The fine-scale architecture of structural variants in 17 mouse genomes.

BACKGROUND: Accurate catalogs of structural variants (SVs) in mammalian genomes are necessary to elucidate the potential mechanisms that drive SV formation and to assess their functional impact. Next generation sequencing methods for SV detection are an advance on array-based methods, but are almost exclusively limited to four basic types: deletions, insertions, inversions and copy number gains. RESULTS: By visual inspection of 100 Mbp of genome to which next generation sequence data from 17 inbred mouse strains had been aligned, we identify and interpret 21 paired-end mapping patterns, which we validate by PCR. These paired-end mapping patterns reveal a greater diversity and complexity in SVs than previously recognized. In addition, Sanger-based sequence analysis of 4,176 breakpoints at 261 SV sites reveal additional complexity at approximately a quarter of structural variants analyzed. We find micro-deletions and micro-insertions at SV breakpoints, ranging from 1 to 107 bp, and SNPs that extend breakpoint micro-homology and may catalyze SV formation. CONCLUSIONS: An integrative approach using experimental analyses to train computational SV calling is essential for the accurate resolution of the architecture of SVs. We find considerable complexity in SV formation; about a quarter of SVs in the mouse are composed of a complex mixture of deletion, insertion, inversion and copy number gain. Computational methods can be adapted to identify most paired-end mapping patterns.

Space-time within general relativity : a structural realist understanding

ABSTRACT This dissertation investigates the, nature of space-time as described by the theory of general relativity. It mainly argues that space-time can be naturally interpreted as a physical structure in the precise sense of a network of concrete space-time relations among concrete space-time points that do not possess any intrinsic properties and any intrinsic identity. Such an interpretation is fundamentally based on two related key features of general relativity, namely substantive general covariance and background independence, where substantive general covariance is understood as a gauge-theoretic invariance under active diffeomorphisms and background independence is understood in the sense that the metric (or gravitational) field is dynamical and that, strictly speaking, it cannot be uniquely split into a purely gravitational part and a fixed purely inertial part or background. More broadly, a precise notion of (physical) structure is developed within the framework of a moderate version of structural realism understood as a metaphysical claim about what there is in the world. So, the developement of this moderate structural realism pursues two main aims. The first is purely metaphysical, the aim being to develop a coherent metaphysics of structures and of objects (particular attention is paid to the questions of identity and individuality of these latter within this structural realist framework). The second is to argue that moderate structural realism provides a convincing interpretation of the world as described by fundamental physics and in particular of space-time as described by general relativity. This structuralist interpretation of space-time is discussed within the traditional substantivalist-relationalist debate, which is best understood within the broader framework of the question about the relationship between space-time on the one hand and matter on the other. In particular, it is claimed that space-time structuralism does not constitute a 'tertium quid' in the traditional debate. Some new light on the question of the nature of space-time may be shed from the fundamental foundational issue of space-time singularities. Their possible 'non-local' (or global) feature is discussed in some detail and it is argued that a broad structuralist conception of space-time may provide a physically meaningful understanding of space-time singularities, which is not plagued by the conceptual difficulties of the usual atomsitic framework. Indeed, part of these difficulties may come from the standard differential geometric description of space-time, which encodes to some extent this atomistic framework; it raises the question of the importance of the mathematical formalism for the interpretation of space-time.

Gestion des hypoglycémies après le bypass gastrique [Management of hyperinsulinemic hypoglycemia post-gastric bypass surgery].

Gastric bypass surgery is an effective treatment for morbid obesity, allowing a substantial weight loss together with an improvement of the cardiovascular and metabolic comorbidities, particularly the glucose control. However, after gastric bypassing, an imbalance between sensitivity and insulin secretion may be observed. This disorder gives rise to hyperinsulinemic hypoglycemia (late dumping syndrome) and is characterized by a dizziness that can be disabling. This problem must be distinguished from conditions provoking similar symptoms, as for instance the early dumping syndrome and the food restriction-related hypoglycemia. Since all these conditions need a particular management, their distinction is essential.

