New insights into the genetic control of gene expression using a Bayesian multi-tissue approach.

The majority of expression quantitative trait locus (eQTL) studies have been carried out in single tissues or cell types, using methods that ignore information shared across tissues. Although global analysis of RNA expression in multiple tissues is now feasible, few integrated statistical frameworks for joint analysis of gene expression across tissues combined with simultaneous analysis of multiple genetic variants have been developed to date. Here, we propose Sparse Bayesian Regression models for mapping eQTLs within individual tissues and simultaneously across tissues. Testing these on a set of 2,000 genes in four tissues, we demonstrate that our methods are more powerful than traditional approaches in revealing the true complexity of the eQTL landscape at the systems-level. Highlighting the power of our method, we identified a two-eQTL model (cis/trans) for the Hopx gene that was experimentally validated and was not detected by conventional approaches. We showed common genetic regulation of gene expression across four tissues for ∼27% of transcripts, providing >5 fold increase in eQTLs detection when compared with single tissue analyses at 5% FDR level. These findings provide a new opportunity to uncover complex genetic regulatory mechanisms controlling global gene expression while the generality of our modelling approach makes it adaptable to other model systems and humans, with broad application to analysis of multiple intermediate and whole-body phenotypes

Nonlinear hydrodynamical evolution of rotating relativistic stars: Numerical methods and code tests

We present numerical hydrodynamical evolutions of rapidly rotating relativistic stars, using an axisymmetric, nonlinear relativistic hydrodynamics code. We use four different high-resolution shock-capturing (HRSC) finite-difference schemes (based on approximate Riemann solvers) and compare their accuracy in preserving uniformly rotating stationary initial configurations in long-term evolutions. Among these four schemes, we find that the third-order PPM scheme is superior in maintaining the initial rotation law in long-term evolutions, especially near the surface of the star. It is further shown that HRSC schemes are suitable for the evolution of perturbed neutron stars and for the accurate identification (via Fourier transforms) of normal modes of oscillation. This is demonstrated for radial and quadrupolar pulsations in the nonrotating limit, where we find good agreement with frequencies obtained with a linear perturbation code. The code can be used for studying small-amplitude or nonlinear pulsations of differentially rotating neutron stars, while our present results serve as testbed computations for three-dimensional general-relativistic evolution codes.Comment: 13 pages, 10 figures, submitted to MNRA

Intravital imaging of the kidney in a rat model of salt-sensitive hypertension

Hypertension is one of the most prevalent diseases worldwide and a major risk factor for renal failure and cardiovascular disease. The role of albuminuria, a common feature of hypertension and robust predictor of cardiorenal disorders, remains incompletely understood. The goal of this study was to investigate the mechanisms leading to albuminuria in the kidney of a rat model of hypertension, the Dahl salt-sensitive (SS) rat. To determine the relative contributions of the glomerulus and proximal tubule (PT) to albuminuria, we applied intravital two-photon-based imaging to investigate the complex renal physiological changes that occur during salt-induced hypertension. Following a high-salt diet, SS rats exhibited elevated blood pressure, increased glomerular sieving of albumin (GSCalb = 0.0686), relative permeability to albumin (+Δ16%), and impaired volume hemodynamics (-Δ14%). Serum albumin but not serum globulins or creatinine concentration was decreased (-0.54 g/dl), which was concomitant with increased filtration of albumin (3.7 vs. 0.8 g/day normal diet). Pathologically, hypertensive animals had significant tubular damage, as indicated by increased prevalence of granular casts, expansion and necrosis of PT epithelial cells (+Δ2.20 score/image), progressive augmentation of red blood cell velocity (+Δ269 µm/s) and micro vessel diameter (+Δ4.3 µm), and increased vascular injury (+Δ0.61 leakage/image). Therefore, development of salt-induced hypertension can be triggered by fast and progressive pathogenic remodeling of PT epithelia, which can be associated with changes in albumin handling. Collectively, these results indicate that both the glomerulus and the PT contribute to albuminuria, and dual treatment of glomerular filtration and albumin reabsorption may represent an effective treatment of salt-sensitive hypertension

