Genetic Association Analysis of Complex Diseases Incorporating Intermediate Phenotype Information

Genetic researchers often collect disease related quantitative traits in addition to disease status because they are interested in understanding the pathophysiology of disease processes. In genome-wide association (GWA) studies, these quantitative phenotypes may be relevant to disease development and serve as intermediate phenotypes or they could be behavioral or other risk factors that predict disease risk. Statistical tests combining both disease status and quantitative risk factors should be more powerful than case-control studies, as the former incorporates more information about the disease. In this paper, we proposed a modified inverse-variance weighted meta-analysis method to combine disease status and quantitative intermediate phenotype information. The simulation results showed that when an intermediate phenotype was available, the inverse-variance weighted method had more power than did a case-control study of complex diseases, especially in identifying susceptibility loci having minor effects. We further applied this modified meta- analysis to a study of imputed lung cancer genotypes with smoking data in 1154 cases and 1137 matched controls. The most significant SNPs came from the CHRNA3-CHRNA5-CHRNB4 region on chromosome 15q24–25.1, which has been replicated in many other studies. Our results confirm that this CHRNA region is associated with both lung cancer development and smoking behavior. We also detected three significant SNPs—rs1800469, rs1982072, and rs2241714—in the promoter region of the TGFB1 gene on chromosome 19 (p = 1.46 X 10-5,1.18 X 10-5, and 6.57 X 10-6, respectively). The SNP rs1800469 is reported to be associated with chronic obstructive pulmonary disease and lung cancer in cigarette smokers. The present study is the first GWA study to replicate this result. Signals in the 3q26 region were also identified in the meta-analysis. We demonstrate the intermediate phenotype can potentially enhance the power of complex disease association analysis and the modified meta-analysis method is robust to incorporate intermediate phenotype or other quantitative risk factor in the analysis

Phenotypic and transcriptional analysis of the osmotic regulator OmpR in Yersinia pestis

<p>Abstract</p> <p>Background</p> <p>The osmotic regulator OmpR in <it>Escherichia coli </it>regulates differentially the expression of major porin proteins OmpF and OmpC. In <it>Yersinia enterocolitica </it>and <it>Y. pseudotuberculosis</it>, OmpR is required for both virulence and survival within macrophages. However, the phenotypic and regulatory roles of OmpR in <it>Y. pestis </it>are not yet fully understood.</p> <p>Results</p> <p><it>Y. pestis </it>OmpR is involved in building resistance against phagocytosis and controls the adaptation to various stressful conditions met in macrophages. The <it>ompR </it>mutation likely did not affect the virulence of <it>Y. pestis </it>strain 201 that was a human-avirulent enzootic strain. The microarray-based comparative transcriptome analysis disclosed a set of 224 genes whose expressions were affected by the <it>ompR </it>mutation, indicating the global regulatory role of OmpR in <it>Y. pestis</it>. Real-time RT-PCR or <it>lacZ </it>fusion reporter assay further validated 16 OmpR-dependent genes, for which OmpR consensus-like sequences were found within their upstream DNA regions. <it>ompC</it>, <it>F</it>, <it>X</it>, and <it>R </it>were up-regulated dramatically with the increase of medium osmolarity, which was mediated by OmpR occupying the target promoter regions in a tandem manner.</p> <p>Conclusion</p> <p>OmpR contributes to the resistance against phagocytosis or survival within macrophages, which is conserved in the pathogenic yersiniae. <it>Y. pestis </it>OmpR regulates <it>ompC</it>, <it>F</it>, <it>X</it>, and <it>R </it>directly through OmpR-promoter DNA association. There is an inducible expressions of the pore-forming proteins OmpF, C, and × at high osmolarity in <it>Y. pestis</it>, in contrast to the reciprocal regulation of them in <it>E. coli</it>. The main difference is that <it>ompF </it>expression is not repressed at high osmolarity in <it>Y. pestis</it>, which is likely due to the absence of a promoter-distal OmpR-binding site for <it>ompF</it>.</p

Regulatory effects of cAMP receptor protein (CRP) on porin genes and its own gene in Yersinia pestis

<p>Abstract</p> <p>Background</p> <p>The cAMP receptor protein (CRP) is a global bacterial regulator that controls many target genes. The CRP-cAMP complex regulates the <it>ompR-envZ </it>operon in <it>E. coli </it>directly, involving both positive and negative regulations of multiple target promoters; further, it controls the production of porins indirectly through its direct action on <it>ompR-envZ</it>. Auto-regulation of CRP has also been established in <it>E. coli</it>. However, the regulation of porin genes and its own gene by CRP remains unclear in <it>Y. pestis</it>.</p> <p>Results</p> <p><it>Y. pestis </it>employs a distinct mechanism indicating that CRP has no regulatory effect on the <it>ompR-envZ </it>operon; however, it stimulates <it>ompC </it>and <it>ompF </it>directly, while repressing <it>ompX</it>. No transcriptional regulatory association between CRP and its own gene can be detected in <it>Y. pestis</it>, which is also in contrast to the fact that CRP acts as both repressor and activator for its own gene in <it>E. coli</it>. It is likely that <it>Y. pestis </it>OmpR and CRP respectively sense different signals (medium osmolarity, and cellular cAMP levels) to regulate porin genes independently.</p> <p>Conclusion</p> <p>Although the CRP of <it>Y. pestis </it>shows a very high homology to that of <it>E. coli</it>, and the consensus DNA sequence recognized by CRP is shared by the two bacteria, the <it>Y. pestis </it>CRP can recognize the promoters of <it>ompC</it>, <it>F</it>, and <it>X </it>directly rather than that of its own gene, which is different from the relevant regulatory circuit of <it>E. coli</it>. Data presented here indicate a remarkable remodeling of the CRP-mediated regulation of porin genes and of its own one between these two bacteria.</p

