Integration of disease-specific single nucleotide polymorphisms, expression quantitative trait loci and coexpression networks reveal novel candidate genes for type 2 diabetes.

Aims/hypothesisWhile genome-wide association studies (GWASs) have been successful in identifying novel variants associated with various diseases, it has been much more difficult to determine the biological mechanisms underlying these associations. Expression quantitative trait loci (eQTL) provide another dimension to these data by associating single nucleotide polymorphisms (SNPs) with gene expression. We hypothesised that integrating SNPs known to be associated with type 2 diabetes with eQTLs and coexpression networks would enable the discovery of novel candidate genes for type 2 diabetes.MethodsWe selected 32 SNPs associated with type 2 diabetes in two or more independent GWASs. We used previously described eQTLs mapped from genotype and gene expression data collected from 1,008 morbidly obese patients to find genes with expression associated with these SNPs. We linked these genes to coexpression modules, and ranked the other genes in these modules using an inverse sum score.ResultsWe found 62 genes with expression associated with type 2 diabetes SNPs. We validated our method by linking highly ranked genes in the coexpression modules back to SNPs through a combined eQTL dataset. We showed that the eQTLs highlighted by this method are significantly enriched for association with type 2 diabetes in data from the Wellcome Trust Case Control Consortium (WTCCC, p = 0.026) and the Gene Environment Association Studies (GENEVA, p = 0.042), validating our approach. Many of the highly ranked genes are also involved in the regulation or metabolism of insulin, glucose or lipids.Conclusions/interpretationWe have devised a novel method, involving the integration of datasets of different modalities, to discover novel candidate genes for type 2 diabetes

Per-Core DVFS with Switched-Capacitor Converters for Energy Efficiency in Manycore Processors

Integrating multiple power converters on-chip improves energy efficiency of manycore architectures. Switched-capacitor (SC) dc-dc converters are compatible with conventional CMOS processes, but traditional implementations suffer from limited conversion efficiency. We propose a dynamic voltage and frequency scaling scheme with SC converters that achieves high converter efficiency by allowing the output voltage to ripple and having the processor core frequency track the ripple. Minimum core energy is achieved by hopping between different converter modes and tuning body-bias voltages. A multicore processor model based on a 28-nm technology shows conversion efficiencies of 90% along with over 25% improvement in the overall chip energy efficiency

A RISC-V Vector Processor With Simultaneous-Switching Switched-Capacitor DC-DC Converters in 28 nm FDSOI

This work demonstrates a RISC-V vector microprocessor implemented in 28 nm FDSOI with fully integrated simultaneous-switching switched-capacitor DC-DC (SC DC-DC) converters and adaptive clocking that generates four on-chip voltages between 0.45 and 1 V using only 1.0 V core and 1.8 V IO voltage inputs. The converters achieve high efficiency at the system level by switching simultaneously to avoid charge-sharing losses and by using an adaptive clock to maximize performance for the resulting voltage ripple. Details about the implementation of the DC-DC switches, DC-DC controller, and adaptive clock are provided, and the sources of conversion loss are analyzed based on measured results. This system pushes the capabilities of dynamic voltage scaling by enabling fast transitions (20 ns), simple packaging (no off-chip passives), low area overhead (16%), high conversion efficiency (80%-86%), and high energy efficiency (26.2 DP GFLOPS/W) for mobile devices

Free-algebra functors from a coalgebraic perspective

Given a set $\Sigma$ of equations, the free-algebra functor $F_{\Sigma}$ associates to each set $X$ of variables the free algebra $F_{\Sigma}(X)$ over $X$. Extending the notion of \emph{derivative} $\Sigma'$ for an arbitrary set $\Sigma$ of equations, originally defined by Dent, Kearnes, and Szendrei, we show that $F_\Sigma$ preserves preimages if and only if $\Sigma \vdash \Sigma'$, i.e. $\Sigma$ derives its derivative $\Sigma'$. If $F_\Sigma$ weakly preserves kernel pairs, then every equation $p(x,x,y)=q(x,y,y)$ gives rise to a term $s(x,y,z,u)$ such that $p(x,y,z)=s(x,y,z,z)$ and $q(x,y,z)=s(x,x,y,z)$. In this case n-permutable varieties must already be permutable, i.e. Mal'cev. Conversely, if $\Sigma$ defines a Mal'cev variety, then $F_\Sigma$ weakly preserves kernel pairs. As a tool, we prove that arbitrary $Set-$endofunctors $F$ weakly preserve kernel pairs if and only if they weakly preserve pullbacks of epis