Three-dimensional general relativistic hydrodynamics II: long-term dynamics of single relativistic stars

This is the second in a series of papers on the construction and validation of a three-dimensional code for the solution of the coupled system of the Einstein equations and of the general relativistic hydrodynamic equations, and on the application of this code to problems in general relativistic astrophysics. In particular, we report on the accuracy of our code in the long-term dynamical evolution of relativistic stars and on some new physics results obtained in the process of code testing. The tests involve single non-rotating stars in stable equilibrium, non-rotating stars undergoing radial and quadrupolar oscillations, non-rotating stars on the unstable branch of the equilibrium configurations migrating to the stable branch, non-rotating stars undergoing gravitational collapse to a black hole, and rapidly rotating stars in stable equilibrium and undergoing quasi-radial oscillations. The numerical evolutions have been carried out in full general relativity using different types of polytropic equations of state using either the rest-mass density only, or the rest-mass density and the internal energy as independent variables. New variants of the spacetime evolution and new high resolution shock capturing (HRSC) treatments based on Riemann solvers and slope limiters have been implemented and the results compared with those obtained from previous methods. Finally, we have obtained the first eigenfrequencies of rotating stars in full general relativity and rapid rotation. A long standing problem, such frequencies have not been obtained by other methods. Overall, and to the best of our knowledge, the results presented in this paper represent the most accurate long-term three-dimensional evolutions of relativistic stars available to date.Comment: 19 pages, 17 figure

The social and political lives of zoonotic disease models: Narratives, science and policy

Zoonotic diseases currently pose both major health threats and complex scientific and policy challenges, to which modelling is increasingly called to respond. In this article we argue that the challenges are best met by combining multiple models and modelling approaches that elucidate the various epidemiological, ecological and social processes at work. These models should not be understood as neutral science informing policy in a linear manner, but as having social and political lives: social, cultural and political norms and values that shape their development and which they carry and project. We develop and illustrate this argument in relation to the cases of H5N1 avian influenza and Ebola, exploring for each the range of modelling approaches deployed and the ways they have been co-constructed with a particular politics of policy. Addressing the complex, uncertain dynamics of zoonotic disease requires such social and political lives to be made explicit in approaches that aim at triangulation rather than integration, and plural and conditional rather than singular forms of policy advice.ESR

US Cosmic Visions: New Ideas in Dark Matter 2017: Community Report

This white paper summarizes the workshop "U.S. Cosmic Visions: New Ideas in Dark Matter" held at University of Maryland on March 23-25, 2017.Comment: 102 pages + reference

Genetic, physiological and comparative genomic studies of hypertension and insulin resistance in the spontaneously hypertensive rat

We previously mapped hypertension-related insulin resistance quantitative trait loci (QTLs) to rat chromosomes 4, 12 and 16 using adipocytes from F2 crosses between spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats, and subsequently identified Cd36 as the gene underlying the chromosome 4 locus. The identity of the chromosome 12 and 16 genes remains unknown. To identify whole-body phenotypes associated with the chromosome 12 and 16 linkage regions, we generated and characterised new congenic strains, with WKY donor segments introgressed onto an SHR genetic background, for the chromosome 12 and 16 linkage regions. We found a >50% increase in insulin sensitivity in both the chromosome 12 and 16 strains. Blood pressure and left ventricular mass were reduced in the two congenic strains consistent with the congenic segments harbouring SHR genes for insulin resistance, hypertension and cardiac hypertrophy. Integrated genomic analysis, using physiological and whole-genome sequence data across 42 rat strains, identified variants within the congenic regions in Upk3bl, RGD1565131 and AABR06087018.1 that were associated with blood pressure, cardiac mass and insulin sensitivity. Quantitative trait transcript analysis across 29 recombinant inbred strains showed correlation between expression of Hspb1, Zkscan5 and Pdgfrl with adipocyte volume, systolic blood pressure and cardiac mass, respectively. Comparative genome analysis showed a marked enrichment of orthologues for human GWAS-associated genes for insulin resistance within the syntenic regions of both the chromosome 12 and 16 congenic intervals. Our study defines whole-body phenotypes associated with the SHR chromosome 12 and 16 insulin-resistance QTLs, identifies candidate genes for these SHR QTLs and finds human orthologues of rat genes in these regions that associate with related human traits. Further study of these genes in the congenic strains will lead to robust identification of the underlying genes and cellular mechanisms

