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BackgroundChronic kidney disease (CKD) increases the risk of cardiovascular disease, including vascular calcification, leading to higher mortality. Release of calcifying extracellular vesicles (EVs) by vascular smooth muscle cells (VSMCs) promotes the ectopic mineralization of vessel walls. Caveolin-1 (CAV1) protein plays a key role in formation of calcifying EVs in VSMCs. Epidermal growth factor receptor (EGFR) co-localizes with and influences the intracellular trafficking of CAV1. MethodsWe computationally analyzed 7651 individuals in the Multi-Ethnic Study of Atherosclerosis (MESA) and Framingham cohorts to assess potential correlations between coronary artery calcium and single nucleotide polymorphisms (SNPs) associated with elevated serum levels of EGFR. Using a diet-induced mouse model of CKD, we measured serum EGFR and assessed the potential of EGFR inhibition to prevent vascular calcification. ResultsIndividuals in the MESA and Framingham cohorts with SNPs associated with increased serum EGFR exhibit elevated coronary artery calcium. Mice with CKD developed widespread vascular calcification, which associated with increased serum levels of EGFR. In both the CKD mice and human VSMC culture, EGFR inhibition significantly reduced vascular calcification by mitigating the release of CAV1-positive calcifying EVs. EGFR inhibition also increased bone mineral density in CKD mice. ConclusionGiven that EGFR inhibitors exhibit clinical safety and efficacy in other pathologies, the current data suggest that EGFR may be an ideal target to prevent pathological vascular calcification. Subject termsGrowth Factors, Vascular Biology, Vascular Disease, Translational Study

Chronic suppurative otitis media (CSOM) is a widespread, debilitating problem with poorly understood immunology. Here, we assess the host response to middle ear infection over the course of a month post-infection in a mouse model of CSOM and in human subjects with the disease. Using multiparameter flow cytometry and a binomial generalized linear machine learning model, we identified Ly6G, a surface marker of mature neutrophils, as the most informative factor of host response driving disease in the CSOM mouse model. Consistent with this, neutrophils were the most abundant cell type in infected mice and Ly6G expression tracked with the course of infection. Moreover, neutrophil-specific immunomodulatory treatment using the neutrophil elastase inhibitor GW 311616A significantly reduces bacterial burden relative to ofloxacin-only treated animals in this model. The levels of dsDNA in middle ear effusion samples are elevated in both humans and mice with CSOM and decreased during treatment, suggesting that dsDNA may serve as a molecular biomarker of treatment response. Together these data strongly implicate neutrophils in the ineffective immune response to P. aeruginosa infection in CSOM and suggest that immunomodulatory strategies may benefit drug-tolerant infections for chronic biofilm-mediated disease.

Cardiovascular disease (CVD) is the leading cause of death worldwide, causing over 17 million deaths per year, which outpaces global cancer mortality rates. Despite these sobering statistics, most bioinformatics and computational biology research and funding to date has been concentrated predominantly on cancer research, with a relatively modest footprint in CVD. In this paper, we review the existing literary landscape and critically assess the unmet need to further develop an emerging field at the multidisciplinary interface of bioinformatics and precision cardiovascular medicine, which we refer to as ‘cardioinformatics’.

Epigenetic processes have been implicated in the pathophysiology of alcohol dependence, but the specific molecular mechanisms mediating dependence-induced neuroadaptations remain largely unknown. Here, we found that a history of alcohol dependence persistently decreased the expression of Prdm2, a histone methyltransferase that monomethylates histone 3 at the lysine 9 residue (H3K9me1), in the rat dorsomedial prefrontal cortex (dmPFC). Downregulation of Prdm2 was associated with decreased H3K9me1, supporting that changes in Prdm2 mRNA levels affected its activity. Chromatin immunoprecipitation followed by massively parallel DNA sequencing showed that genes involved in synaptic communication are epigenetically regulated by H3K9me1 in dependent rats. In non-dependent rats, viral-vector-mediated knockdown of Prdm2 in the dmPFC resulted in expression changes similar to those observed following a history of alcohol dependence. Prdm2 knockdown resulted in increased alcohol self-administration, increased aversion-resistant alcohol intake and enhanced stress-induced relapse to alcohol seeking, a phenocopy of postdependent rats. Collectively, these results identify a novel epigenetic mechanism that contributes to the development of alcohol-seeking behavior following a history of dependence. Funding Agencies|NIAAA division of Intramural Research; Swedish Research Council; NIAAA R01 [1R01AA023781-01A1]; United States Department of Defense (DoD), through the National Defense Science and Engineering Graduate Fellowship (NDSEG) Program; US National Institute of Health [DA035592, MH084880, NS071674]; DoD; Army Research Office (ARO); National Defense Science and Engineering Graduate (NDSEG) Fellowship [32 CFR 168a]

Background Ischemic preconditioning ( IPC ) protects the heart from prolonged ischemic insult and reperfusion injury through a poorly understood mechanism. Post‐translational modifications of histone residues can confer rapid and drastic switches in gene expression in response to various stimuli, including ischemia. The aim of this study was to investigate the effect of histone methylation in the response to cardiac ischemic preconditioning. Methods and Results We used cardiac biopsies from mice subjected to IPC to quantify global levels of 3 of the most well‐studied histone methylation marks (H3K9me2, H3K27me3, and H3K4me3) with Western blot and found that H3K9me2 levels were significantly increased in the area at risk compared to remote myocardium. In order to assess which genes were affected by the increase in H3K9me2 levels, we performed Ch IP ‐Seq and transcriptome profiling using microarray. Two hundred thirty‐seven genes were both transcriptionally repressed and enriched in H3K9me2 in the area at risk of IPC mice. Of these, Mtor (Mechanistic target of rapamycin) was chosen for mechanistic studies. Knockdown of the major H3K9 methyltransferase G9a resulted in a significant decrease in H3K9me2 levels across Mtor , increased Mtor expression, as well as decreased autophagic activity in response to rapamycin and serum starvation. Conclusions IPC confers an increase of H3K9me2 levels throughout the Mtor gene—a master regulator of cellular metabolism and a key player in the cardioprotective effect of IPC —leading to transcriptional repression via the methyltransferase G9a. The results of this study indicate that G9a has an important role in regulating cardiac autophagy and the cardioprotective effect of IPC .