We study gas flows with any finite number of thermal nonequilibrium modes. The equations describing such flows are a hyperbolic system with several relaxation equations. An important feature is ...entropy increase dictated by physics for any irreversible process. Under physical assumptions we obtain properties of thermodynamic variables relevant to stability. By the energy method we prove global existence and uniqueness for the Cauchy problem when the initial data are small perturbations of constant equilibrium states. We give a precise formulation of the fundamental solution for the linearized system, and use it to obtain large time behavior of solutions to the nonlinear system. In particular, we show that the entropy increases but stays bounded. The resulting asymptotic picture of nonequilibrium flows is in a pointwise sense both in space and in time.
Variation in DNA methylation (DNAm) is associated with lifestyle factors such as smoking and body mass index (BMI) but there has been little research exploring its ability to identify individuals ...with major depressive disorder (MDD). Using penalised regression on genome-wide CpG methylation, we tested whether DNAm risk scores (MRS), trained on 1223 MDD cases and 1824 controls, could discriminate between cases (n = 363) and controls (n = 1417) in an independent sample, comparing their predictive accuracy to polygenic risk scores (PRS). The MRS explained 1.75% of the variance in MDD (β = 0.338, p = 1.17 × 10
) and remained associated after adjustment for lifestyle factors (β = 0.219, p = 0.001, R
= 0.68%). When modelled alongside PRS (β = 0.384, p = 4.69 × 10
) the MRS remained associated with MDD (β = 0.327, p = 5.66 × 10
). The MRS was also associated with incident cases of MDD who were well at recruitment but went on to develop MDD at a later assessment (β = 0.193, p = 0.016, R
= 0.52%). Heritability analyses found additive genetic effects explained 22% of variance in the MRS, with a further 19% explained by pedigree-associated genetic effects and 16% by the shared couple environment. Smoking status was also strongly associated with MRS (β = 0.440, p ≤ 2 × 10
). After removing smokers from the training set, the MRS strongly associated with BMI (β = 0.053, p = 0.021). We tested the association of MRS with 61 behavioural phenotypes and found that whilst PRS were associated with psychosocial and mental health phenotypes, MRS were more strongly associated with lifestyle and sociodemographic factors. DNAm-based risk scores of MDD significantly discriminated MDD cases from controls in an independent dataset and may represent an archive of exposures to lifestyle factors that are relevant to the prediction of MDD.
Parent-of-origin effects (POE) exist when there is differential expression of alleles inherited from the two parents. A genome-wide scan for POE on DNA methylation at 639,238 CpGs in 5,101 ...individuals identifies 733 independent methylation CpGs potentially influenced by POE at a false discovery rate ≤ 0.05 of which 331 had not previously been identified. Cis and trans methylation quantitative trait loci (mQTL) regulate methylation variation through POE at 54% (399/733) of the identified POE-influenced CpGs. The combined results provide strong evidence for previously unidentified POE-influenced CpGs at 171 independent loci. Methylation variation at 14 of the POE-influenced CpGs is associated with multiple metabolic traits. A phenome-wide association analysis using the POE mQTL SNPs identifies a previously unidentified imprinted locus associated with waist circumference. These results provide a high resolution population-level map for POE on DNA methylation sites, their local and distant regulators and potential consequences for complex traits.
We consider a 2×2 system of hyperbolic-parabolic balance laws. Our system is the converted form under inverse Hopf-Cole transformation of a Keller-Segel type chemotaxis model with logistic growth, ...logarithmic sensitivity, non-diffusive chemical signal and density-dependent production/consumption rate. We study Cauchy problem when the Cauchy data are near a diffusive contact wave. The contact wave connects two different end-states as x→±∞, reflecting the situation when the logarithmic singularity plays an intrinsic role in the original chemotaxis model. We establish global existence of solution and study time asymptotic behavior of the solution. Consequently, we obtain nonlinear stability of the diffusive contact wave. Our result shows a significant difference when comparing our model to Euler equations with damping. In our case, there exists a secondary wave in the asymptotic ansatz. Therefore, the solution to Cauchy problem converges to the diffusive contact wave slower than in the case of Euler equations with damping. Besides its own physical relevance, our model is a prototype of a general system of hyperbolic-parabolic balance laws. Our results shed light on the future study of nonlinear stability of elementary waves for a general system.
