cells frequently have disease-specific chromosome rearrangements. It is poorly understood why translocations between chromosomes recur at specific breakpoints in the genome. Here we provide evidence that higher-order spatial genome organization is a contributing factor in the formation of recurrent translocations. We show that MYC, BCL and immunoglobulin loci, which are recurrently translocated in various B-cell lymphomas, are preferentially positioned in close spatial proximity relative to each other in normal B cells. Loci in spatial proximity are non-randomly positioned towards the nuclear interior in normal B cells. This locus proximity is the consequence of higher-order genome structure rather than a property of individual genes. Our results suggest that the formation of specific translocations in human lymphomas, and perhaps other tissues, is determined in part by higher-order spatial organization of the genome.     

Common variation at 10p12.31 near MLLT10 influences meningioma risk

To identify susceptibility loci for meningioma, we conducted a genome-wide association study of 859 affected individuals (cases) and 704 controls with validation in two independent sample sets totaling 774 cases and 1,764 controls. We identified a new susceptibility locus for meningioma at 10p12.31 (MLLT10, rs11012732, odds ratio = 1.46, P(combined) = 1.88 × 10(-14)). This finding advances our understanding of the genetic basis of meningioma development.