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The success of species reintroductions can depend on a combination of environmental, demographic, and genetic factors. Although the importance of these factors in the success of reintroductions is well‐accepted, they are typically evaluated independently, which can miss important interactions. For species that persist in metapopulations, movement through and interaction with the landscape is predicted to be a vital component of persistence. Simulation‐based approaches are a promising technique for evaluating the independent and combined effects of these factors on the outcome of various reintroduction and associated management actions. We report results from a simulation study of bull trout (Salvelinus confluentus) reintroduction to three watersheds of the Pend Oreille River system in northeastern Washington State, USA. We used an individual‐based, spatially explicit simulation model to evaluate how reintroduction strategies, life history variation, and riverscape structure (e.g., network topology) interact to influence the demographic and genetic characteristics of reintroduced bull trout populations in three watersheds. Simulation scenarios included a range of initial genetic stocks (informed by empirical bull trout genetic data), variation in migratory tendency and life history, and two landscape connectivity alternatives representing a connected network (isolation‐by‐distance) and a fragmented network (isolation‐by‐barrier, using the known existing barriers). A novel feature of these simulations was the ability to consider the interaction of both demographic and genetic (i.e., demogenetic) factors in riverscapes with implicit asymmetric movement probabilities across the barriers. We found that connectivity (presence or absence of barriers) had the largest effect on demographic and genetic outcomes over 200 yr, with a greater effect than both initial genetic diversity and life history variation. We also identified regions of the study system in which bull trout populations persisted across a wide range of demographic, life history, and environmental connectivity parameters. Finally, we found no evidence that initial neutral genetic diversity influenced genetic diversity and structure after 200 yr; instead, genetic drift due to stray rate and population isolation dominated and erased any initial differences in genetic diversity. Our results highlight the utility of spatially explicit demogenetic approaches in exploring and understanding population dynamics—and their implications for management strategies—in fresh waters.

Genome-wide association studies identified single nucleotide polymorphisms on chromosome 7 upstream of KLF14 to be associated with metabolic syndrome traits and increased risk for Type 2 Diabetes (T2D). The associations were more significant in women than in men. The risk allele carriers expressed lower levels of the transcription factor KLF14 in adipose tissues than non-risk allele carriers. To investigate how adipocyte KLF14 regulates metabolic traits in a sex-dependent manner, we characterized high-fat diet fed male and female mice with adipocyte-specific Klf14 deletion or overexpression. Klf14 deletion resulted in increased fat mass in female mice and decreased fat mass in male mice. Female Klf14-deficient mice had overall smaller adipocytes in subcutaneous fat depots but larger adipocytes in parametrial depots, indicating a shift in lipid storage from subcutaneous to visceral fat depots. They had reduced metabolic rates and increased respiratory exchange ratios consistent with increased utilization of carbohydrates as an energy source. Fasting and isoproterenol-induced adipocyte lipolysis was defective in female Klf14-deficient mice and concomitantly adipocyte triglycerides lipase mRNA levels were downregulated. Female Klf14-deficient mice cleared blood triglyceride and NEFA less efficiently than wild type. Finally, adipocyte-specific overexpression of Klf14 resulted in lower total body fat in female but not male mice. Taken together, consistent with human studies, adipocyte KLF14 deficiency in female but not in male mice causes increased adiposity and redistribution of lipid storage from subcutaneous to visceral adipose tissues. Increasing KLF14 abundance in adipocytes of females with obesity and T2D may provide a novel treatment option to alleviate metabolic abnormalities. Competing Interest Statement K. Musunuru is an advisor to and holds equity in Verve Therapeutics and Variant Bio.

Coronary artery disease (CAD) is the leading cause of death worldwide. Recent meta-analyses of genome-wide association studies (GWAS) have identified over 175 loci associated with CAD. The majority of these loci are in non-coding regions and are predicted to regulate gene expression. Given that vascular smooth muscle cells (SMCs) play critical roles in the development and progression of CAD, we hypothesized that a subset of the CAD GWAS risk loci are associated with the regulation of transcription in distinct SMC phenotypes. Here, we measured gene expression in SMCs isolated from the ascending aortas of 151 ethnically diverse heart transplant donors in quiescent or proliferative conditions and calculated the association of their expression and splicing with ~6.3 million imputed single nucleotide polymorphism (SNP) markers across the genome. We identified 4,910 expression and 4,412 splice quantitative trait loci (sQTL) that represent regions of the genome associated with transcript abundance and splicing. 3,660 of the eQTLs had not been observed in the publicly available Genotype-Tissue Expression dataset. Further, 29 and 880 of the eQTLs were SMC- and sex-specific, respectively. To identify the effector transcript(s) regulated by CAD GWAS loci, we used four distinct colocalization approaches and identified 84 eQTL and 164 sQTLs that colocalized with CAD loci, highlighting the importance of genetic regulation of mRNA splicing as a molecular mechanism for CAD genetic risk. Notably, 20% and 35% of the eQTLs were unique to quiescent or proliferative SMCs, respectively. Two CAD loci colocalized with a SMC sex-specific eQTL (AL160313.1 and TERF2IP) and another locus colocalized with SMC-specific eQTL (ALKBH8). Also, 27% and 37% of the sQTLs were unique to quiescent or proliferative SMCs, respectively. The most significantly associated CAD locus, 9p21, was an sQTL for the long non-coding RNA CDKN2B-AS1, also known as ANRIL, in proliferative SMCs. Collectively, these results provide evidence for the molecular mechanisms of genetic susceptibility to CAD in distinct SMC phenotypes. Competing Interest Statement Johan Bjorkegren is a shareholder in Clinical Gene Network AB that has an invested interest in STARNET. The remaining authors have nothing to disclose. Footnotes * https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE193817 * https://virginia.box.com/s/t5e1tzlaqsf85z13o4ie2f9t1i0zfypd * https://virginia.box.com/s/o81cxrj5xne3xem4au785mupikduuwbu

In this report we have discussed the important role of molecular modeling, especially the use of the molecular dynamics method, in investigating transport processes in nanoporous materials such as membranes. With the availability of high performance computers, molecular modeling can now be used to study rather complex systems at a fraction of the cost or time requirements of experimental studies. Molecular modeling techniques have the advantage of being able to access spatial and temporal resolution which are difficult to reach in experimental studies. For example, sub-Angstrom level spatial resolution is very accessible as is sub-femtosecond temporal resolution. Due to these advantages, simulation can play two important roles: Firstly because of the increased spatial and temporal resolution, it can help understand phenomena not well understood. As an example, we discuss the study of reverse osmosis processes. Before simulations were used it was thought the separation of water from salt was purely a coulombic phenomenon. However, by applying molecular simulation techniques, it was clearly demonstrated that the solvation of ions made the separation in effect a steric separation and it was the flux which was strongly affected by the coulombic interactions between water and the membrane surface. Additionally, because of their relatively low cost and quick turnaround (by using multiple processor systems now increasingly available) simulations can be a useful screening tool to identify membranes for a potential application. To this end, we have described our studies in determining the most suitable zeolite membrane for redox flow battery applications. As computing facilities become more widely available and new computational methods are developed, we believe molecular modeling will become a key tool in the study of transport processes in nanoporous materials.