Extensive Copy-Number Variation of Young Genes across Stickleback Populations

MM received funding from the Max Planck innovation funds for this project. PGDF was supported by a Marie Curie European Reintegration Grant (proposal nr 270891). CE was supported by German Science Foundation grants (DFG, EI 841/4-1 and EI 841/6-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

The muscle – fat duel or why obese children are taller?

BACKGROUND: Obesity the epidemic of our times appears to be a problem that is easy to resolve: just eat less and move more. However, this very common condition has turned out to be extremely troublesome, and in some cases even irreversible. METHODS: The interplay between less muscle and more fat tissue is discussed from physiological perspectives with an emphasis on the early years of childhood. RESULTS: It is suggested that the coordinated muscle-fat interactions lead to a fluctuating exchange economy rate. This bodily economic decision, slides between thrift (more fat) and prodigal (more muscle) strategies. The thrift strategy results not only in obesity and less physical activity but also in other maladies which the body is unable to manage. What leads to obesity (less muscle, more fat) might be very difficult to reverse at adulthood, prevention at childhood is thus recommended. CONCLUSION: Early recognition of the ailment (low muscle mass) is crucial. Based on studies demonstrating a 'rivalry' between muscle build-up and height growth at childhood, it is postulated that among the both taller and more obese children the percentage of children with lower muscle mass will be higher. A special, body/muscle-building gymnastics program for children is suggested as a potential early intervention to prevent the ill progress of obesity

Structure-Function Correlation of the Human Central Retina

The impact of retinal pathology detected by high-resolution imaging on vision remains largely unexplored. Therefore, the aim of the study was to achieve high-resolution structure-function correlation of the human macula in vivo.To obtain high-resolution tomographic and topographic images of the macula spectral-domain optical coherence tomography (SD-OCT) and confocal scanning laser ophthalmoscopy (cSLO), respectively, were used. Functional mapping of the macula was obtained by using fundus-controlled microperimetry. Custom software allowed for co-registration of the fundus mapped microperimetry coordinates with both SD-OCT and cSLO datasets. The method was applied in a cross-sectional observational study of retinal diseases and in a clinical trial investigating the effectiveness of intravitreal ranibizumab in macular telangietasia type 2. There was a significant relationship between outer retinal thickness and retinal sensitivity (p<0.001) and neurodegeneration leaving less than about 50 µm of parafoveal outer retinal thickness completely abolished light sensitivity. In contrast, functional preservation was found if neurodegeneration spared the photoreceptors, but caused quite extensive disruption of the inner retina. Longitudinal data revealed that small lesions affecting the photoreceptor layer typically precede functional detection but later cause severe loss of light sensitivity. Ranibizumab was shown to be ineffective to prevent such functional loss in macular telangietasia type 2.Since there is a general need for efficient monitoring of the effectiveness of therapy in neurodegenerative diseases of the retina and since SD-OCT imaging is becoming more widely available, surrogate endpoints derived from such structure-function correlation may become highly relevant in future clinical trials

An Evolutionary Framework for Association Testing in Resequencing Studies

Sequencing technologies are becoming cheap enough to apply to large numbers of study participants and promise to provide new insights into human phenotypes by bringing to light rare and previously unknown genetic variants. We develop a new framework for the analysis of sequence data that incorporates all of the major features of previously proposed approaches, including those focused on allele counts and allele burden, but is both more general and more powerful. We harness population genetic theory to provide prior information on effect sizes and to create a pooling strategy for information from rare variants. Our method, EMMPAT (Evolutionary Mixed Model for Pooled Association Testing), generates a single test per gene (substantially reducing multiple testing concerns), facilitates graphical summaries, and improves the interpretation of results by allowing calculation of attributable variance. Simulations show that, relative to previously used approaches, our method increases the power to detect genes that affect phenotype when natural selection has kept alleles with large effect sizes rare. We demonstrate our approach on a population-based re-sequencing study of association between serum triglycerides and variation in ANGPTL4

A Collective Household Labour Supply Model with Disability: Evidence from Iraq

In this study we explored the determinants of the women’s labour supply and we attempted to identify the sharing rules for married couples. The analysis relied on data derived by the Iraqi Household Socio-Economic Survey (IHSES) in 2012–2013. The study considered the housework contributed by both spouses and we also included the wife’s disability status as a distribution factor. Moreover, we estimated the sharing rules accounting for female non-participation in the labour market. The household collective model was preferred over the unitary model as the results supported that changes on wages, non-labour income, age, education, number of children, and disability as a distribution factor affect the bargaining power and the share of spouses. The findings showed that for a one percent increase on female’s daily wage rate, her share on full income was increased by 1320 Iraqi Dinar (ID) corresponding to $1.12, while reached 1470 ID ($1.25) when the domestic labour was considered. Similarly, increases on the male’s wage increased her share by 630 ID ($0.50), while increases of 1 ID in the non-labour income increased female’s share by 0.43. The estimates showed that the disabled women decreased the share by 1275 ID ($1.08). Furthermore, the findings illustrated that considering the non-participation of the wife in the labour market, her share and therefore her bargaining power was lower than their earner counterparts