A Kilkenny Post-primary School Survey: A Survey of Knowledge, Attitudes and Behaviour Relevant to Noncommunicable Disease

The Kilkenny post-primary school survey was carried out in the spring of 1987 on a stratified random sample of 445 post-primary school children in county Kilkenny. The study was designed as the basis for evaluation of the Kilkenny Health Project's school health education programme. The study examined knowledge, attitudes and behaviour relevant to non-communicable disease. The results showed that levels of adolescent alcohol and tobacco use were similar to those found in neighbouring countries. Smoking and drinking increased during adolescence and were more prevalent in males. Physical activity decreased throughout adolescence and a high intake of 'snack' foods was found. Health related knowledge levels were high but were not related to behaviour; however attitudes were found to be consistent with behaviour. These and other results are discussed. Literature relevant to school health education and the aetiology of non-communicable disease is described, with particular reference to Ireland. The evidence supporting health promotion intervention programmes against non-communicable disease is examined and WHO and Irish policies on health promotion outlined. The importance of health and disease prevention programmes commencing in youth is emphasised and the suitability and efficacy of school health education programmes are noted. A number of school health education programmes world-wide are described. The role of the community physician in relation to such programmes is discussed. Finally recommendations are made and areas for further research are made.This resource was contributed by The National Documentation Centre on Drug Use.

Reversible acquired epileptic frontal syndrome and CSWS suppression in a child with congenital hemiparesis treated by hemispherotomy.

A boy with a right congenital hemiparesis due to a left pre-natal middle cerebral artery infarct developed focal epilepsy at 33 months and then an insidious and subsequently more rapid, massive cognitive and behavioural regression with a frontal syndrome between the ages of 4 and 5 years with continuous spike-waves during sleep (CSWS) on the EEG. Both the epilepsy and the CSWS were immediately suppressed by hemispherotomy at the age of 5 years and 4 months. A behavioural-cognitive follow-up prior to hemispherotomy, an per-operative EEG and corticography and serial post-operative neuropsychological assessments were performed until the age of 11 years. The spread of the epileptic activity to the "healthy" frontal region was the cause of the reversible frontal syndrome. A later gradual long-term but incomplete cognitive recovery, with moderate mental disability was documented. This outcome is probably explained by another facet of the epilepsy, namely the structural effects of prolonged epileptic discharges in rapidly developing cerebral networks which are, at the same time undergoing the reorganization imposed by a unilateral early hemispheric lesion. Group studies on the outcome of children before and after hemispherectomy using only single IQ measures, pre- and post-operatively, may miss particular epileptic cognitive dysfunctions as they are likely to be different from case to case. Such detailed and rarely available complementary clinical and EEG data obtained in a single case at different time periods in relation to the epilepsy, including per-operative electrophysiological findings, may help to understand the different cognitive deficits and recovery profiles and the limits of full cognitive recovery.

Biological effect of 1-dodecanol in teneral and post-teneral Rhodnius prolixus and Triatoma infestans (Hemiptera: Reduviidae)

Topical application of 1-dodecanol was significantly more toxic against teneral first nymphs (1-3 h old) than post-teneral first nymphs (24 h old). The lethal dose ratios were 711,500 for Rhodnius prolixus and 3613 for Triatoma infestans. No significative difference between LD50 was found when 1-dodecanol was injected in recently hatched adult R. prolixus (1-4 h old) nor in older adults (24 h old). These values were similar to those calculated for deltamethrin (an effective triatomicide), showing that 1-dodecanol had no insecticidal properties when it was applied by injection. Topical application of high dose of 1-dodecanol (1 µg/i) on teneral first nymphs of R. prolixus, produced an interruption of the darkening process of the cuticle, and probably in the development of its physiological properties.

Post-genomic update on a classical candidate gene for coronary artery disease: ESR1.

