Project description:We propose a detailed CellML model of the human cerebral circulation that runs faster than real time on a desktop computer and is designed for use in clinical settings when the speed of response is important. A lumped parameter mathematical model, which is based on a one-dimensional formulation of the flow of an incompressible fluid in distensible vessels, is constructed using a bond graph formulation to ensure mass conservation and energy conservation. The model includes arterial vessels with geometric and anatomical data based on the ADAN circulation model. The peripheral beds are represented by lumped parameter compartments. We compare the hemodynamics predicted by the bond graph formulation of the cerebral circulation with that given by a classical one-dimensional Navier-Stokes model working on top of the whole-body ADAN model. Outputs from the bond graph model, including the pressure and flow signatures and blood volumes, are compared with physiological data.
Project description:Ceramides contribute to the lipotoxicity that underlies diabetes, hepatic steatosis, and heart disease. By genetically engineering mice, we deleted the enzyme dihydroceramide desaturase-1 (DES1) which inserts a conserved double bond into the backbone of ceramides and other predominant sphingolipids. Ablation of DES1 from whole animals, or tissue-specific deletion in the liver, and/or adipose tissue resolved hepatic steatosis and insulin resistance in mice caused by leptin deficiency or obesogenic diets. Mechanistic studies revealed new ceramide actions that promoted lipid uptake and storage and impaired glucose utilization, none of which could be recapitulated by (dihydro)ceramides that lacked the critical double bond. These studies suggest that inhibition of DES1 may provide a means of treating hepatic steatosis and cardiometabolic disorders.
Project description:Background: The ability to form enduring social bonds is characteristic of human nature and as a result, impairments in social affiliation are central features of severe neuropsychiatric disorders including autism spectrum disorders and schizophrenia. Due to its ability to form long-term pair-bonds, the socially monogamous prairie vole (Microtus ochrogaster) has emerged as an excellent model to study the neurobiology of social attachment. Despite the enduring nature of the bond, however, surprisingly few genes have been implicated in the pair-bonding process in either sex. Results: Using RNA-sequencing, we aimed at identifying the transcriptomic regulations in the nucleus accumbens (NAc) underlying the formation and maintenance of a pair-bond in male and female prairie voles and found sex-specific response patterns despite similar behavioral indicators of pair-bond establishment. Indeed, 24 hrs of cohabitation with an opposite-sex partner induced widespread transcriptomic changes that remained sustained to some extent in females after 3 weeks, but returned to baseline before a second set of regulations in males. This led to a highly sexually-biased NAc transcriptome in the later phase of the bond related to processes such as neurotransmission, protein turnover, and DNA transcription. In particular, we found sex-specific alterations of mitochondrial dynamics following cohabitation, with a shift towards fission in males. Conclusions: In addition to identifying the genes, networks, and pathways involved in the pair-bonding process in the NAc, our work illustrates the vast extent of sex differences in the molecular mechanisms underlying pair-bonding in prairie voles, and paves the way to further our understanding of the complex social bonding process.
Project description:Genome graphs, including the recently released draft human pangenome graph, can represent the breadth of genetic diversity and thus transcend the limits of traditional linear reference genomes. However, there are no genome-graph-compatible tools for analyzing whole genome bisulfite sequencing (WGBS) data. To close this gap, we introduce methylGrapher, a tool tailored for accurate DNA methylation analysis by mapping WGBS data to a genome graph. Notably, methylGrapher can reconstruct methylation patterns along haplotype paths precisely and efficiently. To demonstrate the utility of methylGrapher, we analyzed the WGBS data derived from five individuals whose genomes were included in the first Human Pangenome draft as well as WGBS data from ENCODE (EN-TEx). Along with standard performance benchmarking, we show that methylGrapher fully recapitulates DNA methylation patterns defined by classic linear genome analysis approaches. Importantly, methylGrapher captures a substantial number of CpG sites that are missed by linear methods, and improves overall genome coverage while reducing alignment reference bias. Thus, methylGrapher is a first step towards unlocking the full potential of Human Pangenome graphs in genomic DNA methylation analysis.