Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges.

Do people have insight into their face recognition abilities?

Diagnosis of developmental or congenital prosopagnosia (CP) involves self-report of everyday face recognition difficulties, which are corroborated with poor performance on behavioural tests. This approach requires accurate self-evaluation. We examine the extent to which typical adults have insight into their face recognition abilities across four studies involving nearly 300 participants. The studies used five tests of face recognition ability: two that tap into the ability to learn and recognise previously unfamiliar faces (the Cambridge Face Memory Test, CFMT, Duchaine & Nakayama, 2006 and a newly devised test based on the CFMT but where the study phases involve watching short movies rather than viewing static faces – the CFMT-Films) and three that tap face matching (Benton Facial Recognition Test, BFRT, Benton, Sivan, Hamsher, Varney, & Spreen, 1983; and two recently devised sequential face matching tests). Self-reported ability was measured with the 15-item Kennerknecht et al. (2008) questionnaire; two single-item questions assessing face recognition ability; and a new 77-item meta-cognition questionnaire). Overall, we find that adults with typical face recognition abilities have only modest insight into their ability to recognise faces on behavioural tests. In a fifth study, we assess self-reported face recognition ability in people with CP and find that some people who expect to perform poorly on behavioural tests of face recognition do indeed perform poorly. However, it is not yet clear whether individuals within this group of poor performers have greater levels of insight (i.e., into their degree of impairment) than those with more typical levels of performance.

Chemical, biochemical, and molecular characterization of a low vindoline Catharanthus roseus mutant.

The Madagascar periwinkle (Catharanthus roseus) is the sole source of the anticancer drug vinblastine, which is formed via the coupling of monoterpenoid indole alkaloids (MIAs) catharanthine and vindoline. A mutant line of C. roseus (M2-1865) with an altered MIA profile was identified in a screen of 4000 M2 lines generated by ethylmethanesulfonate (EMS) chemical mutagenesis. While this line did not accumulate vinblastine due to reduced levels of vindoline within the leaves, significant levels of 2,3-epoxide derivatives of tabersonine accumulated on the leaf surface. Detailed nucleotide, amino acid, and enzyme activity analyses of tabersonine 3-reductase in the M2-1865 line showed that a single amino acid substitution (H189Y) diminished the biochemical activity of T3R by 95%. Genetic crosses showed the phenotype to be recessive, exhibiting standard Mendelian single-gene inheritance. The usefulness of EMS mutagenesis in elucidating MIA biosynthesis is highlighted by the results of this study.

Entendiendo un programa de reparación: reconstrucción del proceso de creación e implementación de familias en su tierra – FEST– El caso del municipio de La Palma, Cundinamarca

A partir de la reconstrucción del proceso de creación e implementación del programa presidencial para la reparación a población desplazada Familias En Su Tierra, se exploran las dificultades y retos que enfrenta la Ley de Víctimas y Restitución de Tierras.

The long wavelength limit of hard thermal loop effective actions

We derive a closed form expression for the long wavelength limit of the effective action for hard thermal loops in an external gravitational field. It is a function of the metric, independent of time derivatives. It is compared and contrasted with the static limit, and with the corresponding limits in an external Yang-Mills field. (C) 2009 Elsevier B.V. All rights reserved.

Conditions for the validity of the quantum Langevin equation

From microscopic models, a Langevin equation can, in general, be derived only as an approximation. Two possible conditions to validate this approximation are studied. One is, for a linear Langevin equation, that the frequency of the Fourier transform should be close to the natural frequency of the system. The other is by the assumption of "slow" variables. We test this method by comparison with an exactly soluble model and point out its limitations. We base our discussion on two approaches. The first is a direct, elementary treatment of Senitzky. The second is via a generalized Langevin equation as an intermediate step.

Dating the Siple Dome (Antarctica) Ice Core By Manual and Computer Interpretation of Annual Layering

The Holocene portion of the Siple Dome (Antarctica) ice core was dated by interpreting the electrical, visual and chemical properties of the core. The data were interpreted manually and with a computer algorithm. The algorithm interpretation was adjusted to be consistent with atmospheric methane stratigraphic ties to the GISP2 (Greenland Ice Sheet Project 2) ice core, (BE)-B-10 stratigraphic ties to the dendrochronology C-14 record and the dated volcanic stratigraphy. The algorithm interpretation is more consistent and better quantified than the tedious and subjective manual interpretation.

CO(2) Diffusion in Polar Ice: Observations from Naturally Formed CO(2) Spikes in the Siple Dome (Antarctica) Ice Core

One common assumption in interpreting ice-core CO(2) records is that diffusion in the ice does not affect the concentration profile. However, this assumption remains untested because the extremely small CO(2) diffusion coefficient in ice has not been accurately determined in the laboratory. In this study we take advantage of high levels of CO(2) associated with refrozen layers in an ice core from Siple Dome, Antarctica, to study CO(2) diffusion rates. We use noble gases (Xe/Ar and Kr/Ar), electrical conductivity and Ca(2+) ion concentrations to show that substantial CO(2) diffusion may occur in ice on timescales of thousands of years. We estimate the permeation coefficient for CO(2) in ice is similar to 4 x 10(-21) mol m(-1) s(-1) Pa(-1) at -23 degrees C in the top 287 m (corresponding to 2.74 kyr). Smoothing of the CO(2) record by diffusion at this depth/age is one or two orders of magnitude smaller than the smoothing in the firn. However, simulations for depths of similar to 930-950m (similar to 60-70 kyr) indicate that smoothing of the CO(2) record by diffusion in deep ice is comparable to smoothing in the firn. Other types of diffusion (e.g. via liquid in ice grain boundaries or veins) may also be important but their influence has not been quantified.