BACKGROUND: After age, sex is the most important risk factor for coronary artery disease (CAD). The mechanism through which women are protected from CAD is still largely unknown, but the observed sex difference suggests the involvement of the reproductive steroid hormone signaling system. Genetic association studies of the gene-encoding Estrogen Receptor α (ESR1) have shown conflicting results, although only a limited range of variation in the gene has been investigated. METHODS AND RESULTS: We exploited information made available by advanced new methods and resources in complex disease genetics to revisit the question of ESR1's role in risk of CAD. We performed a meta-analysis of 14 genome-wide association studies (CARDIoGRAM discovery analysis, N=≈87,000) to search for population-wide and sex-specific associations between CAD risk and common genetic variants throughout the coding, noncoding, and flanking regions of ESR1. In addition to samples from the MIGen (N=≈6000), WTCCC (N=≈7400), and Framingham (N=≈3700) studies, we extended this search to a larger number of common and uncommon variants by imputation into a panel of haplotypes constructed using data from the 1000 Genomes Project. Despite the widespread expression of ERα in vascular tissues, we found no evidence for involvement of common or low-frequency genetic variation throughout the ESR1 gene in modifying risk of CAD, either in the general population or as a function of sex. CONCLUSIONS: We suggest that future research on the genetic basis of sex-related differences in CAD risk should initially prioritize other genes in the reproductive steroid hormone biosynthesis system.

Decoupled post-glacial history in mutualistic plant-insect interactions: insights from the yellow loosestrife (Lysimachia vulgaris) and its associated oil-collecting bees (Macropis europaea and M-fulvipes)

AimWe take a comparative phylogeographical approach to assess whether three species involved in a specialized oil-rewarding pollination system (i.e. Lysimachia vulgaris and two oil-collecting bees within the genus Macropis) show congruent phylogeographical trajectories during post-glacial colonization processes. Our working hypothesis is that within specialized mutualistic interactions, where each species relies on the co-occurrence of the other for survival and/or reproduction, partners are expected to show congruent evolutionary trajectories, because they are likely to have followed parallel migration routes and to have shared glacial refugia. LocationWestern Palaearctic. MethodsOur analysis relies on the extensive sampling of 104 Western Palaearctic populations (totalling 434, 159 and 74 specimens of Lysimachiavulgaris, Macropiseuropaea and Macropisfulvipes, respectively), genotyped with amplified fragment length polymorphism. Based on this, we evaluated the regional genetic diversity (Shannon diversity and allele rarity index) and genetic structure (assessed using structure, population networks, isolation-by-distance and spatial autocorrelation metrics) of each species. Finally, we compared the general phylogeographical patterns obtained. ResultsContrary to our expectations, the analyses revealed phylogeographical signals suggesting that the investigated organisms demonstrate independent post-glacial trajectories as well as distinct contemporaneous demographic parameters, despite their mutualistic interaction. Main conclusionsThe mutualistic partners investigated here are likely to be experiencing distinct and independent evolutionary dynamics because of their contrasting life-history traits (e.g. dispersal abilities), as well as distinct hubs and migration routes. Such conditions would prevent and/or erase any signature of co-structuring of lineages in space and time. As a result, the lack of phylogeographical congruence driven by differences in life-history traits might have arisen irrespective of the three species having shared similar Pleistocene glacial refugia.

La era post-descentralización : la consolidación de servidores

Aquest projecte estudia el concepte de consolidació de servidors en l'aspecte més general. Consta de dues parts ben diferenciades: l'una d'àmbit teòric i l'altra d'aplicació pràctica d'una solució en concret.

