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: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:Synthetic lethality (SL) has shown great promise for the discovery of novel targets in cancer. CRISPR double-knockout (CDKO) technologies can only screen several hundred genes and their combinations, but not genome-wide. Therefore, good SL prediction models are highly needed for genes and gene pairs selection in CDKO experiments. In this paper, we develop a novel multi-layer encoder for individual sample-specific SL prediction (MLEC-iSL). Unlike existing SL prediction models, MLEC-iSL is built to predict SL connectivity first. Because SL connectivity is scalable from existing genes in the training data to new genes in validation data, we hypothesize MLEC-iSL has better SL prediction performance. MLEC-iSL has three encoders, namely gene encoder, graph encoder, and transformer encoder. MLEC-iSL has high performance in K562 (AUPR, 0.73; AUC, 0.72) and Jurkat (AUPR, 0.73; AUC, 0.71) cells while no existing methods exceed 0.62 AUPR and AUC in either cell. MLEC-iSL guided CDKO experiment in 22Rv1 cells yielded a 46.8% SL ratio amongst its selected gene pairs. Six of top ten SL connectivity hub genes are validated in 22Rv1 cells. It reveals SL gene pairs and dependency between apoptosis and mitosis cell death pathways.
Project description:Recent advances in chromatin architecture profiling technologies, such as single-cell Hi-C (scHi-C), allow us to dissect the heterogeneity of chromosome higher-order structures across diverse cell states and different individuals. However, scHi-C experiments are still expensive and not immediately available for population-scale profiling. Here, we present scENCORE, a computational method, to reconstruct personalized and cell-type-specific higher-order chromatin structures, such as A/B compartments, directly from more cost-effective and widely available single-cell epigenetic data (e.g., scATAC-seq). We apply scENCORE on scATAC-seq data from post-mortem prefrontal cortex brains and demonstrate its utility to 1) project Mega-base scale chromatin regions into lower dimensional space by leveraging graph embedding technologies based on cell-type-specific co-variability patterns, 2) define A/B compartments via unsupervised clustering, 3) perform an alignment algorithm for multi-graph embedding to derive comparable chromatin representations and highlight dynamic chromatin compartments across cell states and individuals. Validated by Hi-C experiments using FACS-sorted cells, scENCORE can faithfully reconstruct cell-type-specific chromatin compartments. Furthermore, scENCORE uniformly constructs chromosome conformation across population-scale scATAC-seq data and discovers key 3D structural switching events associated with psychiatric disorders. In summary, scENCORE allows cost-effective cell-type-specific and personalized reconstruction that delineate higher-order chromatin structures.
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.