The role of common genetic variants for predicting the modulation of cardiovascular outcomes

Attrition is a major issue in the drug development process with 79% of clinical failures due to safety and efficacy concerns. Genetic research can provide supporting evidence of a clear causal relationship between the drug target and disease or reveal unintended effects through associations with non-relevant phenotypes informing on potential drug safety. However, due to the underlying genetic architecture, it is often unclear which gene or variant in the loci identified through genetic analyses is driving the association. Due to recent advancements in CRISPR-Cas9 gene-editing, it is now possible to relatively easily perform whole gene knock-out studies and single base-edits to validate genetic findings of the most likely causal variant and gene. Utilising a combination of genetic approaches and functional studies can provide supporting evidence of the therapeutic profile and potential effects of drug therapies and improve our overall understanding of biological pathways and disease mechanisms. The primary aim of this thesis is to provide genetic data to support the ongoing clinical development of hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitors (PHIs) for treating anaemia of chronic kidney disease (CKD). Genome-wide association studies (GWAS) were used to identify genetic variants lying within or nearby genes encoding the drug target (prolyl hydroxylase [PHD] enzymes). These identified variants were used in Mendelian Randomisation analysis and phenome-wide association studies to genetically mirror the pharmaceutical effects of PHIs and investigate cardiovascular safety. Functional validation studies were employed to functionally validate a genetic variant for use as a proxy and to obtain a better understanding of the downstream causal pathways and biological mechanisms of the drug target. In summary, this thesis demonstrates how a combination of genetic analyses and functional validation studies is a powerful approach to validate GWAS results and further characterise therapeutic effects. This PhD project identified relevant genetic markers to genetically proxy therapeutic modulation of biomarker levels through PHD inhibition and could potentially inform further research using patient-level clinical data from Phase III trials

Cobalt base superalloy has outstanding properties up to 1478 K (2200 F)

Alloy VM-103 is especially promising for use in applications requiring short time exposure to very high temperatures. Its properties over broad range of temperatures are superior to those of comparable commercial wrought cobalt-base superalloys, L-605 and HS-188

Burst avalanches in solvable models of fibrous materials

We review limiting models for fracture in bundles of fibers, with statistically distributed thresholds for breakdown of individual fibers. During the breakdown process, avalanches consisting of simultaneous rupture of several fibers occur, and the distribution $D(\Delta)$ of the magnitude $\Delta$ of such avalanches is the central characteristics in our analysis. For a bundle of parallel fibers two limiting models of load sharing are studied and contrasted: the global model in which the load carried by a bursting fiber is equally distributed among the surviving members, and the local model in which the nearest surviving neighbors take up the load. For the global model we investigate in particular the conditions on the threshold distribution which would lead to anomalous behavior, i.e. deviations from the asymptotics $D(\Delta) \sim \Delta^{-5/2}$, known to be the generic behavior. For the local model no universal power-law asymptotics exists, but we show for a particular threshold distribution how the avalanche distribution can nevertheless be explicitly calculated in the large-bundle limit.Comment: 28 pages, RevTeX, 3 Postscript figure

Research Note:<br>Derivation of temperature lapse rates in semi-arid south-eastern Arizona

International audienceEcological and hydrological modelling at the regional scale requires distributed information on weather variables, and temperature is important among these. In an area of basin and range topography with a wide range of elevations, such as south-eastern Arizona, measurements are usually available only at a relatively small number of locations and elevations, and temperatures elsewhere must be estimated from atmospheric lapse rate. This paper derives the lapse rates to estimate maximum, minimum and mean daily temperatures from elevation. Lapse rates were calculated using air temperatures at 2 m collected during 2002 at 18 locations across south-eastern Arizona, with elevations from 779 to 2512 m. The lapse rate predicted for the minimum temperature was lower than the mean environmental lapse rate (MELR), i.e. 6 K km?1, whereas those predicted for the mean and maximum daily temperature were very similar to the MELR. Lapse rates were also derived from radiosonde data at 00 and 12 UTC (5 pm and 5 am local time, respectively). The lapse rates calculated from radiosonde data were greater than those from the 2 m measurements, presumably because the effect of the surface was less. Given temperatures measured at Tucson airport, temperatures at the other sites were predicted using the different estimates of lapse rates. The best predictions of temperatures used the locally predicted lapse rates. In the case of maximum and mean temperature, using the MELR also resulted in accurate predictions. Keywords: near surface lapse rates, semi-arid climate, mean minimum and maximum temperatures, basin and range topograph

Gender Attitudes and Fertility Aspirations among Young Men in Five High Fertility East African Countries

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97275/1/j.1728-4465.2013.00341.x.pd

Bayesian and maximum likelihood phylogenetic analyses of protein sequence data under relative branch-length differences and model violation