La diversité des motivations des employés publics : recherche exploratoire dans un contexte post-bureaucratique en Suisse

Durant les dernières décennies, la recherche portant sur la motivation des fonctionnaires a été dominée par deux courants théoriques : l'approche dite des choix rationnels, et celle portant sur la motivation au service public. Dans l'environnement post-bureaucratique actuel, cette vision simplifiée, qui reflète aussi dans une certaine mesure la dichotomie « public-privé », ne reflète plus de manière adéquate la complexité et l'hétérogénéité des motivations des agents publics. Basée sur des données empiriques qualitatives et quantitatives, une typologie originale des motivations dans l'univers post-bureaucratique est développée et testée dans plusieurs organisations publiques suisses. Elle révèle des facteurs de motivations qui combinent de manière originale des éléments classiques de la bureaucratie avec d'autres sources de motivation caractéristiques de formes modernes d'administration publique.

Infection by Mycobacterium leprae of household contacts of lepromatous leprosy patients from a post-elimination leprosy region of Colombia

The Leprosy Control Program of Antioquia, (post-elimination leprosy state of Colombia), had registered by 1999, 56 lepromatous leprosy patients and their household contacts (HHC). Our interest was to detect Mycobacterium leprae infection in these HHC. Clinical examination, acid-fast bacillary staining (AFB) in nasal secretions, and slit skin samples, IgM anti-PGL-I in serum and Lepromine A (Mitsuda) reactivity were tested. Two hundred forty eight HHC were studied, 49% were male. After clinical examination, two HHC were diagnosed as multi bacillary patients; 13% showed positive IgM anti-PGL-I titers; Mitsuda reaction (> 4 mm) was positive in 59%; AFB was negative in all samples, except in the two new patients. HHC were classified according to test results.Group 1: two new multi bacillary patients. Group 2: 15 HHC seropositive, Mitsuda-negative. Group 3: 13 HHC seropositive, Mitsuda-positive. Group 4: 130 HHC seronegative, Mitsuda-positive. Group 5: 88 HHC seronegative, Mitsuda-negative. These results are an indication that the transmission of the infection is still happening in a region considered in the post elimination phase. The two new patients represent an infection source for others contacts, and groups 2 and 3 are infected HHC that could develop the disease in future. Follow up of high risk population is necessary to achieve real elimination of leprosy.

Mycobacterium bovis identification by a molecular method from post-mortem inspected cattle obtained in abattoirs of Mato Grosso do Sul, Brazil

The presence of Mycobacterium bovis in bovine carcasses with lesions suggestive of tuberculosis was evaluated. Seventy-two carcass samples were selected during slaughter inspection procedures in abattoirs in the state of Mato Grosso do Sul, Brazil. Seventeen (23.6%) of samples showed colonies suggestive of mycobacteria that were confirmed to be acid-fast bacilli by Ziehl-Neelsen staining. Polymerase chain reaction (PCR) using primers specific for M. bovis identified M. bovis in 13 (76.5%) isolates. The PCR-restriction enzyme pattern analysis using gene encoding for the 65-kDa protein and two restriction enzymes identified the remaining four isolates that were represented by two M. tuberculosis complex and two nontuberculous mycobacteria. The results are indicative of infection of slaughter cattle by M. bovis and other mycobacteria in the state of Mato Grosso do Sul.

Strategic review of health inequalities in England post 2010 (Marmot review consultation paper)

In November 2008, Professor Sir Michael Marmot was asked to advise the Secretary of State for Health on the future development of a health inequalities strategy in England post-2010. The consultation relates to the first phase of the review and is based on submissions from nine task groups, who considered the evidence base across the social determinants of health. This document discusses issues raised during this first phase of the review and identifies key questions for respondents. The consultation document is set out in the following sections: Section 1 The Review Consultation: Aims and consultation questions Section 2 The Strategic Review of Health inequalities: The Background to the Review, the remit, structure, context and the social determinants approach to health inequalities. Section 3 Key Strategic Themes: A summary of a thematic analysis of proposals made by the Review task groups. Each task group was asked to assess national and international evidence about interventions and policies from within their policy area, which would likely lead to reductions in health inequalities. Section 4 Cross-Cutting Challenges for the Review: A summary of challenges currently under consideration by the Review.