Politicising government engagement with corporate social responsibility: “CSR” as an empty signifier

Governments are widely viewed by academics and practitioners (and society more generally) as the key societal actors who are capable of compelling businesses to practice corporate social responsibility (CSR). Arguably, such government involvement could be seen as a technocratic device for encouraging ethical business behaviour. In this paper, we offer a more politicised interpretation of government engagement with CSR where “CSR” is not a desired form of business conduct but an element of discourse that governments can deploy in structuring their relationships with other social actors. We build our argument through a historical analysis of government CSR discourse in the Russian Federation. Laclau and Mouffe's (Hegemony and socialist strategy: Towards a radical democratic politics,Verso Books, London, 1985) social theory of hegemony underpins our research. We find that “CSR” in the Russian government’s discourse served to legitimise its power over large businesses. Using this case, we contribute to wider academic debates by providing fresh empirical evidence that allows the development of critical evaluation tools in relation to governments’ engagement with “CSR”. We find that governments are capable of hijacking CSR for their own self-interested gain. We close the paper by reflecting on the merit of exploring the case of the Russian Federation. As a “non-core”, non-western exemplar, it provides a useful “mirror” with which to reflect on the more widely used test-bed of Western industrial democracies when scrutinising CSR. Based on our findings, we invite other scholars to adopt a more critical, politicised stance when researching the role of governments in relation to CSR in other parts of the world

Toll-like receptor 4 signaling in liver injury and hepatic fibrogenesis

Toll-like receptors (TLRs) are a family of transmembrane pattern recognition receptors (PRR) that play a key role in innate and adaptive immunity by recognizing structural components unique to bacteria, fungi and viruses. TLR4 is the most studied of the TLRs, and its primary exogenous ligand is lipopolysaccharide, a component of Gram-negative bacterial walls. In the absence of exogenous microbes, endogenous ligands including damage-associated molecular pattern molecules from damaged matrix and injured cells can also activate TLR4 signaling. In humans, single nucleotide polymorphisms of the TLR4 gene have an effect on its signal transduction and on associated risks of specific diseases, including cirrhosis. In liver, TLR4 is expressed by all parenchymal and non-parenchymal cell types, and contributes to tissue damage caused by a variety of etiologies. Intact TLR4 signaling was identified in hepatic stellate cells (HSCs), the major fibrogenic cell type in injured liver, and mediates key responses including an inflammatory phenotype, fibrogenesis and anti-apoptotic properties. Further clarification of the function and endogenous ligands of TLR4 signaling in HSCs and other liver cells could uncover novel mechanisms of fibrogenesis and facilitate the development of therapeutic strategies

A supermatrix analysis of genomic, morphological, and paleontological data from crown Cetacea

<p>Abstract</p> <p>Background</p> <p>Cetacea (dolphins, porpoises, and whales) is a clade of aquatic species that includes the most massive, deepest diving, and largest brained mammals. Understanding the temporal pattern of diversification in the group as well as the evolution of cetacean anatomy and behavior requires a robust and well-resolved phylogenetic hypothesis. Although a large body of molecular data has accumulated over the past 20 years, DNA sequences of cetaceans have not been directly integrated with the rich, cetacean fossil record to reconcile discrepancies among molecular and morphological characters.</p> <p>Results</p> <p>We combined new nuclear DNA sequences, including segments of six genes (~2800 basepairs) from the functionally extinct Yangtze River dolphin, with an expanded morphological matrix and published genomic data. Diverse analyses of these data resolved the relationships of 74 taxa that represent all extant families and 11 extinct families of Cetacea. The resulting supermatrix (61,155 characters) and its sub-partitions were analyzed using parsimony methods. Bayesian and maximum likelihood (ML) searches were conducted on the molecular partition, and a molecular scaffold obtained from these searches was used to constrain a parsimony search of the morphological partition. Based on analysis of the supermatrix and model-based analyses of the molecular partition, we found overwhelming support for 15 extant clades. When extinct taxa are included, we recovered trees that are significantly correlated with the fossil record. These trees were used to reconstruct the timing of cetacean diversification and the evolution of characters shared by "river dolphins," a non-monophyletic set of species according to all of our phylogenetic analyses.</p> <p>Conclusions</p> <p>The parsimony analysis of the supermatrix and the analysis of morphology constrained to fit the ML/Bayesian molecular tree yielded broadly congruent phylogenetic hypotheses. In trees from both analyses, all Oligocene taxa included in our study fell outside crown Mysticeti and crown Odontoceti, suggesting that these two clades radiated in the late Oligocene or later, contra some recent molecular clock studies. Our trees also imply that many character states shared by river dolphins evolved in their oceanic ancestors, contradicting the hypothesis that these characters are convergent adaptations to fluvial habitats.</p

100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care — Preliminary Report

BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection. METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis. RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives. CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.)