The Friedmann-Lemaitre-Robertson-Walker Big Bang singularities are well behaved

We show that the Big Bang singularity of the Friedmann-Lemaitre-Robertson-Walker model does not raise major problems to General Relativity. We prove a theorem showing that the Einstein equation can be written in a non-singular form, which allows the extension of the spacetime before the Big Bang. The physical interpretation of the fields used is discussed. These results follow from our research on singular semi-Riemannian geometry and singular General Relativity.Comment: 10 pages, 5 figure

Pyrimidine biosynthesis is not an essential function for trypanosoma brucei bloodstream forms

<p>Background: African trypanosomes are capable of both pyrimidine biosynthesis and salvage of preformed pyrimidines from the host, but it is unknown whether either process is essential to the parasite.</p> <p>Methodology/Principal Findings: Pyrimidine requirements for growth were investigated using strictly pyrimidine-free media, with or without single added pyrimidine sources. Growth rates of wild-type bloodstream form Trypanosoma brucei brucei were unchanged in pyrimidine-free medium. The essentiality of the de novo pyrimidine biosynthesis pathway was studied by knocking out the PYR6-5 locus that produces a fusion product of orotate phosphoribosyltransferase (OPRT) and Orotidine Monophosphate Decarboxylase (OMPDCase). The pyrimidine auxotroph was dependent on a suitable extracellular pyrimidine source. Pyrimidine starvation was rapidly lethal and non-reversible, causing incomplete DNA content in new cells. The phenotype could be rescued by addition of uracil; supplementation with uridine, 2′deoxyuridine, and cytidine allowed a diminished growth rate and density. PYR6-5−/− trypanosomes were more sensitive to pyrimidine antimetabolites and displayed increased uracil transport rates and uridine phosphorylase activity. Pyrimidine auxotrophs were able to infect mice although the infection developed much more slowly than infection with the parental, prototrophic trypanosome line.</p> <p>Conclusions/Significance: Pyrimidine salvage was not an essential function for bloodstream T. b. brucei. However, trypanosomes lacking de novo pyrimidine biosynthesis are completely dependent on an extracellular pyrimidine source, strongly preferring uracil, and display reduced infectivity. As T. brucei are able to salvage sufficient pyrimidines from the host environment, the pyrimidine biosynthesis pathway is not a viable drug target, although any interruption of pyrimidine supply was lethal.</p&gt

Geodesic Flow on the Diffeomorphism Group of the circle

We show that certain right-invariant metrics endow the infinite-dimensional Lie group of all smooth orientation-preserving diffeomorphisms of the circle with a Riemannian structure. The study of the Riemannian exponential map allows us to prove infinite-dimensional counterparts of results from classical Riemannian geometry: the Riemannian exponential map is a smooth local diffeomorphism and the length-minimizing property of the geodesics holds.Comment: 15 page

Towards an analytical framework of science communication models

This chapter reviews the discussion in science communication circles of models for public communication of science and technology (PCST). It questions the claim that there has been a large-scale shift from a ‘deficit model’ of communication to a ‘dialogue model’, and it demonstrates the survival of the deficit model along with the ambiguities of that model. Similar discussions in related fields of communication, including the critique of dialogue, are briefly sketched. Outlining the complex circumstances governing approaches to PCST, the author argues that communications models often perceived to be opposed can, in fact, coexist when the choices are made explicit. To aid this process, the author proposes an analytical framework of communication models based on deficit, dialogue and participation, including variations on each

Optimising infection prevention and control practice using behavior change: a systematic review

Despite significant investment in infection prevention and control (IPC), there has been little consideration of the effectiveness of behaviour change interventions or the application of behavioural theory (BT) or social marketing (SM) to influence healthcare workers' (HCWs) behaviour and to reduce healthcare associated infection

Amelioration of bleomycin-induced lung fibrosis in hamsters by dietary supplementation with taurine and niacin: biochemical mechanisms.

Interstitial pulmonary fibrosis induced by intratracheal instillation of bleomycin (BL) involves an excess production of reactive oxygen species, unavailability of adequate levels of NAD and ATP to repair the injured pulmonary epithelium, and an overexuberant lung collagen reactivity followed by deposition of highly cross-linked mature collagen fibrils resistant to enzymatic degradation. In the present study, we have demonstrated that dietary supplementation with taurine and niacin offered almost complete protection against the lung fibrosis in a multidose BL hamster model. The mechanisms for the protective effect of taurine and niacin are multifaceted. These include the ability of taurine to scavenge HOCl and stabilize the biomembrane; niacin's ability to replenish the BL-induced depletion of NAD and ATP; and the combined effect of taurine and niacin to suppress all aspects of BL-induced increases in the lung collagen reactivity, a hallmark of interstitial pulmonary fibrosis. It was concluded from the data presented at this Conference that the combined treatment with taurine and niacin, which offers a multipronged approach, will have great therapeutic potential in the intervention of the development of chemically induced interstitial lung fibrosis in animals and humans