Structural insights into RNA processing by the human RISC-loading complex.

Targeted gene silencing by RNA interference (RNAi) requires loading of a short guide RNA (small interfering RNA (siRNA) or microRNA (miRNA)) onto an Argonaute protein to form the functional center of an RNA-induced silencing complex (RISC). In humans, Argonaute2 (AGO2) assembles with the guide RNA-generating enzyme Dicer and the RNA-binding protein TRBP to form a RISC-loading complex (RLC), which is necessary for efficient transfer of nascent siRNAs and miRNAs from Dicer to AGO2. Here, using single-particle EM analysis, we show that human Dicer has an L-shaped structure. The RLC Dicer's N-terminal DExH/D domain, located in a short 'base branch', interacts with TRBP, whereas its C-terminal catalytic domains in the main body are proximal to AGO2. A model generated by docking the available atomic structures of Dicer and Argonaute homologs into the RLC reconstruction suggests a mechanism for siRNA transfer from Dicer to AGO2

From wormhole to time machine: Comments on Hawking's Chronology Protection Conjecture

The recent interest in ``time machines'' has been largely fueled by the apparent ease with which such systems may be formed in general relativity, given relatively benign initial conditions such as the existence of traversable wormholes or of infinite cosmic strings. This rather disturbing state of affairs has led Hawking to formulate his Chronology Protection Conjecture, whereby the formation of ``time machines'' is forbidden. This paper will use several simple examples to argue that the universe appears to exhibit a ``defense in depth'' strategy in this regard. For appropriate parameter regimes Casimir effects, wormhole disruption effects, and gravitational back reaction effects all contribute to the fight against time travel. Particular attention is paid to the role of the quantum gravity cutoff. For the class of model problems considered it is shown that the gravitational back reaction becomes large before the Planck scale quantum gravity cutoff is reached, thus supporting Hawking's conjecture.Comment: 43 pages,ReV_TeX,major revision

The Appearance and Modulation of Osteocyte Marker Expression during Calcification of Vascular Smooth Muscle Cells

Vascular calcification is an indicator of elevated cardiovascular risk. Vascular smooth muscle cells (VSMCs), the predominant cell type involved in medial vascular calcification, can undergo phenotypic transition to both osteoblastic and chondrocytic cells within a calcifying environment.In the present study, using in vitro VSMC calcification studies in conjunction with ex vivo analyses of a mouse model of medial calcification, we show that vascular calcification is also associated with the expression of osteocyte phenotype markers. As controls, the terminal differentiation of murine calvarial osteoblasts into osteocytes was induced in vitro in the presence of calcifying medium (containing ß-glycerophosphate and ascorbic acid), as determined by increased expression of the osteocyte markers DMP-1, E11 and sclerostin. Culture of murine aortic VSMCs under identical conditions confirmed that the calcification of these cells can also be induced in similar calcifying medium. Calcified VSMCs had increased alkaline phosphatase activity and PiT-1 expression, which are recognized markers of vascular calcification. Expression of DMP-1, E11 and sclerostin was up-regulated during VSMC calcification in vitro. Increased protein expression of E11, an early osteocyte marker, and sclerostin, expressed by more mature osteocytes was also observed in the calcified media of Enpp1(-/-) mouse aortic tissue.This study has demonstrated the up-regulation of key osteocytic molecules during the vascular calcification process. A fuller understanding of the functional role of osteocyte formation and specifically sclerostin and E11 expression in the vascular calcification process may identify novel potential therapeutic strategies for clinical intervention

Monitoring international migration flows in Europe. Towards a statistical data base combining data from different sources

The paper reviews techniques developed in demography, geography and statistics that are useful for bridging the gap between available data on international migration flows and the information required for policy making and research. The basic idea of the paper is as follows: to establish a coherent and consistent data base that contains sufficiently detailed, up-to-date and accurate information, data from several sources should be combined. That raises issues of definition and measurement, and of how to combine data from different origins properly. The issues may be tackled more easily if the statistics that are being compiled are viewed as different outcomes or manifestations of underlying stochastic processes governing migration. The link between the processes and their outcomes is described by models, the parameters of which must be estimated from the available data. That may be done within the context of socio-demographic accounting. The paper discusses the experience of the U.S. Bureau of the Census in combining migration data from several sources. It also summarizes the many efforts in Europe to establish a coherent and consistent data base on international migration. The paper was written at IIASA. It is part of the Migration Estimation Study, which is a collaborative IIASA-University of Groningen project, funded by the Netherlands Organization for Scientific Research (NWO). The project aims at developing techniques to obtain improved estimates of international migration flows by country of origin and country of destination