This paper analyzes the impact of macroeconomic variables on house price volatility under different regimes of policy uncertainty, incorporating the Economic Policy Uncertainty Index and several ...Chinese macroeconomic data sets for the period from 1999 to 2014. We adopt a logistic smooth transition vector autoregressive model and a generalized impulse response function. The results show that macroeconomic progress leads to house price growth, which is augmented by policy uncertainty. In addition, the effect of macroeconomic shocks on house price volatility varies under different regimes of policy uncertainty. We find that shocks are asymmetric under regimes of high and low policy uncertainty. Under a high policy uncertainty regime, expansionary quantitative monetary policy can facilitate house price growth, whereas a contractionary monetary policy gives rise to an enduring "Home Price Puzzle," which makes it difficult to regulate house prices.
We consider a Keller–Segel type chemotaxis model with logarithmic sensitivity and logistic growth. The logarithmic singularity in the system is removed via the inverse Hopf–Cole transformation. We ...then linearize the system around a constant equilibrium state, and obtain a detailed, pointwise description of the Green’s function. The result provides a complete solution picture for the linear problem. It also helps to shed light on small solutions of the nonlinear system.
The variation in the rate at which humans age may be rooted in early events acting through the genomic regions that are influenced by such events and subsequently are related to health phenotypes in ...later life. The parent-of-origin-effect (POE)-regulated methylome includes regions enriched for genetically controlled imprinting effects (the typical type of POE) and regions influenced by environmental effects associated with parents (the atypical POE). This part of the methylome is heavily influenced by early events, making it a potential route connecting early exposures, the epigenome, and aging. We aim to test the association of POE-CpGs with early and later exposures and subsequently with health-related phenotypes and adult aging.
We perform a phenome-wide association analysis for the POE-influenced methylome using GS:SFHS (N
= 5087, N
= 4450). We identify and replicate 92 POE-CpG-phenotype associations. Most of the associations are contributed by the POE-CpGs belonging to the atypical class where the most strongly enriched associations are with aging (DNAmTL acceleration), intelligence, and parental (maternal) smoking exposure phenotypes. A proportion of the atypical POE-CpGs form co-methylation networks (modules) which are associated with these phenotypes, with one of the aging-associated modules displaying increased within-module methylation connectivity with age. The atypical POE-CpGs also display high levels of methylation heterogeneity, fast information loss with age, and a strong correlation with CpGs contained within epigenetic clocks.
These results identify the association between the atypical POE-influenced methylome and aging and provide new evidence for the "early development of origin" hypothesis for aging in humans.
To efficiently transform genetic associations into drug targets requires evidence that a particular gene, and its encoded protein, contribute causally to a disease. To achieve this, we employ a ...three-step proteome-by-phenome Mendelian Randomization (MR) approach. In step one, 154 protein quantitative trait loci (pQTLs) were identified and independently replicated. From these pQTLs, 64 replicated locally-acting variants were used as instrumental variables for proteome-by-phenome MR across 846 traits (step two). When its assumptions are met, proteome-by-phenome MR, is equivalent to simultaneously running many randomized controlled trials. Step 2 yielded 38 proteins that significantly predicted variation in traits and diseases in 509 instances. Step 3 revealed that amongst the 271 instances from GeneAtlas (UK Biobank), 77 showed little evidence of pleiotropy (HEIDI), and 92 evidence of colocalization (eCAVIAR). Results were wide ranging: including, for example, new evidence for a causal role of tyrosine-protein phosphatase non-receptor type substrate 1 (SHPS1; SIRPA) in schizophrenia, and a new finding that intestinal fatty acid binding protein (FABP2) abundance contributes to the pathogenesis of cardiovascular disease. We also demonstrated confirmatory evidence for the causal role of four further proteins (FGF5, IL6R, LPL, LTA) in cardiovascular disease risk.
Variation in obesity-related traits has a genetic basis with heritabilities between 40 and 70%. While the global obesity pandemic is usually associated with environmental changes related to lifestyle ...and socioeconomic changes, most genetic studies do not include all relevant environmental covariates, so the genetic contribution to variation in obesity-related traits cannot be accurately assessed. Some studies have described interactions between a few individual genes linked to obesity and environmental variables but there is no agreement on their total contribution to differences between individuals. Here we compared self-reported smoking data and a methylation-based proxy to explore the effect of smoking and genome-by-smoking interactions on obesity related traits from a genome-wide perspective to estimate the amount of variance they explain. Our results indicate that exploiting omic measures can improve models for complex traits such as obesity and can be used as a substitute for, or jointly with, environmental records to better understand causes of disease.
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