Project description:Dysregulated extravillous trophoblast invasion and proliferation are known to increase the risk of recurrent spontaneous abortion (RSA); however, the underlying mechanism remains unclear. Herein, in our retrospective observational case-control study we show that villous samples from RSA patients, compared to healthy controls, display reduced succinate dehydrogenase complex iron sulfur subunit (SDHB) DNA methylation, elevated SDHB expression, and reduced succinate levels, indicating that low succinate levels correlate with RSA. Moreover, we find high succinate levels in early pregnant women are correlated with successful embryo implantation. SDHB promoter methylation recruited MBD1 and excluded c-Fos, inactivating SDHB expression and causing intracellular succinate accumulation which mimicked hypoxia in extravillous trophoblasts cell lines JEG3 and HTR8 via the PHD2-VHL-HIF-1α pathway; however, low succinate levels reversed this effect and increased the risk of abortion in mouse model. This study reveals that abnormal metabolite levels inhibit extravillous trophoblast function and highlights an approach for RSA intervention.
Project description:Prostate cancer (PCa) is a major health problem worldwide with variable incidence, progression and outcomes depending on genetic, environmental and socio-economic factors. This study compares gene expression profiles in PCa patients from South Africa (RSA) and the United States (USA) using RNA sequencing in whole blood and pathway analyses. Whole blood samples were collected in Wren RNA stabilization tubes from RSA-PCa (n=6), RSA-controls (n=6), USA-PCa (n=7) and USA-Controls (n=11). RNA sequencing revealed 1,627 differentially expressed genes (DEGs) in RSA-PCa vs. RSA-controls, and 2,193 DEGs in USA-PCa vs. USA-Controls. Pathway analyses identified geographical region-specific variations; RSA-PCa had upregulated myeloid suppressor cell pathways and immunosuppressive markers while USA-PCa samples exhibited upregulated cytokine signaling and inflammatory pathways. Comparative analysis of healthy controls revealed 2,280 DEGs, which indicated significant differences in molecular profile of the geographic locations. qRT-PCR undertaken on 27 biomarkers related to PCa in whole blood (PROSTest) identified that 26 (96%) of the marker genes were commonly expressed. RNAseq and normalized PCR gene expression of these markers were well-correlated (r=0.44, p=0.0012, n=30 pairs). The results of this study indicate that there are geographic differences in blood-based gene expression in both controls and individuals with PCa. Genes associated with a clinically validated molecular assay (PROSTest) were identified in both populations, but significant differences in gene expression relevant to tumor pathobiology were identified. These immune-associated signaling pathways suggest differences between these two cohorts in blood-based molecular architecture related to PCa. They also suggest the need to consider population-specific biomarkers to better understand this disease. Ultimately, optimizing blood-based molecular diagnostic and therapeutic approaches will require population-level studies. Introduction
Project description:The present study aimed to investigate the profile of serum-circulating miRNAs and their target genes and elucidate their role in infected and non-infected C. trachomatis RSA patients by microarray miRNAs and mRNAs were found to be differentially expressed in C. trachomatis-positive RSA patients Non-heparinized blood samples were collected from 25 RSA patients with history of three or more consecutive abortions
Project description:Transcriptional profiling of Coxiella burnetii phase I (RSA 493) submitting either to Cold and Heat shock comparing to control untreated Coxiella burnetii phase I (RSA 493) grown at 35°C.
Project description:Our study found that low SDHB expression and high succinate levels are important for maintaining embryo implantation in the first trimester; therefore, high SDHB expression and low succinate levels during early pregnancy may increase the risk of RSA. To investigate why villous SDHB expression increases pathologically in RSA but exhibits dynamically low levels during the first trimester followed by high levels under physiological conditions, we detected CpG site methylation levels in the SDHB promoter region of villi from both individuals with RSA and controls.
Project description:To explore the changes of local microenvironment in the feto-maternal interface during early pregnancy in RSA, we next examined the transcriptional profiles of the decidua tissue by RNA sequencing using samples from 3 RSA patients and 3 healthy controls
Project description:Model Context: Model of neural control of cardiovascular behavior and its interaction with respiratory behavior
Primary goal of the model: The primary objective of the modeling study was to evaluate the role of neural signals in controlling the dynamic behavior of the heart, particularly in regulating cardiovascular metrics such as heart rate and blood pressure. We also seek to understand neural control of respiratory sinus arrhythmia, a natural acceleration and deceleration of heart rate in synchronization with respiration, which is characteristic of good cardiovascular health.
Our model builds on a previously developed model of neural control of the heart.1 We extended this model by integrating the “little brain of the heart”, the intrinsic cardiac nervous system (ICN), to study its contributions to cardiovascular control. This newly developed model with the ICN also integrates modeling of the cardiac phase-dependent effect of parasympathetic activity on heart rate deceleration and gating of signals in the brainstem in based on respiratory phase to represent a possible mechanism of respiratory sinus arrhythmia (RSA). Our expanded model can be utilized to explore the role of the ICN on beat-to-beat cardiovascular behavior, specifically RSA. Simulations can be performed to explore regulation of cardiovascular behavior in response to changes in lung tidal volume and electrical stimulation of the vagus nerve, which connects the brain and the heart.
Project description:Objective: Cocaine use disorders (CUD) represent a major public health problem in many countries. To better understand the interaction between the environmental modulations and phenotype, the aim of the present study was to investigate the DNA methylation pattern of CUD patients, which were concomitant dependents of cocaine and crack, and healthy controls. Methods: We studied DNA methylation profiles in the peripheral blood of 23 CUD patients and 24 healthy control subjects using the Illumina Infinium HumanMethylation450 BeadChip arrays. Results: Comparison between CUD patients and controls revealed 186 differentially methylated positions (DMPs, adjP<10-5) related to 152 genes, with a subset of CpGs confirmed by pyrosequencing. DNA methylation patterns discriminated CUD patients and control groups. A gene network approach showed that EHMT1, EHMT2, MAPK1, MAPK3, MAP2K1 and HDAC5 genes, which are involved in transcription and chromatin regulation cellular signaling pathways, were also associated with cocaine dependence. Conclusion: The investigation of DNA methylation patterns in CUD patients may contribute to a better understanding of the biological mechanisms involved in cocaine use disorders.
Project description:Primary outcome(s): Diagnostic accuracy of DNA methylation analysis for ulcerative colitis patients complicated with colorectal cancer using rectal mucosa from ulcerative colitis