Regularizing Portfolio Optimization

The optimization of large portfolios displays an inherent instability to estimation error. This poses a fundamental problem, because solutions that are not stable under sample fluctuations may look optimal for a given sample, but are, in effect, very far from optimal with respect to the average risk. In this paper, we approach the problem from the point of view of statistical learning theory. The occurrence of the instability is intimately related to over-fitting which can be avoided using known regularization methods. We show how regularized portfolio optimization with the expected shortfall as a risk measure is related to support vector regression. The budget constraint dictates a modification. We present the resulting optimization problem and discuss the solution. The L2 norm of the weight vector is used as a regularizer, which corresponds to a diversification "pressure". This means that diversification, besides counteracting downward fluctuations in some assets by upward fluctuations in others, is also crucial because it improves the stability of the solution. The approach we provide here allows for the simultaneous treatment of optimization and diversification in one framework that enables the investor to trade-off between the two, depending on the size of the available data set

Enhancing reductive cleavage of aromatic carboxamides

[GRAPHICS] A set of aromatic and especially heteroaromatic N-benzyl carboxamides, derived from naphthalene, pyridine, pyrazine, and quinoline, and the corresponding tert-butyl acylcarbamates have been synthesized and studied by cyclic voltammetry with respect to facilitated reduction. The latter undergo regiospecific cleavage of their C(O)-N bonds under very mild reductive conditions with formation of Boc-protected (benzyl)amine in most cases in nearly quantitative yields, Examples of preparative cleavage by controlled potential electrolysis, activated aluminum, and NaBH4 are given

Kepler observations of variability in B-type stars

The analysis of the light curves of 48 B-type stars observed by Kepler is presented. Among these are 15 pulsating stars, all of which show low frequencies characteristic of SPB stars. Seven of these stars also show a few weak, isolated high frequencies and they could be considered as SPB/beta Cep hybrids. In all cases the frequency spectra are quite different from what is seen from ground-based observations. We suggest that this is because most of the low frequencies are modes of high degree which are predicted to be unstable in models of mid-B stars. We find that there are non-pulsating stars within the beta Cep and SPB instability strips. Apart from the pulsating stars, we can identify stars with frequency groupings similar to what is seen in Be stars but which are not Be stars. The origin of the groupings is not clear, but may be related to rotation. We find periodic variations in other stars which we attribute to proximity effects in binary systems or possibly rotational modulation. We find no evidence for pulsating stars between the cool edge of the SPB and the hot edge of the delta Sct instability strips. None of the stars show the broad features which can be attributed to stochastically-excited modes as recently proposed. Among our sample of B stars are two chemically peculiar stars, one of which is a HgMn star showing rotational modulation in the light curve.Comment: 19 pages, 11 figures, 4 table

Contrasting prefrontal cortex contributions to episodic memory dysfunction in behavioural variant frontotemporal dementia and alzheimer's disease

Recent evidence has questioned the integrity of episodic memory in behavioural variant frontotemporal dementia (bvFTD), where recall performance is impaired to the same extent as in Alzheimer's disease (AD). While these deficits appear to be mediated by divergent patterns of brain atrophy, there is evidence to suggest that certain prefrontal regions are implicated across both patient groups. In this study we sought to further elucidate the dorsolateral (DLPFC) and ventromedial (VMPFC) prefrontal contributions to episodic memory impairment in bvFTD and AD. Performance on episodic memory tasks and neuropsychological measures typically tapping into either DLPFC or VMPFC functions was assessed in 22 bvFTD, 32 AD patients and 35 age- and education-matched controls. Behaviourally, patient groups did not differ on measures of episodic memory recall or DLPFC-mediated executive functions. BvFTD patients were significantly more impaired on measures of VMPFC-mediated executive functions. Composite measures of the recall, DLPFC and VMPFC task scores were covaried against the T1 MRI scans of all participants to identify regions of atrophy correlating with performance on these tasks. Imaging analysis showed that impaired recall performance is associated with divergent patterns of PFC atrophy in bvFTD and AD. Whereas in bvFTD, PFC atrophy covariates for recall encompassed both DLPFC and VMPFC regions, only the DLPFC was implicated in AD. Our results suggest that episodic memory deficits in bvFTD and AD are underpinned by divergent prefrontal mechanisms. Moreover, we argue that these differences are not adequately captured by existing neuropsychological measures

Determination of the scalar polarizabilities of the proton using beam asymmetry Σ3\Sigma_{3} in Compton scattering

The scalar dipole polarizabilities, $\alpha_{E1}$ and $\beta_{M1}$, are fundamental properties related to the internal dynamics of the nucleon. The currently accepted values of the proton polarizabilities were determined by fitting to unpolarized proton Compton scattering cross section data. The measurement of the beam asymmetry $\Sigma_{3}$ in a certain kinematical range provides an alternative approach to the extraction of the scalar polarizabilities. At the Mainz Microtron (MAMI) the beam asymmetry was measured for Compton scattering below pion photoproduction threshold for the first time. The results are compared with model calculations and the influence of the experimental data on the extraction of the scalar polarizabilities is determined.Comment: 6 pages, 5 figure