A 12,000 Year Record of Explosive Volcanism in the Siple Dome Ice Core, West Antarctica

Air mass trajectories in the Southern Hemisphere provide a mechanism for transport to and deposition of volcanic products on the Antarctic ice sheet from local volcanoes and from tropical and subtropical volcanic centers. This study extends the detailed record of Antarctic, South American, and equatorial volcanism over the last 12,000 years using continuous glaciochemical series developed from the Siple Dome A (SDMA) ice core, West Antarctica. The largest volcanic sulfate spike ( 280 mu g/L) occurs at 5881 B. C. E. Other large signals with unknown sources are observed around 325 B. C. E. ( 270 mu g/L) and 2818 B. C. E. ( 191 mu g/L). Ages of several large equatorial or Southern Hemisphere volcanic eruptions are synchronous with many sulfate peaks detected in the SDMA volcanic ice chemistry record. The microprobe "fingerprinting'' of glass shards in the SDMA core points to the following Antarctic volcanic centers as sources of tephra found in the SDMA core: Balenny Island, Pleiades, Mount Berlin, Mount Takahe, and Mount Melbourne as well as Mount Hudson and possibly Mount Burney volcanoes of South America. Identified volcanic sources provide an insight into the poorly resolved transport history of volcanic products from source volcanoes to the West Antarctic ice sheet.

A Record of Atmospheric Co2 During the Last 40,000 Years from the Siple Dome, Antarctica Ice Core

We have measured the CO2 concentration of air occluded during the last 40,000 years in the deep Siple Dome A ( hereafter Siple Dome) ice core, Antarctica. The general trend of CO2 concentration from Siple Dome ice follows the temperature inferred from the isotopic composition of the ice and is mostly in agreement with other Antarctic ice core CO2 records. CO2 rose initially at similar to 17.5 kyr B. P. ( thousand years before 1950), decreased slowly during the Antarctic Cold Reversal, rose during the Younger Dryas, fell to a local minimum at around 8 kyr B. P., and rose continuously since then. The CO2 concentration never reached steady state during the Holocene, as also found in the Taylor Dome and EPICA Dome C ( hereafter Dome C) records. During the last glacial termination, a lag of CO2 versus Siple Dome isotopic temperature is probable. The Siple Dome CO2 concentrations during the last glacial termination and in the Holocene are at certain times greater than in other Antarctic ice cores by up to 20 ppm (mumol CO2/mol air). While in situ production of CO2 is one possible cause of the sporadic elevated levels, the mechanism leading to the enrichment is not yet clear.

Les juifs de l'occident et le judai͏̈sme moderne

trad. de l'Anglais par M.-J. Wertheimer

L'israelitismo moderno

M. Soave

De legibus Hebraeorum ritualibus, et earum rationibus : libri tres

authore Joanne Spencero

New LA-ICP-MS cryocell and calibration technique for sub-millimeter analysis of ice cores

Ice cores provide a robust reconstruction of past climate. However, development of timescales by annual-layer counting, essential to detailed climate reconstruction and interpretation, on ice cores collected at low-accumulation sites or in regions of compressed ice, is problematic due to closely spaced layers. Ice-core analysis by laser ablation–inductively coupled plasma–mass spectrometry (LA-ICP-MS) provides sub-millimeter-scale sampling resolution (on the order of 100μm in this study) and the low detection limits (ng L–1) necessary to measure the chemical constituents preserved in ice cores. We present a newly developed cryocell that can hold a 1m long section of ice core, and an alternative strategy for calibration. Using ice-core samples from central Greenland, we demonstrate the repeatability of multiple ablation passes, highlight the improved sampling resolution, verify the calibration technique and identify annual layers in the chemical profile in a deep section of an ice core where annual layers have not previously been identified using chemistry. In addition, using sections of cores from the Swiss/Italian Alps we illustrate the relationship between Ca, Na and Fe and particle concentration and conductivity, and validate the LA-ICP-MS Ca profile through a direct comparison with continuous flow analysis results.

TrypanoCyc: a community-led biochemical pathways database for Trypanosoma brucei.

The metabolic network of a cell represents the catabolic and anabolic reactions that interconvert small molecules (metabolites) through the activity of enzymes, transporters and non-catalyzed chemical reactions. Our understanding of individual metabolic networks is increasing as we learn more about the enzymes that are active in particular cells under particular conditions and as technologies advance to allow detailed measurements of the cellular metabolome. Metabolic network databases are of increasing importance in allowing us to contextualise data sets emerging from transcriptomic, proteomic and metabolomic experiments. Here we present a dynamic database, TrypanoCyc (http://www.metexplore.fr/trypanocyc/), which describes the generic and condition-specific metabolic network of Trypanosoma brucei, a parasitic protozoan responsible for human and animal African trypanosomiasis. In addition to enabling navigation through the BioCyc-based TrypanoCyc interface, we have also implemented a network-based representation of the information through MetExplore, yielding a novel environment in which to visualise the metabolism of this important parasite.