Enhancing Winter Climate Simulations of the Great Lakes: Insights from a New Coupled Lake-Ice-Atmosphere (CLIAv1) Model on the Importance of Integrating 3D Hydrodynamics with a Regional Climate Model

The Laurentian Great Lakes significantly influence the climate of the Midwest and Northeast United States, due to their vast thermal inertia, moisture source potential, and unique heat and moisture flux dynamics. This study presents a newly developed coupled lake-ice-atmosphere (CLIAv1) modeling system for the Great Lakes by coupling the National Aeronautics and Space Administration (NASA)-Unified Weather Research and Forecasting (NU-WRF) regional climate model (RCM) with the three-dimensional (3D) Finite Volume Community Ocean Model (FVCOM) and investigates the impact of coupled dynamics on simulating the Great Lakes' winter climate. By integrating 3D lake hydrodynamics, CLIAv1 addresses the limitations of traditional one-dimensional (1D) lake and demonstrates superior performance in reproducing observed LSTs, ice cover distribution, and the vertical thermal structure of the Great Lakes compared to the NU-WRF model coupled with the default 1D Lake Ice Snow and Sediment Simulator (LISSS). CLIAv1 also enhances simulation of over-lake atmospheric conditions, including air temperature, wind speed, and sensible and latent heat fluxes, underscoring the importance of resolving complex lake dynamics for reliable climate projections. More importantly, this study addresses the crucial question about what are the key processes influencing lake thermal structure and ice cover that are missed by 1D lake models but effectively captured by 3D lake models. Through process-oriented numerical experiments, we identify key 3D hydrodynamic processes &ndash; ice transport, heat advection, and shear production in turbulence &ndash; that explain the superiority of 3D lake models over 1D lake models, particularly in cold season performance and lake-atmosphere interactions. Properly resolving these processes using 3D hydrodynamic model is crucial for successfully simulating the lake-ice-atmosphere coupled Great Lakes winter system. This research underscores the necessity of incorporating 3D hydrodynamic models in RCMs to improve our predictive understanding of the Great Lakes' response to climate change. The findings advocate for a shift towards high-resolution, physics-based modeling approaches to ensure accurate future climate and limnological projections for large freshwater systems

Long-term trends and drivers of aerosol pH in eastern China

Aerosol acidity plays a key role in regulating the chemistry and toxicity of atmospheric aerosol particles. The trend of aerosol pH and its drivers is crucial in understanding the multiphase formation pathways of aerosols. Here, we reported the first trend analysis of aerosol pH from 2011 to 2019 in eastern China, calculated with the ISORROPIA model based on observed gas and aerosol compositions. The implementation of the Air Pollution Prevention and Control Action Plan led to −35.8 %, −37.6 %, −9.6 %, −81.0 % and 1.2 % changes of PM2.5, SO42-, NHx, non-volatile cations (NVCs) and NO3- in the Yangtze River Delta (YRD) region during this period. Different from the drastic changes of aerosol compositions due to the implementation of the Air Pollution Prevention and Control Action Plan, aerosol pH showed a minor change of −0.24 over the 9 years. Besides the multiphase buffer effect, the opposite effects from the changes of SO42- and non-volatile cations played key roles in determining this minor pH trend, contributing to a change of +0.38 and −0.35, respectively. Seasonal variations in aerosol pH were mainly driven by the temperature, while the diurnal variations were driven by both temperature and relative humidity. In the future, SO2, NOx and NH3 emissions are expected to be further reduced by 86.9 %, 74.9 % and 41.7 % in 2050 according to the best health effect pollution control scenario (SSP1-26-BHE). The corresponding aerosol pH in eastern China is estimated to increase by ∼0.19, resulting in 0.04 less NO3- and 0.12 less NH4+ partitioning ratios, which suggests that NH3 and NOx emission controls are effective in mitigating haze pollution in eastern China.</p

DNA barcoding of marine fish species in the waters surrounding Hainan Island, northern South China Sea

IntroductionHainan Island is encompassed within the shallow waters of the tropical continental shelf in China, which is recognized as a significant hotspot for fish biodiversity. Despite extensive research conducted on marine fish taxonomy surrounding Hainan Island, there remains a substantial gap between our current understanding and the actual fish diversity within this oceanic area.MethodsIn this study, we employed DNA barcoding and molecular identification approaches to explore the species diversity and distribution pattern of marine fish in both the northern and southern sea areas of Hainan Island in the northern South China Sea.ResultsA total of 186 sequences were obtained from the collected marine fish samples in the two sea areas surrounding Hainan Island. Through DNA identification, it was confirmed that all 186 sequences corresponded to typical fish species found in the northern South China Sea, all sequences represented a total of 56 species, 47 genera, 34 families, and 17 orders. The average Kimura 2-parameter (K2P) distances within species, genus, family, order and class were 0.15%, 6.53%, 13.17%, 16.95% and 24.81%, respectively.DiscussionOur investigation in the northern sea areas of Hainan Islands identified a total of 33 distinct species, while the southern sea areas exhibited 29 distinct species, with only 5 species found to be shared between both regions. These findings clearly indicate a significant disparity in the species composition of fish communities between the northern and southern sea regions