BACKGROUND: Bayesian phylogenetic inference holds promise as an alternative to maximum likelihood, particularly for large molecular-sequence data sets. We have investigated the performance of Bayesian inference with empirical and simulated protein-sequence data under conditions of relative branch-length differences and model violation. RESULTS: With empirical protein-sequence data, Bayesian posterior probabilities provide more-generous estimates of subtree reliability than does the nonparametric bootstrap combined with maximum likelihood inference, reaching 100% posterior probability at bootstrap proportions around 80%. With simulated 7-taxon protein-sequence datasets, Bayesian posterior probabilities are somewhat more generous than bootstrap proportions, but do not saturate. Compared with likelihood, Bayesian phylogenetic inference can be as or more robust to relative branch-length differences for datasets of this size, particularly when among-sites rate variation is modeled using a gamma distribution. When the (known) correct model was used to infer trees, Bayesian inference recovered the (known) correct tree in 100% of instances in which one or two branches were up to 20-fold longer than the others. At ratios more extreme than 20-fold, topological accuracy of reconstruction degraded only slowly when only one branch was of relatively greater length, but more rapidly when there were two such branches. Under an incorrect model of sequence change, inaccurate trees were sometimes observed at less extreme branch-length ratios, and (particularly for trees with single long branches) such trees tended to be more inaccurate. The effect of model violation on accuracy of reconstruction for trees with two long branches was more variable, but gamma-corrected Bayesian inference nonetheless yielded more-accurate trees than did either maximum likelihood or uncorrected Bayesian inference across the range of conditions we examined. Assuming an exponential Bayesian prior on branch lengths did not improve, and under certain extreme conditions significantly diminished, performance. The two topology-comparison metrics we employed, edit distance and Robinson-Foulds symmetric distance, yielded different but highly complementary measures of performance. CONCLUSIONS: Our results demonstrate that Bayesian inference can be relatively robust against biologically reasonable levels of relative branch-length differences and model violation, and thus may provide a promising alternative to maximum likelihood for inference of phylogenetic trees from protein-sequence data

The Influence of PCl 3 on Planarisation and Selectivity of InP Regrowth by Atmospheric Pressure MOVPE

The introduction of phosphorus trichloride into the AP-MOVPE growth of InP has been found to dramatically improve the regrowth adjacent to mesa structures. By suppressing growth in the [100] direction and enhancing growth in the [311] directions planar regrowth is achieved. Polycrystalline deposits on dielectric masks can also be completely suppresse

Sodium and Water Fluxes in Free-Living Crocodylus Porosus in Marine and Brackish Conditions

Radioactive sodium and water were used to determine total body water (TBW), exchangeable sodium (ExNa) and water and sodium fluxes in free-living Crocodylus porosus in marine (hyperosmotic; salinity = 250/00-350/00) and brackish (hypoosmotic; salinity = 20/00-7.50/00) sections of the Tomkinson River in northern Australia. At capture, size-corrected TBW and ExNa pools in 62 crocodiles (hatchlings, juveniles, and subadults; weight, 0.108-54.4 kg) were independent of salinity history. To determine fluxes, all animals were released at their capture sites and left undisturbed until recapture. Thirty-seven were recaptured after 7-18 days. Fifteen of the 17 hatchlings recaptured from both salinity categories grew and maintained their condition and hydration status. In contrast, all 20 juveniles and subadults lost weight in the same period, and juveniles in hyperosmotic conditions showed significantly lower hydration and condition factors. Water effluxes in hatchlings were ~80 and ~160 ml kg-0.63 day-1 in marine and brackish conditions, respectively. Comparable sodium effluxes were 7.5 and 4.4 mmol kg-0.63 day1. All crocodiles in hyperosmotic conditions had consistently lower water effluxes (~ X0.5) and higher sodium effluxes (~ X 1.6) than did crocodiles in brackish water. In both salinity categories, hatchlings had greater water turnover (~ X 1.3, X 1.6) and sodium turnover (~ X 1.5, X 1.25) than did juveniles and subadults. Interpretation of the field data is complicated by integumentary exchange of sodium and water, a size-related aphagia apparently induced by disturbance, and difficulties of adjusting for allometric differences across a wide range of sizes. Nevertheless, it is clear that C. porosus is able to effect considerable economies of water turnover in hyperosmotic salt water and that the secretory capacity of the lingual glands, as measured in the laboratory, is more than enough to account for the highest sodium effluxes that we measured in C. porosus in the field

Cloning and expression of a mammalian peptide chain release factor with sequence similarity to tryptophanyl-tRNA synthetases

The termination of protein synthesis is encoded by in-frame nonsense (stop) codons. Most organisms use three nonsense codons: UGA, UAG, and UAA. In contrast to sense codons, which are decoded by specific tRNAs, nonsense codons are decoded by proteins called release factors (RFs). Here we report the cloning of a mammalian RF cDNA by the use of monoclonal antibodies specific for rabbit RF. Functional studies showed that, when expressed in Escherichia coli, the protein encoded by this cDNA has in vitro biochemical characteristics similar to those of previously characterized mammalian RFs. DNA sequencing of this eukaryotic RF cDNA revealed a remarkable sequence similarity to bacterial and mitochondrial tryptophanyl-tRNA synthetases, with the greatest similarity confined to the synthetase active site, and no obvious similarity to bacterial RFs