Dopamine D4 Receptor Gene Associated with Fairness Preference in Ultimatum Game

In experimental economics, the preference for reciprocal fairness has been observed in the controlled and incentivized laboratory setting of the ultimatum game, in which two individuals decide on how to divide a sum of money, with one proposing the share while the second deciding whether to accept. Should the proposal be accepted, the amount is divided accordingly. Otherwise, both would receive no money. A recent twin study has shown that fairness preference inferred from responder behavior is heritable, yet its neurogenetic basis remains unknown. The D4 receptor (DRD4) exon3 is a well-characterized functional polymorphism, which is known to be associated with attention deficit hyperactivity disorder and personality traits including novelty seeking and self-report altruism. Applying a neurogenetic approach, we find that DRD4 is significantly associated with fairness preference. Additionally, the interaction among this gene, season of birth, and gender is highly significant. This is the first result to link preference for reciprocal fairness to a specific gene and suggests that gene × environment interactions contribute to economic decision making

Interpreting Precessionâ Driven δ18O Variability in the South Asian Monsoon Region

Speleothem records from the South Asian summer monsoon (SASM) region display variability in the ratio of 18O and 16O (δ18O) in calcium carbonate at orbital frequencies. The dominant mode of variability in many of these records reflects cycles of precession. There are several potential explanations for why SASM speleothem records show a strong precession signal, including changes in temperature, precipitation, and circulation. Here we use an Earth system model with water isotope tracers and waterâ tagging capability to deconstruct the precession signal found in SASM speleothem records. Our results show that cycles of precessionâ eccentricity produce changes in SASM intensity that correlate with local temperature, precipitation, and δ18O. However, neither the amount effect nor temperature differences are responsible for the majority of the SASM δ18O variability. Instead, changes in the relative moisture contributions from different source regions drive much of the SASM δ18O signal, with more nearby moisture sources during Northern Hemisphere summer at aphelion and more distant moisture sources during Northern Hemisphere summer at perihelion. Further, we find that evaporation amplifies the δ18O signal of soil water relative to that of precipitation, providing a better match with the SASM speleothem records. This work helps explain a significant portion of the longâ term variability found in SASM speleothem records.Plain Language SummaryCave records suggest that there has been significant longâ term climate variability in India related to changes in Earth’s orbit. However, these records are difficult to interpret because the signals can represent several different climate responses. Here we use a climate model that directly simulates the isotopic data captured in the cave records to better interpret their physical meaning. From these model simulations, we show that a large portion of the orbital signals found in the cave records are due to changes in the amount of water vapor coming from different sources. Changes in the amount of local evaporation compared to precipitation also have a large effect on the signals found in the cave records.Key PointsAn Earth system model with stable water isotope tracers is used to examine precessionâ driven variability of the South Asian monsoonSouth Asian monsoon variability in δ18O of precipitation is due to changes in the amount of moisture sourced from different regionsUsing simulated δ18O of soil water improves modelâ speleothem signal agreementPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144678/1/jgrd54673_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144678/2/jgrd54673.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144678/3/jgrd54673-sup-0001-SASM_draft_AGU_format_Supp_revised_6-4.pd